Expansion culture of tumor-infiltrating lymphocytes (TILs) using adenosine A2A receptor antagonists, and therapeutic combinations of TILs and adenosine A2A receptor antagonists.

Abstract

Providing expanded cultures of tumor-infiltrating lymphocytes (TILs) using adenosine A2A receptor antagonists. [Solution] A method comprising: (a) obtaining a first TIL population from a previously excised tumor by processing a tumor sample into a plurality of tumor fragments; (b) adding the tumor fragments to a closed system; (c) performing a first expansion culture to produce a second TIL population by culturing the first TIL population in a cell culture medium containing IL-2 and optionally OKT-3; (d) performing a second expansion culture to produce a third TIL population by supplementing the cell culture medium of the second TIL population with additional IL-2, OKT-3 and antigen-presenting cells (APCs); (e) recovering the therapeutic TIL population obtained from step (d); and (f) transferring the recovered TIL population from step (e) to an infusion bag.

Description

[Technical Field]

[0001] Cross-reference of related applications

[0001] This international application claims priority to U.S. Provisional Patent Application No. 62 / 630,010 filed on 13 February 2018, U.S. Provisional Patent Application No. 62 / 637,603 filed on 2 March 2018, and U.S. Provisional Patent Application No. 62 / 684,698 filed on 13 June 2018, all of which are incorporated herein by reference.

[0002] Field of Invention

[0002] Disclosed herein are methods for expanding tumor-infiltrating lymphocytes (TILs) in the presence of adenosine A2A receptor (A2aR) antagonists such as vipardenant, siphoradenant (CPI-444), SCH58261, SYN115, ZM241385, SCH420814, xanthine superfamily A2aR antagonists, or related adenosine receptor 2A antagonists, as well as the use of expanded cultured TILs in the treatment of diseases such as cancer. Furthermore, therapeutic combinations of TILs and A2aR antagonists, including compositions and their use in the treatment of diseases such as cancer, are disclosed herein. [Background technology]

[0003]

[0003] Treatment of bulky, resistant cancers using adoptive autotransplantation of tumor-infiltrating lymphocytes (TILs) is a powerful approach to treating patients with poor prognosis. Gattinoni, et al., Nat. Rev. Immunol. 2006, 6, 383-393. TILs are T cell-dominant, and IL-2-based TIL expansion culture followed by a "rapid expansion culture process" (REP) has become the preferred method for TIL expansion culture due to its speed and efficiency. Dudley, et al., Science 2002, 298, 850-54; Dudley, et al., J. Clin. Oncol. 2005, 23, 2346-57; Dudley, et al., J. Clin. Oncol. 2008, 26, 5233-39; Riddell, et al., Science 1992, 257, 238-41; Dudley, et al., J. Immunother. 2003, 26, 332-42. Several approaches have been explored to improve the clinical response to TIL therapy in melanoma and to extend TIL therapy to other types of tumors, but with limited success, this area remains challenging. Goff, et al., J. Clin. Oncol. 2016, 34, 2389-97; Dudley, et al., J. Clin. Oncol. 2008, 26, 5233-39; Rosenberg, et al., Clin. Cancer Res. 2011, 17, 4550-57. Specific subsets (CD8) + There is considerable focus on the selection of TILs during expansion culture to select T cells (or other cells) or to target driver mutations such as the mutated ERBB2IP epitope or driver mutations in the KRAS oncogene. Tran, et al., N. Engl.J. Med.2016, 375, 2255-62; Tran, et al., Science 2014, 344, 641-45. However, even if such selective approaches can be developed to demonstrate efficacy in large-scale clinical trials, they significantly increase the duration, complexity, and cost of TIL therapy, limiting the potential for widespread use of TIL therapy in different types of cancer.

[0004]

[0004] Adenosine A2A (or A 2A The receptors are A1, A 2B A2A receptors, along with A3, are members of the adenosine receptor group of G protein-coupled receptors and are highly expressed in the spleen, thymus, leukocytes, platelets, and olfactory bulb. The presence of relatively high concentrations of adenosine in the immune microenvironment, which leads to A2a receptor activation, has been shown to represent a negative feedback loop that allows tumors to evade immune recognition. Therefore, A2A receptor (A2AR) antagonists are attracting attention as a novel form of checkpoint blockade for cancer immunotherapy. Leone, et al., Comp. Struct. Biotechnol. J. 2015, 13, 265-272. In solid tumors... The immunosuppressive extracellular concentration of adenosine is in the μM range (10 to 20 times the normal concentration). This is known and needs to be overcome by A2AR antagonists. Blay, et al., Cancer Res. 1997, 57, 2602-2605. [Overview of the Initiative] [Means for solving the problem]

[0005]

[0005] The present invention provides the unexpected finding that adenosine receptor antagonists, such as A2AR antagonists, are useful for expanding the culture of TILs from tumors and are even more useful for treating patients in combination with TIL therapy.

[0006] Summary of the Invention

[0006] In one embodiment, the present invention is a method for treating cancer with a tumor-infiltrating lymphocyte (TIL) population, (a) The step of removing the tumor from the patient; (b) Steps to obtain a first TIL population from the tumor; (c) A step of obtaining a second TIL population by performing an initial expansion culture of a first TIL population in a first cell culture medium, wherein the second TIL population is at least five times larger in number than the first TIL population, the first cell culture medium contains IL-2 and tumor necrosis factor receptor superfamily (TNFRSF) agonists, and the initial expansion culture is performed for a period of 21 days or less; (d) A step of obtaining a third TIL population by performing rapid expansion culture of a second TIL population in a second cell culture medium, wherein seven days after the start of rapid expansion culture, the third TIL population is at least 50 times larger in number than the second TIL population, the second cell culture medium contains IL-2, OKT-3 (anti-CD3 antibody), peripheral blood mononuclear cells (PBMCs), and optionally a TNFRSF agonist, and the rapid expansion culture is performed for a period of 14 days or less; (e) the step of recovering the third TIL group; and (f) The step of administering the therapeutically effective portion of the third TIL population to a patient with cancer. This provides a method that includes [something].

[0007]

[0007] A method for treating cancer with a tumor-infiltrating lymphocyte (TIL) population, (a) The step of removing the tumor from the patient; (b) Steps to obtain a first TIL population from the tumor; (c) A step of obtaining a second TIL population by performing an initial expansion culture of a first TIL population in a first cell culture medium, wherein the second TIL population is at least five times larger in number than the first TIL population, the first cell culture medium contains IL-2 and an adenosine 2A receptor (A2aR) antagonist, and the initial expansion culture is performed for a period of 21 days or less; (d) A step of obtaining a third TIL population by performing rapid expansion culture of a second TIL population in a second cell culture medium, wherein seven days after the start of rapid expansion culture, the third TIL population is at least 50 times larger in number than the second TIL population, the second cell culture medium contains IL-2, OKT-3 (anti-CD3) antibody, peripheral blood mononuclear cells (PBMCs), and optionally an adenosine 2A receptor (A2aR) antagonist and a second adenosine 2A receptor (A2aR) antagonist, and the rapid expansion culture is performed for a period of 14 days or less; (e) the step of recovering the third TIL group; and (f) The step of administering the therapeutically effective portion of the third TIL population to the patient. This method includes [something].

[0008]

[0008] In one embodiment, the present invention provides a method for expanding the culture of tumor-infiltrating lymphocytes (TILs).

[0009]

[0009] The present invention provides a method for expanding the culture of tumor-infiltrating lymphocytes (TILs), and this method is (a) Obtaining a tumor sample from a patient, wherein the tumor sample includes a first TIL population; (b) Processing the tumor sample into multiple tumor fragments; (c) Adding the tumor fragment to a sealed container; (d) Obtaining a second TIL population by performing an initial expansion culture of the first TIL population in a first cell culture medium, wherein the first cell culture medium comprises IL-2 and at least one adenosine 2A receptor (A2aR) antagonist, and the initial expansion culture is performed in a medium of at least 100 cm². 2 The initial expansion culture is carried out in a closed container that provides a gas-permeable surface area, and the initial expansion culture is carried out over a first period of about 7 to 14 days to obtain a second TIL population, the second TIL population being at least 50 times larger in number than the first TIL population, and the transition from step (c) to step (d) occurs without opening the system; (e) Expanding the second TIL population in a second cell culture medium, the second cell culture medium comprising IL-2, OKT-3 and at least one adenosine 2A receptor (A2aR) antagonist and peripheral blood mononuclear cells (PBMCs, also known as mononuclear cells (MNCs)), wherein the expansion culture is carried out over a second period of about 7 to 14 days to obtain a third TIL population, the third TIL population exhibiting an increased effector T cell and / or central memory T cell subpopulation compared to the second TIL population, and the expansion culture is carried out over at least 500 cm². 2 The process is carried out in a closed container that provides a gas-permeable surface area, and the transition from step (d) to step (e) occurs without opening the system, during the expansion culture; (f) Recovering the third TIL group obtained from step (e), wherein the transition from step (e) to step (f) occurs without opening the system; and (g) (g) Transferring the recovered TIL mass from step (f) to an infusion bag, wherein the transfer from step (f) to (g) occurs without opening the system. Includes.

[0010]

[0010] In some embodiments, this method is an in vitro or ex vivo method.

[0011]

[0011] In some embodiments, the method further includes recovery via a cell processing system, such as a Fresenius Kabi LOVO system, in step (f). The term “LOVO cell processing system” also refers to any equipment or apparatus manufactured by any vendor that enables continuous flow and cell processing, in a sterile and / or closed system environment, through a membrane or filter such as a rotating membrane or rotating filter, to deliver a solution containing cells and remove the supernatant or cell culture without pelletizing. In some cases, the cell processing system can perform cell separation, washing, fluid exchange, concentration and / or other cell processing steps in a closed sterile system.

[0012]

[0012] In some embodiments, the closed container is selected from the group consisting of G containers and Xuri cell culture bags.

[0013]

[0013] In some embodiments, the infusion bag of step (g) contains HypoThermosol This is an import bag.

[0014]

[0014] In some embodiments, the first period of step (d) and the second period of step (e) are carried out individually within periods of 10, 11, or 12 days, respectively.

[0015]

[0015] In some embodiments, the first period of step (d) and the second period of step (e) are carried out separately within a period of 11 days.

[0016]

[0016] In some embodiments, steps (a) to (g) are carried out within a period of approximately 25 to 30 days.

[0017]

[0017] In some embodiments, steps (a) to (g) are carried out within a period of about 20 to 25 days.

[0018]

[0018] In some embodiments, steps (a) to (g) are carried out within a period of about 20 to 22 days.

[0019]

[0019] In some embodiments, steps (a) to (g) are carried out within 22 days.

[0020]

[0020] In some embodiments, steps (c) to (f) are performed in a single container, and performing steps (c) to (f) in a single container results in an increased TIL yield per excised tumor compared to performing steps (c) to (f) in multiple containers.

[0021]

[0021] In some embodiments, the PBMC is added to the TIL during the second period of step (e) without opening the system.

[0022]

[0022] In some embodiments, effector T cells and / or central memory T cells obtained from the third TIL population exhibit one or more features selected from the group consisting of CD27+ expression, CD28+ expression, longer telomeres, increased CD57 expression, and decreased CD56 expression, compared to effector T cells and / or central memory T cells obtained from the second cell population.

[0023]

[0023] In some embodiments, effector T cells and / or central memory T cells obtained from a third TIL population exhibit increased CD57 expression and decreased CD56 expression compared to effector T cells and / or central memory T cells obtained from a second cell population.

[0024]

[0024] In some embodiments, the risk of microbial contamination is reduced compared to open systems.

[0025]

[0025] In some embodiments, the TIL from step (g) is injected into the patient. In some embodiments, the TIL from step (g) is injected into the patient in combination with an adenosine A2A receptor antagonist. In some embodiments, the A2aR antagonist is CPI-444 or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal or prodrug thereof and combinations thereof. In some embodiments, the adenosine 2A receptor (A2aR) antagonist is selected from the group consisting of CPI-444, SCH58261, ZM241385, SCH420814, SYN115, 8-CSC, KW-6002, A2A receptor antagonist 1, ADZ4635, vipardenant, ST4206, KF21213, SCH412348, 7MMG-49 or pharmaceutically acceptable salts, solvates, hydrates, cocrystals or prodrugs thereof, and combinations thereof.

[0026]

[0026] The present invention also provides a method for treating a patient's cancer with a tumor-infiltrating lymphocyte (TIL) population, the method of which (a) A step of obtaining a tumor sample from a patient, wherein the tumor sample comprises a first TIL population; (b) The step of processing the tumor sample into multiple tumor fragments; (c) Adding the tumor fragment to a sealed container; (d) A step of obtaining a second TIL population by performing an initial expansion culture of the first TIL population in a first cell culture medium, wherein the first cell culture medium comprises IL-2 and at least one adenosine 2A receptor (A2aR) antagonist, the initial expansion culture is performed in a closed container providing a gas-permeable surface area of ​​at least 100 cm2, the initial expansion culture is performed over a first period of about 7 to 14 days to obtain a second TIL population, the second TIL population being at least 50 times larger in number than the first TIL population, and the transition from step (c) to step (d) occurs without opening the system; (e) Expanding the second TIL population in a second cell culture medium, the second cell culture medium comprising IL-2, OKT-3, and at least one adenosine 2A receptor (A2aR) antagonist and peripheral blood mononuclear cells (PBMCs), the expansion culture being carried out over a second period of about 7 to 14 days to obtain a third TIL population, the third TIL population exhibiting an increased effector T cell and / or central memory T cell subpopulation compared to the second TIL population, and the expansion culture being carried out over at least 500 cm². 2 The process is carried out in a closed container that provides a gas-permeable surface area, and the transition from step (d) to step (e) occurs without opening the system; (f) A step of recovering the third TIL group obtained from step (e), wherein the transition from step (e) to step (f) occurs without opening the system; (g) a step of transferring the recovered TIL mass from step (f) to an infusion bag, wherein the transfer from step (f) to (g) occurs without opening the system; and (h) Step (g) administering a therapeutically effective amount of TIL cells from the infusion bag of step (g) to the patient. Includes.

[0027]

[0027] In some embodiments, a therapeutically effective amount of TIL cells from the infusion bag in step (h) is administered to the patient in combination with an adenosine A2A receptor antagonist. In some embodiments, the A2aR antagonist is CPI-444 or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal or prodrug thereof, or a combination thereof. In some embodiments, the adenosine 2A receptor (A2aR) antagonist is selected from the group consisting of CPI-444, SCH58261, ZM241385, SCH420814, SYN115, 8-CSC, KW-6002, A2A receptor antagonist 1, ADZ4635, vipardenant, ST4206, KF21213, SCH412348, 7MMG-49 or pharmaceutically acceptable salts, solvates, hydrates, cocrystals or prodrugs thereof, and combinations thereof.

[0028]

[0028] In some embodiments, the present invention also includes tumor-infiltrating lymphocyte populations for use in cancer treatment, the TIL population comprising: (b) processing a tumor sample obtained from a patient, the tumor sample comprising a first TIL population which is excised into a plurality of tumor fragments; (c) adding the tumor fragments to a closed container; (d) performing an initial expansion culture of the first TIL population in a first cell culture medium to obtain a second TIL population, the first cell culture medium comprising IL-2, and the initial expansion culture comprising at least 100 cm² 2 This is carried out in the closed container that provides the gas permeable surface area, The initial expansion culture is carried out within a first period of about 7–14 days to obtain a second TIL population, the second TIL population being at least 50 times larger in number than the first TIL population, and the transition from step (c) to step (d) occurs without opening the system; (e) expanding the second TIL population in a second cell culture medium, the second cell culture medium comprising IL-2, OKT-3 and at least one adenosine 2A receptor (A2aR) antagonist and peripheral blood mononuclear cells (PBMCs), the expansion culture is carried out within a second period of about 7–14 days to obtain a third TIL population, the third TIL population showing an increase in effector T cells and / or central memory T cell subpopulations compared to the second TIL population, and the expansion culture is carried out at least 500 cm² 2 The method is carried out in a closed container that provides a gas-permeable surface area, and the transition from step (d) to step (e) occurs without opening the system; (f) a step of recovering the third TIL population obtained from step (e), the transition from step (e) to step (f) occurs without opening the system; (g) a step of transferring the recovered TIL population from step (f) to an infusion bag, the transition from step (f) to (g) occurs without opening the system. In some embodiments, the method is obtained from a first step (a) of obtaining a tumor sample from a patient, the tumor sample comprising a first TIL population. In some embodiments, the TIL population is to be administered in a therapeutically effective dose from the infusion bag in step (g).

[0029]

[0029] In some embodiments, the third TIL population is maintained in a medium or formulation comprising an adenosine 2A receptor (A2aR) antagonist. In some embodiments, the A2aR antagonist is CPI-444 or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal or prodrug thereof and combinations thereof. In some embodiments, the adenosine 2A receptor (A2aR) antagonist is selected from the group consisting of CPI-444, SCH58261, ZM241385, SCH420814, SYN115, 8-CSC, KW-6002, A2A receptor antagonist 1, ADZ4635, bipadenant, ST4206, KF21213, SCH412348, 7MMG-49 or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal or prodrug thereof and combinations thereof.

[0030]

[0030] In some embodiments, a myeloablative lymphodepletion regimen is administered to the patient prior to administering a therapeutically effective amount of TIL cells in step (h). In some embodiments, the TIL population is for administration to a patient who has received a myeloablative lymphodepletion regimen.

[0031]

[0031] In some embodiments, the myeloablative lymphodepletion regimen comprises administration of cyclophosphamide at a dose of 60 mg / m 2 / day for 2 days, followed by administration of fludarabine at a dose of 25 mg / m 2 / day for 5 days.

[0032]

[0032] In some embodiments, the method further comprises treating the patient with a high-dose IL-2 regimen that begins on the day following administration of the TIL cells to the patient in step (h). In some embodiments, the TIL population is for administration prior to the high-dose IL-2 regimen. In some embodiments, the TIL population is for administration 1 day prior to the start of the high-dose IL-2 regimen.

[0033]

[0033] In some embodiments, the high-dose IL-2 regimen includes 600,000 or 720,000 IU / kg, which is administered as a 15-minute bolus intravenous infusion every 8 hours until an acceptable dose is reached.

[0034]

[0034] In some embodiments, effector T cells and / or central memory T cells obtained from the third TIL population exhibit one or more features selected from the group consisting of CD27+ expression, CD28+ expression, longer telomeres, increased CD57 expression, and decreased CD56 expression, compared to effector T cells and / or central memory T cells obtained from the second cell population.

[0035]

[0035] In some embodiments, effector T cells and / or central memory T cells obtained from a third TIL population exhibit increased CD57 expression and decreased CD56 expression compared to effector T cells and / or central memory T cells obtained from a second cell population.

[0036]

[0036] The present invention also provides a method for expanding tumor-infiltrating lymphocytes (TILs), the method comprising: (a) adding a treated tumor fragment to a closed system; (b) performing a first expansion culture of the first TIL population in a first cell culture medium to obtain a second TIL population, wherein the first cell culture medium comprises IL-2 and at least one adenosine 2A receptor (A2aR) antagonist, the first expansion culture is performed in a closed container providing a first gas-permeable surface area, the first expansion culture is performed within a first period of about 3 to 14 days to obtain a second TIL population, the second TIL population being at least 50 times larger in number than the first TIL population, and the transition from step (a) to step (b) occurring without opening the system; (c) expanding culture the second TIL population in a second cell culture medium, wherein the second cell culture medium comprises IL-2 The culture comprises OKT-3 and at least one adenosine 2A receptor (A2aR) antagonist and antigen-presenting cells, wherein the expansion culture is carried out over a second period of about 7 to 14 days to obtain a third TIL population, the third TIL population showing an increase in effector T cells and / or central memory T cell subpopulations compared to the second TIL population, the expansion culture is carried out in a closed container providing a second gas-permeable surface area, the transition from step (b) to step (c) occurs without opening the system, the step includes; (d) recovering the third TIL population obtained from step (c), the transition from step (c) to step (d) occurs without opening the system, and (e) transferring the recovered TIL population from step (d) to an infusion bag, the transition from step (d) to (e) occurs without opening the system.

[0037]

[0037] In some embodiments, the method further includes the step of cryopreserving the infusion bag containing the recovered TIL population using a cryopreservation process. In some embodiments, the cryopreservation process is carried out using a ratio of 1:1 between the recovered TIL population and CS10 medium.

[0038]

[0038] In some embodiments, the method further comprises adding an adenosine 2A receptor (A2aR) antagonist to a first TIL culture medium. In some embodiments, the A2aR antagonist is CPI-444 or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal or prodrug thereof and combinations thereof. In some embodiments, the adenosine 2A receptor (A2aR) antagonist is selected from the group consisting of CPI-444, SCH58261, ZM241385, SCH420814, SYN115, 8-CSC, KW-6002, A2A receptor antagonist 1, ADZ4635, vipardenant, ST4206, KF21213, SCH412348, 7MMG-49 or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal or prodrug thereof and combinations thereof.

[0039]

[0039] In some embodiments, the method further comprises adding an adenosine 2A receptor (A2aR) antagonist to a second TIL culture medium. The R antagonist is CPI-444 or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, or prodrugs, and combinations thereof. In some embodiments, the adenosine 2A receptor (A2aR) antagonist is selected from the group consisting of CPI-444, SCH58261, ZM241385, SCH420814, SYN115, 8-CSC, KW-6002, A2A receptor antagonist 1, ADZ4635, vipardenant, ST4206, KF21213, SCH412348, 7MMG-49 or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, or prodrugs, and combinations thereof.

[0040]

[0040] In some embodiments, the antigen-presenting cells are peripheral blood mononuclear cells (PBMCs). In some embodiments, the antigen-presenting cells are artificial antigen-presenting cells.

[0041]

[0041] In some embodiments, the collection in step (d) is carried out using a LOVO cell processing system.

[0042]

[0042] In some embodiments, the multiple fragments include about 50 fragments, each fragment being about 27 mm 3 It has a volume of approximately 1300 mm. In some embodiments, the multiple fragments are approximately 1300 mm 3 ~about 1500mm 3 It contains approximately 30 to 60 fragments with a total volume of approximately 1350 mm. In some embodiments, the fragments are approximately 1350 mm 3 It contains about 50 fragments having a total volume of . In some embodiments, the fragments include about 50 fragments having a total mass of about 1 g to about 1.5 g.

[0043]

[0043] In some embodiments, the second cell culture medium is provided in a container selected from the group consisting of G containers and Xuri cell culture bags.

[0044]

[0044] In some embodiments, the infusion bag of step (e) contains HypoThermosol This is an import bag.

[0045]

[0045] In some embodiments, the first period of step (b) and the second period of step (c) are carried out individually within a period of 10, 11, or 12 days, respectively. In some embodiments, the first period of step (b) and the second period of step (c) are carried out individually within a period of 11 days, respectively.

[0046]

[0046] In some embodiments, steps (a) to (e) are carried out within a period of about 25 to 30 days. In some embodiments, steps (a) to (e) are carried out within a period of about 20 to 25 days. In some embodiments, steps (a) to (e) are carried out within a period of about 20 to 22 days. In some embodiments, steps (a) to (e) are carried out within 22 days. In some embodiments, steps (a) to (e) and cryopreservation are carried out within 22 days.

[0047]

[0047] In some embodiments, steps (b) to (e) are performed in a single closed system, and performing steps (b) to (e) in a single container results in an increased TIL yield per excised tumor compared to performing steps (b) to (e) in multiple containers.

[0048]

[0048] In some embodiments, antigen-presenting cells are added to the TIL during the second period of step (c) without opening the system.

[0049]

[0049] In some embodiments, effector T cells and / or central memory T cells obtained from the third TIL population are obtained from the second cell population Compared to T cells and / or central memory T cells, they exhibit one or more features selected from the group consisting of CD27+ expression, CD28+ expression, longer telomeres, increased CD57 expression, and decreased CD56 expression.

[0050]

[0050] In some embodiments, effector T cells and / or central memory T cells obtained from a third TIL population exhibit increased CD57 expression and decreased CD56 expression compared to effector T cells and / or central memory T cells obtained from a second cell population.

[0051]

[0051] In some embodiments, the risk of microbial contamination is reduced compared to open systems.

[0052]

[0052] In some embodiments, the TIL from step (e) is injected into the patient.

[0053]

[0053] In some embodiments, the TIL from step (e) is infused to the patient in combination with at least one adenosine 2A receptor antagonist. In some embodiments, the A2aR antagonist is CPI-444 or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals or prodrugs and combinations thereof. In some embodiments, the adenosine 2A receptor (A2aR) antagonist is selected from the group consisting of CPI-444, SCH58261, ZM241385, SCH420814, SYN115, 8-CSC, KW-6002, A2A receptor antagonist 1, ADZ4635, vipardenant, ST4206, KF21213, SCH412348, 7MMG-49 or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals or prodrugs and combinations thereof.

[0054]

[0054] In some embodiments, the present invention also includes a tumor-infiltrating lymphocyte (TIL) population for use in the treatment of cancer, administered to patients receiving an adenosine 2A receptor antagonist (A2aR). In some embodiments, the A2aR is administered orally. In some embodiments, the A2aR is first co-administered with the tumor-infiltrating lymphocyte (TIL) population and then administered orally. In some embodiments, the A2aR is administered orally once daily. In some embodiments, the A2aR is administered orally twice daily. In some embodiments, the A2aR is administered orally three times daily. In some embodiments, the A2aR is CPI-444 or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal or prodrug thereof and combinations thereof. In some embodiments, the adenosine 2A receptor (A2aR) antagonist is selected from the group consisting of CPI-444, SCH58261, ZM241385, SCH420814, SYN115, 8-CSC, KW-6002, A2A receptor antagonist 1, ADZ4635, vipardenant, ST4206, KF21213, SCH412348, 7MMG-49 or pharmaceutically acceptable salts, solvates, hydrates, cocrystals or prodrugs thereof, and combinations thereof.

[0055]

[0055] In some embodiments, the method further includes treating the patient with an adenosine 2A receptor antagonist (A2aR) before performing step (a). In some embodiments, the patient is treated for at least 1 day; 2 days; 3 days or more; 7 days or more; 7 days or more; less than 14 days; 14 days or more.

[0056]

[0056] In some embodiments, the closed container includes a single bioreactor. In some embodiments, the closed container includes G-REX-10. In some embodiments, the closed container includes G-REX-100. In some embodiments, the closed container includes G-Rex 500. In some embodiments, the closed container includes Xuri or Wave bioreactor gas permeable bag Includes.

[0057]

[0057] In some embodiments, the Disclosure also provides a method for expanding the culture of tumor-infiltrating lymphocytes (TILs) into a therapeutic TIL population, the method being (b) Adding tumor fragments to a closed system, wherein the tumor fragments include a first TIL population; (c) Performing a first expansion culture to produce a second TIL population by culturing a first TIL population in a cell culture medium containing IL-2 and at least one adenosine 2A receptor (A2aR) antagonist, wherein the first expansion culture is performed in a closed container providing a first gas-permeable surface area, the first expansion culture is performed for approximately 3 to 14 days to obtain a second TIL population, the second TIL population being at least 50 times larger than the first TIL population, and the transition from step (b) to step (c) occurs without opening the system; (d) Performing a second expansion culture of the cell culture medium of the second TIL population by supplementing it with additional IL-2, OKT-3, and at least one adenosine 2A receptor (A2aR) antagonist and antigen-presenting cells (APCs) to produce a third TIL population, the second expansion culture being performed over approximately 7–14 days to obtain the third TIL population, the third TIL population being a T-cell therapeutic TIL population including an increased subpopulation of effector T cells and / or central memory T cells compared to the second TIL population, the second expansion culture being performed in a closed vessel providing a second gas-permeable surface area, and the transition from step (c) to step (d) occurring without opening the system; (e) Recovering the therapeutic TIL population obtained from step (d), wherein the transition from step (d) to step (e) occurs without opening the system; and (f) Transferring the TIL population recovered from step (e) to an infusion bag, wherein the transition from step (e) to (f) occurs without opening the system. Includes.

[0058]

[0058] In some embodiments, the method includes, as a first step, (a) Obtain a first TIL population from tumors resected from patients by processing tumor samples obtained from patients into multiple tumor fragments. This also includes.

[0059]

[0059] In one embodiment, the method is an in vitro or ex vivo method.

[0060]

[0060] In some embodiments, the Disclosure also provides a method for expanding the culture of tumor-infiltrating lymphocytes (TILs) into a therapeutic TIL population, the method being (a) Obtaining a first TIL population from tumors resected from patients by processing tumor samples obtained from patients into multiple tumor fragments; (b) Adding tumor fragments to a closed system; (c) Performing a first expansion culture to produce a second TIL population by culturing a first TIL population in a cell culture medium containing IL-2 and at least one adenosine 2A receptor (A2aR) antagonist, wherein the first expansion culture is performed in a closed container providing a first gas-permeable surface area, the first expansion culture is performed for approximately 3 to 14 days to obtain a second TIL population, the second TIL population being at least 50 times larger than the first TIL population, and the transition from step (b) to step (c) occurs without opening the system; (d) A second expansion culture is performed to generate a third TIL population by supplementing the cell culture medium of the second TIL population with additional IL-2, OKT-3, and optionally at least one adenosine 2A receptor (A2aR) antagonist and antigen-presenting cells (APCs), wherein the second expansion culture is performed for approximately 7 to 14 days to obtain the third TIL population. The process is carried out over time, and the third TIL population is a T-cell therapeutic TIL population that includes an increased subpopulation of effector T cells and / or central memory T cells compared to the second TIL population, the second expansion culture is carried out in a closed vessel that provides a second gas-permeable surface area, and the transition from step (c) to step (d) occurs without opening the system; (e) Recovering the therapeutic TIL population obtained from step (d), wherein the transition from step (d) to step (e) occurs without opening the system; and (f) Transferring the TIL population recovered from step (e) to an infusion bag, wherein the transition from step (e) to (f) occurs without opening the system. Includes.

[0061]

[0061] In one embodiment, the method is an in vitro or ex vivo method.

[0062]

[0062] In some embodiments, the method further includes the step of freezing and preserving the infusion bag containing the TIL population recovered from step (f) using a cryopreservation process.

[0063]

[0063] In some embodiments, the cryopreservation process is carried out using a ratio of 1:1 between the recovered TIL population and the cryopreservation medium. In some embodiments, the cryopreservation medium contains dimethyl sulfoxide. In some embodiments, the cryopreservation medium is selected from the group consisting of Cryostor CS10, HypoThermosol, or a combination thereof.

[0064]

[0064] In some embodiments, the antigen-presenting cells are peripheral blood mononuclear cells (PBMCs).

[0065]

[0065] In some embodiments, the PBMCs are irradiated and homogeneous.

[0066]

[0066] In some embodiments, the PBMCs are added to the cell culture in step (d) on either day 9 to 14.

[0067]

[0067] In some embodiments, the antigen-presenting cells are artificial antigen-presenting cells.

[0068]

[0068] In some embodiments, the recovery in step (e) is carried out using the LOVO cell process system.

[0069]

[0069] In some embodiments, the tumor fragment is a plurality of fragments, comprising about 4 to about 50 fragments, each fragment being about 27 mm 3 It has a volume of approximately 1300 mm. In some embodiments, the multiple fragments are approximately 1300 mm 3 ~about 1500mm 3 It contains approximately 30 to 60 fragments with a total volume of approximately 1350 mm. In some embodiments, the fragments are approximately 1350 mm 3 It contains about 50 fragments having a total volume of . In some embodiments, the fragments include about 50 fragments having a total mass of about 1 g to about 1.5 g.

[0070]

[0070] In some embodiments, the cell culture medium is provided in a container selected from the group consisting of G containers and Xuri cell culture bags.

[0071]

[0071] In some embodiments, the infusion bag of step (f) contains HypoThermosol This is an import bag.

[0072]

[0072] In some embodiments, the first period of step (c) and the second period of step (e) are carried out individually within periods of 10, 11, or 12 days, respectively. In some embodiments, the first period of step (c) and the second period of step (e) are carried out individually within a period of 11 days. In some embodiments, steps (a) to (f) are carried out within a period of approximately 25 to 30 days. In some embodiments, steps (a) to (f) are carried out within a period of approximately 20 to 25 days. In some embodiments, steps (a) to (f) are carried out within a period of approximately 20 to 22 days. In some embodiments, steps (a) to (f) are carried out within 22 days. In some embodiments, steps (a) to (f) and cryopreservation are carried out within 22 days.

[0073]

[0073] In some embodiments, the therapeutic TIL population recovered from step (e) contains enough TILs to constitute a therapeutically effective dose of TILs. In some embodiments, the number of TILs sufficient to constitute a therapeutically effective dose is about 2.3 × 10¹⁰ to about 13.7 × 10¹⁰.

[0074]

[0074] In some embodiments, steps (b) to (e) are performed in a single container, and performing steps (b) to (e) in a single container results in an increased TIL yield per excised tumor compared to performing steps (b) to (e) in multiple containers.

[0075]

[0075] In some embodiments, antigen-presenting cells are added to the TIL during the second period of step (d) without opening the system.

[0076]

[0076] In some embodiments, effector T cells and / or central memory T cells in a therapeutic TIL population exhibit one or more features selected from the group consisting of CD27+ expression, CD28+ expression, longer telomeres, increased CD57 expression, and decreased CD56 expression, compared to effector T cells and / or central memory T cells obtained from a second cell population.

[0077]

[0077] In some embodiments, effector T cells and / or central memory T cells obtained from a third TIL population exhibit increased CD57 expression and decreased CD56 expression compared to effector T cells and / or central memory T cells obtained from a second cell population.

[0078]

[0078] In some embodiments, the risk of microbial contamination is reduced compared to open systems.

[0079]

[0079] In one embodiment, the present invention is a method for treating cancer with a tumor-infiltrating lymphocyte (TIL) population, (a) The step of removing the tumor from the patient; (b) Steps to obtain a first TIL population from the tumor; (c) A step of obtaining a second TIL population by performing an initial expansion culture of a first TIL population in a first cell culture medium, wherein the second TIL population is at least five times larger in number than the first TIL population, the first cell culture medium contains IL-2, at least one adenosine 2A receptor (A2aR) antagonist and a tumor necrosis factor receptor superfamily (TNFRSF) agonist, and the initial expansion culture is performed for a period of 21 days or less; (d) A step of obtaining a third TIL population by performing rapid expansion culture of the second TIL population in a second cell culture medium, wherein seven days after the start of rapid expansion culture, the third TIL population is at least 50 times larger in number than the second TIL population, and the second cell culture medium contains IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally a TNFRSF agonist. The rapid expansion culture is carried out over a period of 14 days or less; (e) the step of recovering the third TIL group; and (f) A step of administering the therapeutic active portion of a third TIL population to a patient with cancer, wherein the TNFRSF agonist is selected from the group consisting of 4-1BB agonist, OX40 agonist, CD27 agonist, GITR agonist, HVEM agonist, CD95 agonist and combinations thereof. This provides a method that includes [something].

[0080]

[0080] In one embodiment, the present invention is a method for treating cancer with a tumor-infiltrating lymphocyte (TIL) population, (a) The step of removing the tumor from the patient; (b) Steps to obtain a first TIL population from the tumor; (c) A step of obtaining a second TIL population by performing an initial expansion culture of a first TIL population in a first cell culture medium, wherein the second TIL population is at least five times larger in number than the first TIL population, the first cell culture medium contains IL-2, at least one adenosine 2A receptor (A2aR) antagonist and a tumor necrosis factor receptor superfamily (TNFRSF) agonist, and the initial expansion culture is performed for a period of 21 days or less; (d) A step of obtaining a third TIL population by performing rapid expansion culture of a second TIL population in a second cell culture medium, wherein seven days after the start of rapid expansion culture, the third TIL population is at least 50 times larger in number than the second TIL population, the second cell culture medium contains IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally a TNFRSF agonist, and the rapid expansion culture is performed for a period of 14 days or less; (e) the step of recovering the third TIL group; and (f) A step of administering the therapeutic active portion of a third TIL population to a patient with cancer, wherein the TNFRSF agonist is a 4-1BB agonist, and the 4-1BB agonist is selected from the group consisting of urelumab, utomirumab, EU-101 and its fragments, derivatives, variants, biosimilars and combinations thereof. This provides a method that includes [something].

[0081]

[0081] In one embodiment, the present invention relates to a method for treating cancer with a tumor-infiltrating lymphocyte (TIL) population, (a) The step of removing the tumor from the patient; (b) Steps to obtain a first TIL population from the tumor; (c) A step of obtaining a second TIL population by performing an initial expansion culture of a first TIL population in a first cell culture medium containing at least one adenosine 2A receptor (A2aR) antagonist, wherein the second TIL population is at least five times larger in number than the first TIL population, the first cell culture medium contains IL-2, at least one adenosine 2A receptor (A2aR) antagonist and a tumor necrosis factor receptor superfamily (TNFRSF) agonist, and the initial expansion culture is performed for a period of 21 days or less; (d) A step of obtaining a third TIL population by performing rapid expansion culture of a second TIL population in a second cell culture medium, wherein seven days after the start of rapid expansion culture, the third TIL population is at least 50 times larger in number than the second TIL population, the second cell culture medium contains IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally a TNFRSF agonist, and the rapid expansion culture is performed for a period of 14 days or less; (e) the step of recovering the third TIL group; and (f) A step of administering the therapeutic active portion of a third TIL population to a patient with cancer, wherein the TNFRSF agonist is a 4-1BB agonist and a 4-1BB agonist This is a step protein, which is a 4-1BB agonist fusion protein. This provides a method that includes [something].

[0082]

[0082] In one embodiment, the present invention relates to a method for treating cancer with a tumor-infiltrating lymphocyte (TIL) population, (a) The step of removing the tumor from the patient; (b) Steps to obtain a first TIL population from the tumor; (c) A step of obtaining a second TIL population by performing an initial expansion culture of a first TIL population in a first cell culture medium, wherein the second TIL population is at least five times larger in number than the first TIL population, the first cell culture medium contains IL-2, at least one adenosine 2A receptor (A2aR) antagonist and a tumor necrosis factor receptor superfamily (TNFRSF) agonist, and the initial expansion culture is performed for a period of 21 days or less; (d) A step of obtaining a third TIL population by performing rapid expansion culture of a second TIL population in a second cell culture medium, wherein seven days after the start of rapid expansion culture, the third TIL population is at least 50 times larger in number than the second TIL population, the second cell culture medium contains IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally a TNFRSF agonist, and the rapid expansion culture is performed for a period of 14 days or less; (e) the step of recovering the third TIL group; and (f) A step of administering the therapeutically active portion of a third TIL population to a patient with cancer, wherein the TNFRSF agonist is a 4-1BB agonist fusion protein, and the 4-1BB agonist fusion protein comprises (i) a first soluble 4-1BB binding domain, (ii) a first peptide linker, (iii) a second soluble 4-1BB binding domain, (iv) a second peptide linker, and (v) a third soluble 4-1BB binding domain, and further comprises additional domains at the N-terminus and / or C-terminus, the additional domains comprising an Fc fragment domain and a hinge domain, and the fusion protein has a dimeric structure according to structure IA or structure IB. This provides a method that includes [something].

[0083]

[0083] In one embodiment, the present invention is a method for treating cancer with a tumor-infiltrating lymphocyte (TIL) population, (a) The step of removing the tumor from the patient; (b) Steps to obtain a first TIL population from the tumor; (c) A step of obtaining a second TIL population by performing an initial expansion culture of a first TIL population in a first cell culture medium, wherein the second TIL population is at least five times larger in number than the first TIL population, the first cell culture medium contains IL-2, at least one adenosine 2A receptor (A2aR) antagonist and a tumor necrosis factor receptor superfamily (TNFRSF) agonist, and the initial expansion culture is performed for a period of 21 days or less; (d) A step of obtaining a third TIL population by performing rapid expansion culture of a second TIL population in a second cell culture medium, wherein seven days after the start of rapid expansion culture, the third TIL population is at least 50 times larger in number than the second TIL population, the second cell culture medium contains IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally a TNFRSF agonist, and the rapid expansion culture is performed for a period of 14 days or less; (e) the step of recovering the third TIL group; and (f) A step of administering the therapeutic active portion of a third TIL population to a patient with cancer, wherein the TNFRSF agonist is an OX40 agonist, and the OX40 agonist is tavorixizumab, GSK3174998, MEDI6469, MEDI6383, MO A step selected from the group consisting of XR0916, PF-04518600, Creative Biolabs MOM-18455, and their fragments, derivatives, variants, biosimilars, and combinations. This provides a method that includes [something].

[0084]

[0084] In one embodiment, the present invention is a method for treating cancer with a tumor-infiltrating lymphocyte (TIL) population, (a) The step of removing the tumor from the patient; (b) Steps to obtain a first TIL population from the tumor; (c) A step of obtaining a second TIL population by performing an initial expansion culture of a first TIL population in a first cell culture medium, wherein the second TIL population is at least five times larger in number than the first TIL population, the first cell culture medium contains IL-2, at least one adenosine 2A receptor (A2aR) antagonist and a tumor necrosis factor receptor superfamily (TNFRSF) agonist, and the initial expansion culture is performed for a period of 21 days or less; (d) A step of obtaining a third TIL population by performing rapid expansion culture of a second TIL population in a second cell culture medium, wherein seven days after the start of rapid expansion culture, the third TIL population is at least 50 times larger in number than the second TIL population, the second cell culture medium contains IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally a TNFRSF agonist, and the rapid expansion culture is performed for a period of 14 days or less; (e) the step of recovering the third TIL group; and (f) A step of administering the therapeutically effective portion of a third TIL population to a patient with cancer, wherein the TNFRSF agonist is an OX40 agonist, and the OX40 agonist is an OX40 agonist fusion protein. This provides a method that includes [something].

[0085]

[0085] In one embodiment, the present invention relates to a method for treating cancer with a tumor-infiltrating lymphocyte (TIL) population, (a) The step of removing the tumor from the patient; (b) Steps to obtain a first TIL population from the tumor; (c) A step of obtaining a second TIL population by performing an initial expansion culture of a first TIL population in a first cell culture medium, wherein the second TIL population is at least five times larger in number than the first TIL population, the first cell culture medium contains IL-2, at least one adenosine 2A receptor (A2aR) antagonist and a tumor necrosis factor receptor superfamily (TNFRSF) agonist, and the initial expansion culture is performed for a period of 21 days or less; (d) A step of obtaining a third TIL population by performing rapid expansion culture of a second TIL population in a second cell culture medium, wherein seven days after the start of rapid expansion culture, the third TIL population is at least 50 times larger in number than the second TIL population, the second cell culture medium contains IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally a TNFRSF agonist, and the rapid expansion culture is performed for a period of 14 days or less; (e) the step of recovering the third TIL group; and (f) A step of administering the therapeutically active portion of a third TIL population to a patient with cancer, wherein the TNFRSF agonist is an OX40 agonist fusion protein, and the OX40 agonist fusion protein comprises (i) a first soluble OX40 binding domain, (ii) a first peptide linker, (iii) a second soluble OX40 binding domain, (iv) a second peptide linker, and (v) a third soluble OX40 binding domain, and further comprises additional domains at the N-terminus and / or C-terminus, the additional domains comprising an Fc fragment domain and a hinge domain, and the fusion protein has a dimeric structure according to structure IA or structure IB. Step This provides a method that includes [something].

[0086]

[0086] In one embodiment, the present invention is a method for treating cancer with a tumor-infiltrating lymphocyte (TIL) population, (a) The step of removing the tumor from the patient; (b) Steps to obtain a first TIL population from the tumor; (c) A step of obtaining a second TIL population by performing an initial expansion culture of a first TIL population in a first cell culture medium, wherein the second TIL population is at least five times larger in number than the first TIL population, the first cell culture medium contains IL-2, at least one adenosine 2A receptor (A2aR) antagonist and a tumor necrosis factor receptor superfamily (TNFRSF) agonist, and the initial expansion culture is performed for a period of 21 days or less; (d) A step of obtaining a third TIL population by performing rapid expansion culture of a second TIL population in a second cell culture medium, wherein seven days after the start of rapid expansion culture, the third TIL population is at least 50 times larger in number than the second TIL population, the second cell culture medium contains IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally a TNFRSF agonist, and the rapid expansion culture is performed for a period of 14 days or less; (e) the step of recovering the third TIL group; and (f) A step of administering the therapeutic active portion of a third TIL population to a patient with cancer, wherein the TNFRSF agonist is a CD27 agonist, and the CD27 agonist is valrirumab or a fragment, derivative, variant or biosimilar thereof. This provides a method that includes [something].

[0087]

[0087] In one embodiment, the present invention is a method for treating cancer with a tumor-infiltrating lymphocyte (TIL) population, (a) The step of removing the tumor from the patient; (b) Steps to obtain a first TIL population from the tumor; (c) A step of obtaining a second TIL population by performing an initial expansion culture of a first TIL population in a first cell culture medium, wherein the second TIL population is at least five times larger in number than the first TIL population, the first cell culture medium contains IL-2, at least one adenosine 2A receptor (A2aR) antagonist and a tumor necrosis factor receptor superfamily (TNFRSF) agonist, and the initial expansion culture is performed for a period of 21 days or less; (d) A step of obtaining a third TIL population by performing rapid expansion culture of a second TIL population in a second cell culture medium, wherein seven days after the start of rapid expansion culture, the third TIL population is at least 50 times larger in number than the second TIL population, the second cell culture medium contains IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally a TNFRSF agonist, and the rapid expansion culture is performed for a period of 14 days or less; (e) the step of recovering the third TIL group; and (f) A step of administering the therapeutically effective portion of a third TIL population to a patient with cancer, wherein the TNFRSF agonist is a CD27 agonist and the CD27 agonist is a CD27 agonist fusion protein. This provides a method that includes [something].

[0088]

[0088] In one embodiment, the present invention relates to a method for treating cancer with a tumor-infiltrating lymphocyte (TIL) population, (a) The step of removing the tumor from the patient; (b) Steps to obtain a first TIL population from the tumor; (c) A step of obtaining a second TIL population by performing an initial expansion culture of a first TIL population in a first cell culture medium, wherein the second TIL population is at least five times larger in number than the first TIL population, the first cell culture medium contains IL-2, at least one adenosine 2A receptor (A2aR) antagonist and a tumor necrosis factor receptor superfamily (TNFRSF) agonist, and the initial expansion culture is performed for a period of 21 days or less; (d) A step of obtaining a third TIL population by performing rapid expansion culture of a second TIL population in a second cell culture medium, wherein seven days after the start of rapid expansion culture, the third TIL population is at least 50 times larger in number than the second TIL population, the second cell culture medium contains IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally a TNFRSF agonist, and the rapid expansion culture is performed for a period of 14 days or less; (e) the step of recovering the third TIL group; and (f) A step of administering the therapeutically active portion of a third TIL population to a patient with cancer, wherein the TNFRSF agonist is a CD27 agonist and the CD27 agonist fusion protein comprises (i) a first soluble CD27 binding domain, (ii) a first peptide linker, (iii) a second soluble CD27 binding domain, (iv) a second peptide linker, and (v) a third soluble CD27 binding domain, and further comprises additional domains at the N-terminus and / or C-terminus, the additional domains comprising an Fc fragment domain and a hinge domain, and the fusion protein has a dimeric structure according to structure IA or structure IB. This provides a method that includes [something].

[0089]

[0089] In one embodiment, the present invention is a method for treating cancer with a tumor-infiltrating lymphocyte (TIL) population, (a) The step of removing the tumor from the patient; (b) Steps to obtain a first TIL population from the tumor; (c) A step of obtaining a second TIL population by performing an initial expansion culture of a first TIL population in a first cell culture medium, wherein the second TIL population is at least five times larger in number than the first TIL population, the first cell culture medium contains IL-2, at least one adenosine 2A receptor (A2aR) antagonist and a tumor necrosis factor receptor superfamily (TNFRSF) agonist, and the initial expansion culture is performed for a period of 21 days or less; (d) A step of obtaining a third TIL population by performing rapid expansion culture of a second TIL population in a second cell culture medium, wherein seven days after the start of rapid expansion culture, the third TIL population is at least 50 times larger in number than the second TIL population, the second cell culture medium contains IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally a TNFRSF agonist, and the rapid expansion culture is performed for a period of 14 days or less; (e) the step of recovering the third TIL group; and (f) A step of administering the therapeutic active portion of a third TIL population to a patient with cancer, wherein the TNFRSF agonist is a GITR agonist, and the GITR agonists are TRX518, 6C8, 36E5, 3D6, 61G6, 6H6, 61F6, 1D8, 17F10, 35D8, 49A1, 9E5, 31H6, 2155, 698, 706, Steps selected from the group consisting of 827, 1649, 1718, 1D7, 33C9, 33F6, 34G4, 35B10, 41E11, 41G5, 42A11, 44C1, 45A8, 46E11, 48H12, 48H7, 49D9, 49E2, 48A9, 5H7, 7A10, 9H6 and their fragments, derivatives, variants, biosimilars and combinations. This provides a method that includes [something].

[0090]

[0090] In one embodiment, the present invention is a method for treating cancer with a tumor-infiltrating lymphocyte (TIL) population, (a) The step of removing the tumor from the patient; (b) Steps to obtain a first TIL population from the tumor; (c) A step of obtaining a second TIL population by performing an initial expansion culture of a first TIL population in a first cell culture medium, wherein the second TIL population is at least five times larger in number than the first TIL population, the first cell culture medium contains IL-2, at least one adenosine 2A receptor (A2aR) antagonist and a tumor necrosis factor receptor superfamily (TNFRSF) agonist, and the initial expansion culture is performed for a period of 21 days or less; (d) A step of obtaining a third TIL population by performing rapid expansion culture of a second TIL population in a second cell culture medium, wherein seven days after the start of rapid expansion culture, the third TIL population is at least 50 times larger in number than the second TIL population, the second cell culture medium contains IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally a TNFRSF agonist, and the rapid expansion culture is performed for a period of 14 days or less; (e) the step of recovering the third TIL group; and (f) A step of administering the therapeutically active portion of a third TIL population to a patient with cancer, wherein the TNFRSF agonist is a GITR agonist, and the GITR agonist is a GITR agonist fusion protein. This provides a method that includes [something].

[0091]

[0091] In one embodiment, the present invention is a method for treating cancer with a tumor-infiltrating lymphocyte (TIL) population, (a) The step of removing the tumor from the patient; (b) Steps to obtain a first TIL population from the tumor; (c) A step of obtaining a second TIL population by performing an initial expansion culture of a first TIL population in a first cell culture medium, wherein the second TIL population is at least five times larger in number than the first TIL population, the first cell culture medium contains IL-2, at least one adenosine 2A receptor (A2aR) antagonist and a tumor necrosis factor receptor superfamily (TNFRSF) agonist, and the initial expansion culture is performed for a period of 21 days or less; (d) A step of obtaining a third TIL population by performing rapid expansion culture of a second TIL population in a second cell culture medium, wherein seven days after the start of rapid expansion culture, the third TIL population is at least 50 times larger in number than the second TIL population, the second cell culture medium contains IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally a TNFRSF agonist, and the rapid expansion culture is performed for a period of 14 days or less; (e) the step of recovering the third TIL group; and (f) A step of administering the therapeutically active portion of a third TIL population to a patient with cancer, wherein the TNFRSF agonist is a GITR agonist fusion protein, and the GITR agonist fusion protein comprises (i) a first soluble GITR binding domain, (ii) a first peptide linker, (iii) a second soluble GITR binding domain, (iv) a second peptide linker, and (v) a third soluble GITR binding domain, and further comprises additional domains at the N-terminus and / or C-terminus, the additional domains comprising an Fc fragment domain and a hinge domain, and the fusion protein has a dimeric structure according to structure IA or structure IB. This provides a method that includes [something].

[0092]

[0092] In one embodiment, the present invention relates to a method for treating cancer with a tumor-infiltrating lymphocyte (TIL) population, (a) The step of removing the tumor from the patient; (b) Steps to obtain a first TIL population from the tumor; (c) A step of obtaining a second TIL population by performing an initial expansion culture of a first TIL population in a first cell culture medium, wherein the second TIL population is at least five times larger in number than the first TIL population, the first cell culture medium contains IL-2, at least one adenosine 2A receptor (A2aR) antagonist and a tumor necrosis factor receptor superfamily (TNFRSF) agonist, and the initial expansion culture is performed for a period of 21 days or less; (d) A step of obtaining a third TIL population by performing rapid expansion culture of a second TIL population in a second cell culture medium, wherein seven days after the start of rapid expansion culture, the third TIL population is at least 50 times larger in number than the second TIL population, the second cell culture medium contains IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally a TNFRSF agonist, and the rapid expansion culture is performed for a period of 14 days or less; (e) the step of recovering the third TIL group; and (f) A step of administering the therapeutic active portion of a third TIL population to a patient with cancer, wherein the TNFRSF agonist is an HVEM agonist. This provides a method that includes [something].

[0093]

[0093] In one embodiment, the present invention is a method for treating cancer with a tumor-infiltrating lymphocyte (TIL) population, (a) The step of removing the tumor from the patient; (b) Steps to obtain a first TIL population from the tumor; (c) A step of obtaining a second TIL population by performing an initial expansion culture of a first TIL population in a first cell culture medium, wherein the second TIL population is at least five times larger in number than the first TIL population, the first cell culture medium contains IL-2, at least one adenosine 2A receptor (A2aR) antagonist and a tumor necrosis factor receptor superfamily (TNFRSF) agonist, and the initial expansion culture is performed for a period of 21 days or less; (d) A step of obtaining a third TIL population by performing rapid expansion culture of a second TIL population in a second cell culture medium, wherein seven days after the start of rapid expansion culture, the third TIL population is at least 50 times larger in number than the second TIL population, the second cell culture medium contains IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally a TNFRSF agonist, and the rapid expansion culture is performed for a period of 14 days or less; (e) the step of recovering the third TIL group; and (f) A step of administering the therapeutically active portion of a third TIL population to a patient with cancer, wherein the TNFRSF agonist is an HVEM agonist, and the HVEM agonist is an HVEM agonist fusion protein. This provides a method that includes [something].

[0094]

[0094] In one embodiment, the present invention is a method for treating cancer with a tumor-infiltrating lymphocyte (TIL) population, (a) The step of removing the tumor from the patient; (b) Steps to obtain a first TIL population from the tumor; (c) A step of obtaining a second TIL population by performing an initial expansion culture of the first TIL population in a first cell culture medium, wherein the second TIL population is at least five times larger in number than the first TIL population, and the first cell culture medium contains IL-2 and at least one adenosine 2A The initial expansion culture, comprising a receptor (A2aR) antagonist and a tumor necrosis factor receptor superfamily (TNFRSF) agonist, is carried out over a period of 21 days or less; (d) A step of obtaining a third TIL population by performing rapid expansion culture of a second TIL population in a second cell culture medium, wherein seven days after the start of rapid expansion culture, the third TIL population is at least 50 times larger in number than the second TIL population, the second cell culture medium contains IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally a TNFRSF agonist, and the rapid expansion culture is performed for a period of 14 days or less; (e) the step of recovering the third TIL group; and (f) A step of administering the therapeutically active portion of a third TIL population to a patient with cancer, wherein the TNFRSF agonist is an HVEM agonist fusion protein, and the HVEM agonist fusion protein comprises (i) a first soluble HVEM binding domain, (ii) a first peptide linker, (iii) a second soluble HVEM binding domain, (iv) a second peptide linker, and (v) a third soluble HVEM binding domain, and further comprises additional domains at the N-terminus and / or C-terminus, the additional domains comprising an Fc fragment domain and a hinge domain, and the fusion protein has a dimeric structure according to structure IA or structure IB. This provides a method that includes [something].

[0095]

[0095] In one embodiment, the present invention is a method for treating cancer with a tumor-infiltrating lymphocyte (TIL) population, (a) The step of removing the tumor from the patient; (b) Steps to obtain a first TIL population from the tumor; (c) A step of obtaining a second TIL population by performing an initial expansion culture of a first TIL population in a first cell culture medium, wherein the second TIL population is at least five times larger in number than the first TIL population, the first cell culture medium contains IL-2, at least one adenosine 2A receptor (A2aR) antagonist and a tumor necrosis factor receptor superfamily (TNFRSF) agonist, and the initial expansion culture is performed for a period of 21 days or less; (d) A step of obtaining a third TIL population by performing rapid expansion culture of a second TIL population in a second cell culture medium, wherein seven days after the start of rapid expansion culture, the third TIL population is at least 50 times larger in number than the second TIL population, the second cell culture medium contains IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally a TNFRSF agonist, and the rapid expansion culture is performed for a period of 14 days or less; (e) the step of recovering the third TIL group; and (f) A step of administering the therapeutic active portion of a third TIL population to a patient with cancer, further comprising a step of treating the patient with a TNFRSF agonist, which is administered intravenously at a dose of 0.1 mg / kg to 50 mg / kg every four weeks for up to eight cycles. This provides a method that includes [something].

[0096]

[0096] In one embodiment, the present invention relates to a method for treating cancer with a tumor-infiltrating lymphocyte (TIL) population, (a) The step of removing the tumor from the patient; (b) Steps to obtain a first TIL population from the tumor; (c) A step of obtaining a second TIL population by performing an initial expansion culture of the first TIL population in a first cell culture medium, wherein the second TIL population is at least five times larger in number than the first TIL population, and the first cell culture medium contains IL-2 and at least one adenosine 2A The initial expansion culture, comprising a receptor (A2aR) antagonist and a tumor necrosis factor receptor superfamily (TNFRSF) agonist, is carried out over a period of 21 days or less; (d) A step of obtaining a third TIL population by performing rapid expansion culture of a second TIL population in a second cell culture medium, wherein seven days after the start of rapid expansion culture, the third TIL population is at least 50 times larger in number than the second TIL population, the second cell culture medium contains IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally a TNFRSF agonist, and the rapid expansion culture is performed for a period of 14 days or less; (e) the step of recovering the third TIL group; and (f) A step of administering the therapeutic active portion of a third TIL population to a patient having cancer, further comprising the step of treating the patient with a TNFRSF agonist prior to the step of resecting the tumor from the patient, wherein the TNFRSF agonist is administered intravenously at doses of 0.1 mg / kg to 50 mg / kg every four weeks for up to eight cycles. This provides a method that includes [something].

[0097]

[0097] In one embodiment, the present invention is a method for treating cancer with a tumor-infiltrating lymphocyte (TIL) population, (a) The step of removing the tumor from the patient; (b) Steps to obtain a first TIL population from the tumor; (c) A step of obtaining a second TIL population by performing an initial expansion culture of a first TIL population in a first cell culture medium, wherein the second TIL population is at least five times larger in number than the first TIL population, the first cell culture medium contains IL-2, at least one adenosine 2A receptor (A2aR) antagonist and a tumor necrosis factor receptor superfamily (TNFRSF) agonist, and the initial expansion culture is performed for a period of 21 days or less; (d) A step of obtaining a third TIL population by performing rapid expansion culture of a second TIL population in a second cell culture medium, wherein seven days after the start of rapid expansion culture, the third TIL population is at least 50 times larger in number than the second TIL population, the second cell culture medium contains IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally a TNFRSF agonist, and the rapid expansion culture is performed for a period of 14 days or less; (e) the step of recovering the third TIL group; and (f) A step of administering the therapeutic active portion of a third TIL population to a patient with cancer, wherein the TNFRSF agonist is selected from the group consisting of urelumab, utomirumab, EU-101, tavorixizumab, Creative Biolabs MOM-18455 and its fragments, derivatives, variants, biosimilars and combinations. This provides a method that includes [something].

[0098]

[0098] In one embodiment, the present invention is a method for treating cancer with a tumor-infiltrating lymphocyte (TIL) population, (a) The step of removing the tumor from the patient; (b) Steps to obtain a first TIL population from the tumor; (c) A step of obtaining a second TIL population by performing an initial expansion culture of a first TIL population in a first cell culture medium, wherein the second TIL population is at least five times larger in number than the first TIL population, the first cell culture medium contains IL-2, at least one adenosine 2A receptor (A2aR) antagonist and a tumor necrosis factor receptor superfamily (TNFRSF) agonist, and the initial expansion culture is performed for a period of 21 days or less; (d) Rapid expansion culture of the second TIL population in the second cell culture medium to produce a third TIL Step 1: Obtaining a population, where 7 days after the start of rapid expansion culture, the third TIL population is at least 50 times larger in number than the second TIL population, the second cell culture medium contains IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally a TNFRSF agonist, and the rapid expansion culture is carried out for a period of 14 days or less; (e) the step of recovering the third TIL group; and (f) A step of administering the therapeutically effective portion of a third TIL population to a patient with cancer, wherein the first cell culture medium comprises a second TNFRSF agonist. This provides a method that includes [something].

[0099]

[0099] In one embodiment, the present invention is a method for treating cancer with a tumor-infiltrating lymphocyte (TIL) population, (a) The step of removing the tumor from the patient; (b) Steps to obtain a first TIL population from the tumor; (c) A step of obtaining a second TIL population by performing an initial expansion culture of a first TIL population in a first cell culture medium, wherein the second TIL population is at least five times larger in number than the first TIL population, the first cell culture medium contains IL-2, at least one adenosine 2A receptor (A2aR) antagonist and a tumor necrosis factor receptor superfamily (TNFRSF) agonist, and the initial expansion culture is performed for a period of 21 days or less; (d) A step of obtaining a third TIL population by performing rapid expansion culture of a second TIL population in a second cell culture medium, wherein seven days after the start of rapid expansion culture, the third TIL population is at least 50 times larger in number than the second TIL population, the second cell culture medium contains IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally a TNFRSF agonist, and the rapid expansion culture is performed for a period of 14 days or less; (e) the step of recovering the third TIL group; and (f) A step of administering the therapeutically effective portion of a third TIL population to a patient with cancer, wherein the TNFRSF agonist is added to the first cell culture medium at intervals selected from the group consisting of daily, every two days, every three days, every four days, every five days, every six days, every seven days and every two weeks during the initial expansion culture. This provides a method that includes [something].

[0100]

[0100] In one embodiment, the present invention treats cancer in a tumor-infiltrating lymphocyte (TIL) population. A method of placement, (a) The step of removing the tumor from the patient; (b) Steps to obtain a first TIL population from the tumor; (c) A step of obtaining a second TIL population by performing an initial expansion culture of a first TIL population in a first cell culture medium, wherein the second TIL population is at least five times larger in number than the first TIL population, the first cell culture medium contains IL-2, at least one adenosine 2A receptor (A2aR) antagonist and a tumor necrosis factor receptor superfamily (TNFRSF) agonist, and the initial expansion culture is performed for a period of 21 days or less; (d) A step of obtaining a third TIL population by performing rapid expansion culture of a second TIL population in a second cell culture medium, wherein seven days after the start of rapid expansion culture, the third TIL population is at least 50 times larger in number than the second TIL population, the second cell culture medium contains IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally a TNFRSF agonist, and the rapid expansion culture is performed for a period of 14 days or less; (e) the step of recovering the third TIL group; and (f) A step of administering the therapeutic active portion of a third TIL population to a patient with cancer, wherein a TNFRSF agonist and at least one adenosine 2A receptor (A2aR) antagonist are added to a second cell culture medium at intervals selected from the group consisting of daily, every 2 days, every 3 days, every 4 days, every 5 days, every 6 days, every 7 days and every 2 weeks during rapid expansion culture. This provides a method that includes [something].

[0101]

[0101] In one embodiment, the present invention treats cancer in a tumor-infiltrating lymphocyte (TIL) population. A method of placement, (a) The step of removing the tumor from the patient; (b) Steps to obtain a first TIL population from the tumor; (c) A step of obtaining a second TIL population by performing an initial expansion culture of a first TIL population in a first cell culture medium, wherein the second TIL population is at least five times larger in number than the first TIL population, the first cell culture medium contains IL-2, at least one adenosine 2A receptor (A2aR) antagonist and a tumor necrosis factor receptor superfamily (TNFRSF) agonist, and the initial expansion culture is performed for a period of 21 days or less; (d) A step of obtaining a third TIL population by performing rapid expansion culture of a second TIL population in a second cell culture medium, wherein seven days after the start of rapid expansion culture, the third TIL population is at least 50 times larger in number than the second TIL population, the second cell culture medium contains IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally a TNFRSF agonist, and the rapid expansion culture is performed for a period of 14 days or less; (e) the step of recovering the third TIL group; and (f) A step of administering the therapeutic active portion of a third TIL population to a patient with cancer, wherein the TNFRSF agonist is added in a cell culture medium at a concentration sufficient to achieve a concentration of 0.1 μg / mL to 100 μg / mL, and at least one adenosine 2A receptor (A2aR) antagonist is added to achieve functional antagonism of the A2aR signaling pathway. This provides a method that includes [something].

[0102]

[0102] In one embodiment, the present invention treats cancer in a tumor-infiltrating lymphocyte (TIL) population. A method of placement, (a) The step of removing the tumor from the patient; (b) Steps to obtain a first TIL population from the tumor; (c) A step of obtaining a second TIL population by performing an initial expansion culture of a first TIL population in a first cell culture medium, wherein the second TIL population is at least five times larger in number than the first TIL population, the first cell culture medium contains IL-2, at least one adenosine 2A receptor (A2aR) antagonist and a tumor necrosis factor receptor superfamily (TNFRSF) agonist, and the initial expansion culture is performed for a period of 21 days or less; (d) A step of obtaining a third TIL population by performing rapid expansion culture of a second TIL population in a second cell culture medium, wherein seven days after the start of rapid expansion culture, the third TIL population is at least 50 times larger in number than the second TIL population, the second cell culture medium contains IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally a TNFRSF agonist, and the rapid expansion culture is performed for a period of 14 days or less; (e) the step of recovering the third TIL group; and (f) A step of administering the therapeutically effective portion of the third TIL population to a patient with cancer, wherein the TNFRSF agonist is administered in cell culture medium at a concentration of 20 μg / mL to 40 μg / mL Step This provides a method that includes [something].

[0103]

[0103] In one embodiment, the present invention treats cancer in a tumor-infiltrating lymphocyte (TIL) population. A method of placement, (a) The step of removing the tumor from the patient; (b) Steps to obtain a first TIL population from the tumor; (c) A step of obtaining a second TIL population by performing an initial expansion culture of a first TIL population in a first cell culture medium, wherein the second TIL population is at least five times larger in number than the first TIL population, the first cell culture medium contains IL-2, at least one adenosine 2A receptor (A2aR) antagonist and a tumor necrosis factor receptor superfamily (TNFRSF) agonist, and the initial expansion culture is performed for a period of 21 days or less; (d) A step of obtaining a third TIL population by performing rapid expansion culture of a second TIL population in a second cell culture medium, wherein seven days after the start of rapid expansion culture, the third TIL population is at least 50 times larger in number than the second TIL population, the second cell culture medium contains IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally a TNFRSF agonist, and the rapid expansion culture is performed for a period of 14 days or less; (e) the step of recovering the third TIL group; and (f) A step of administering the therapeutically effective portion of a third TIL population to a patient with cancer, wherein IL-2 is present in the first cell culture medium at an initial concentration of about 10 to about 6000 IU / mL. This provides a method that includes [something].

[0104]

[0104] In one embodiment, the present invention treats cancer in a tumor-infiltrating lymphocyte (TIL) population. A method of placement, (a) The step of removing the tumor from the patient; (b) Steps to obtain a first TIL population from the tumor; (c) A step of obtaining a second TIL population by performing an initial expansion culture of a first TIL population in a first cell culture medium, wherein the second TIL population is at least five times larger in number than the first TIL population, the first cell culture medium contains IL-2, at least one adenosine 2A receptor (A2aR) antagonist and a tumor necrosis factor receptor superfamily (TNFRSF) agonist, and the initial expansion culture is performed for a period of 21 days or less; (d) A step of obtaining a third TIL population by performing rapid expansion culture of a second TIL population in a second cell culture medium, wherein seven days after the start of rapid expansion culture, the third TIL population is at least 50 times larger in number than the second TIL population, the second cell culture medium contains IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally a TNFRSF agonist, and the rapid expansion culture is performed for a period of 14 days or less; (e) the step of recovering the third TIL group; and (f) A step of administering the therapeutically effective portion of a third TIL population to a patient with cancer, wherein IL-2 is present in the first cell culture medium at an initial concentration of approximately 3000 IU / mL. This provides a method that includes [something].

[0105]

[0105] In a further embodiment, the therapeutically effective portion of the third TIL population is cancer The patient is administered the drug, and at least one adenosine 2A receptor (A2aR) antagonist is present in the first cell culture medium.

[0106]

[0106] In one embodiment, the present invention treats cancer in a tumor-infiltrating lymphocyte (TIL) population. A method of placement, (a) The step of removing the tumor from the patient; (b) Steps to obtain a first TIL population from the tumor; (c) A step of obtaining a second TIL population by performing an initial expansion culture of a first TIL population in a first cell culture medium, wherein the second TIL population is at least five times larger in number than the first TIL population, the first cell culture medium contains IL-2, at least one adenosine 2A receptor (A2aR) antagonist and a tumor necrosis factor receptor superfamily (TNFRSF) agonist, and the initial expansion culture is performed for a period of 21 days or less; (d) A step of obtaining a third TIL population by performing rapid expansion culture of a second TIL population in a second cell culture medium, wherein seven days after the start of rapid expansion culture, the third TIL population is at least 50 times larger in number than the second TIL population, the second cell culture medium contains IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally a TNFRSF agonist, and the rapid expansion culture is performed for a period of 14 days or less; (e) the step of recovering the third TIL group; and (f) The step of administering the therapeutically effective portion of a third TIL population to a patient having cancer (the method of claim 31), wherein IL-2 is present in a first cell culture medium at an initial concentration of about 800 IU / mL to about 1100 IU / mL. This provides a method that includes [something].

[0107]

[0107] In one embodiment, the present invention treats cancer in a tumor-infiltrating lymphocyte (TIL) population. A method of placement, (a) The step of removing the tumor from the patient; (b) Steps to obtain a first TIL population from the tumor; (c) A step of obtaining a second TIL population by performing an initial expansion culture of a first TIL population in a first cell culture medium, wherein the second TIL population is at least five times larger in number than the first TIL population, the first cell culture medium contains IL-2, at least one adenosine 2A receptor (A2aR) antagonist and a tumor necrosis factor receptor superfamily (TNFRSF) agonist, and the initial expansion culture is performed for a period of 21 days or less; (d) A step of obtaining a third TIL population by performing rapid expansion culture of a second TIL population in a second cell culture medium, wherein seven days after the start of rapid expansion culture, the third TIL population is at least 50 times larger in number than the second TIL population, the second cell culture medium contains IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally a TNFRSF agonist, and the rapid expansion culture is performed for a period of 14 days or less; (e) the step of recovering the third TIL group; and (f) A step of administering the therapeutically effective portion of a third TIL population to a patient with cancer, wherein IL-2 is present in the first cell culture medium at an initial concentration of about 1000 IU / mL. This provides a method that includes [something].

[0108]

[0108] In one embodiment, the present invention treats cancer in a tumor-infiltrating lymphocyte (TIL) population. A method of placement, (a) The step of removing the tumor from the patient; (b) Steps to obtain a first TIL population from the tumor; (c) Perform initial expansion culture of the first TIL population in the first cell culture medium to produce the second TIL Step 1: Obtain a population, wherein the second TIL population is at least five times larger in number than the first TIL population, the first cell culture medium contains IL-2, at least one adenosine 2A receptor (A2aR) antagonist and a tumor necrosis factor receptor superfamily (TNFRSF) agonist, and the initial expansion culture is carried out for a period of 21 days or less; (d) A step of obtaining a third TIL population by performing rapid expansion culture of a second TIL population in a second cell culture medium, wherein seven days after the start of rapid expansion culture, the third TIL population is at least 50 times larger in number than the second TIL population, the second cell culture medium contains IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally a TNFRSF agonist, and the rapid expansion culture is performed for a period of 14 days or less; (e) the step of recovering the third TIL group; and (f) A step of administering the therapeutically effective portion of a third TIL population to a patient with cancer, wherein IL-2 is present in the second cell culture medium at an initial concentration of about 10 to about 6000 IU / mL. This provides a method that includes [something].

[0109]

[0109] In one embodiment, the present invention treats cancer in a tumor-infiltrating lymphocyte (TIL) population. A method of placement, (a) The step of removing the tumor from the patient; (b) Steps to obtain a first TIL population from the tumor; (c) A step of obtaining a second TIL population by performing an initial expansion culture of a first TIL population in a first cell culture medium, wherein the second TIL population is at least five times larger in number than the first TIL population, the first cell culture medium contains IL-2, at least one adenosine 2A receptor (A2aR) antagonist and a tumor necrosis factor receptor superfamily (TNFRSF) agonist, and the initial expansion culture is performed for a period of 21 days or less; (d) A step of obtaining a third TIL population by performing rapid expansion culture of a second TIL population in a second cell culture medium, wherein seven days after the start of rapid expansion culture, the third TIL population is at least 50 times larger in number than the second TIL population, the second cell culture medium contains IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally a TNFRSF agonist, and the rapid expansion culture is performed for a period of 14 days or less; (e) the step of recovering the third TIL group; and (f) A step of administering the therapeutically effective portion of a third TIL population to a patient with cancer, wherein IL-2 is present in the second cell culture medium at an initial concentration of approximately 3000 IU / mL. This provides a method that includes [something].

[0110]

[0110] In one embodiment, the present invention treats cancer in a tumor-infiltrating lymphocyte (TIL) population. A method of placement, (a) The step of removing the tumor from the patient; (b) Steps to obtain a first TIL population from the tumor; (c) A step of obtaining a second TIL population by performing an initial expansion culture of a first TIL population in a first cell culture medium, wherein the second TIL population is at least five times larger in number than the first TIL population, the first cell culture medium contains IL-2, at least one adenosine 2A receptor (A2aR) antagonist and a tumor necrosis factor receptor superfamily (TNFRSF) agonist, and the initial expansion culture is performed for a period of 21 days or less; (d) Rapid expansion culture of the second TIL population in the second cell culture medium to produce a third TIL Step 1: Obtaining a population, where 7 days after the start of rapid expansion culture, the third TIL population is at least 50 times larger in number than the second TIL population, the second cell culture medium contains IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally a TNFRSF agonist, and the rapid expansion culture is carried out for a period of 14 days or less; (e) the step of recovering the third TIL group; and (f) A step of administering the therapeutically effective portion of a third TIL population to a patient with cancer, wherein IL-2 is present in the second cell culture medium at an initial concentration of approximately 800 IU / mL to approximately 1100 IU / mL. This provides a method that includes [something].

[0111]

[0111] In one embodiment, the present invention treats cancer in a tumor-infiltrating lymphocyte (TIL) population. A method of placement, (a) The step of removing the tumor from the patient; (b) Steps to obtain a first TIL population from the tumor; (c) A step of obtaining a second TIL population by performing an initial expansion culture of a first TIL population in a first cell culture medium, wherein the second TIL population is at least five times larger in number than the first TIL population, the first cell culture medium contains IL-2, at least one adenosine 2A receptor (A2aR) antagonist and a tumor necrosis factor receptor superfamily (TNFRSF) agonist, and the initial expansion culture is performed for a period of 21 days or less; (d) A step of obtaining a third TIL population by performing rapid expansion culture of a second TIL population in a second cell culture medium, wherein seven days after the start of rapid expansion culture, the third TIL population is at least 50 times larger in number than the second TIL population, the second cell culture medium contains IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally a TNFRSF agonist, and the rapid expansion culture is performed for a period of 14 days or less; (e) the step of recovering the third TIL group; and (f) A step of administering the therapeutically effective portion of a third TIL population to a patient with cancer, wherein IL-2 is present in the second cell culture medium at an initial concentration of approximately 1000 IU / mL, and the A2aR antagonist is present at a concentration sufficient to attenuate signaling via the A2aR pathway. This provides a method that includes [something].

[0112]

[0112] In one embodiment, the present invention treats cancer in a tumor-infiltrating lymphocyte (TIL) population. A method of placement, (a) The step of removing the tumor from the patient; (b) Steps to obtain a first TIL population from the tumor; (c) A step of obtaining a second TIL population by performing an initial expansion culture of a first TIL population in a first cell culture medium, wherein the second TIL population is at least five times larger in number than the first TIL population, the first cell culture medium contains IL-2, at least one adenosine 2A receptor (A2aR) antagonist and a tumor necrosis factor receptor superfamily (TNFRSF) agonist, and the initial expansion culture is performed for a period of 21 days or less; (d) A step of obtaining a third TIL population by performing rapid expansion culture of a second TIL population in a second cell culture medium, wherein seven days after the start of rapid expansion culture, the third TIL population is at least 50 times larger in number than the second TIL population, the second cell culture medium contains IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally a TNFRSF agonist, and the rapid expansion culture is performed for a period of 14 days or less; (e) the step of recovering the third TIL group; and (f) A step of administering the therapeutically effective portion of a third TIL population to a patient with cancer, wherein IL-15 is present in the first cell culture medium. This provides a method that includes [something].

[0113]

[0113] In one embodiment, the present invention treats cancer in a tumor-infiltrating lymphocyte (TIL) population. A method of placement, (a) The step of removing the tumor from the patient; (b) Steps to obtain a first TIL population from the tumor; (c) A step of obtaining a second TIL population by performing an initial expansion culture of a first TIL population in a first cell culture medium, wherein the second TIL population is at least five times larger in number than the first TIL population, the first cell culture medium contains IL-2, at least one adenosine 2A receptor (A2aR) antagonist and a tumor necrosis factor receptor superfamily (TNFRSF) agonist, and the initial expansion culture is performed for a period of 21 days or less; (d) A step of obtaining a third TIL population by performing rapid expansion culture of a second TIL population in a second cell culture medium, wherein seven days after the start of rapid expansion culture, the third TIL population is at least 50 times larger in number than the second TIL population, the second cell culture medium contains IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally a TNFRSF agonist, and the rapid expansion culture is performed for a period of 14 days or less; (e) the step of recovering the third TIL group; and (f) A step of administering the therapeutically effective portion of a third TIL population to a patient with cancer, wherein IL-15 is present in the first cell culture medium at an initial concentration of approximately 5 ng / mL to approximately 20 ng / mL. This provides a method that includes [something].

[0114]

[0114] In one embodiment, the present invention treats cancer in a tumor-infiltrating lymphocyte (TIL) population. A method of placement, (a) The step of removing the tumor from the patient; (b) Steps to obtain a first TIL population from the tumor; (c) A step of obtaining a second TIL population by performing an initial expansion culture of a first TIL population in a first cell culture medium, wherein the second TIL population is at least five times larger in number than the first TIL population, the first cell culture medium contains IL-2, at least one adenosine 2A receptor (A2aR) antagonist and a tumor necrosis factor receptor superfamily (TNFRSF) agonist, and the initial expansion culture is performed for a period of 21 days or less; (d) A step of obtaining a third TIL population by performing rapid expansion culture of a second TIL population in a second cell culture medium, wherein seven days after the start of rapid expansion culture, the third TIL population is at least 50 times larger in number than the second TIL population, the second cell culture medium contains IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally a TNFRSF agonist, and the rapid expansion culture is performed for a period of 14 days or less; (e) the step of recovering the third TIL group; and (f) A step of administering the therapeutically effective portion of a third TIL population to a patient with cancer, wherein IL-15 is present in a second cell culture medium. This provides a method that includes [something].

[0115]

[0115] In one embodiment, the present invention treats cancer in a tumor-infiltrating lymphocyte (TIL) population. A method of placement, (a) The step of removing the tumor from the patient; (b) Steps to obtain a first TIL population from the tumor; (c) A step of obtaining a second TIL population by performing an initial expansion culture of a first TIL population in a first cell culture medium, wherein the second TIL population is at least five times larger in number than the first TIL population, the first cell culture medium contains IL-2, at least one adenosine 2A receptor (A2aR) antagonist and a tumor necrosis factor receptor superfamily (TNFRSF) agonist, and the initial expansion culture is performed for a period of 21 days or less; (d) A step of obtaining a third TIL population by performing rapid expansion culture of a second TIL population in a second cell culture medium, wherein seven days after the start of rapid expansion culture, the third TIL population is at least 50 times larger in number than the second TIL population, the second cell culture medium contains IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally a TNFRSF agonist, and the rapid expansion culture is performed for a period of 14 days or less; (e) the step of recovering the third TIL group; and (f) A step of administering the therapeutically effective portion of a third TIL population to a patient with cancer, wherein IL-15 is present in the second cell culture medium at an initial concentration of approximately 5 ng / mL to approximately 20 ng / mL. This provides a method that includes [something].

[0116]

[0116] In one embodiment, the present invention treats cancer in a tumor-infiltrating lymphocyte (TIL) population. A method of placement, (a) The step of removing the tumor from the patient; (b) Steps to obtain a first TIL population from the tumor; (c) A step of obtaining a second TIL population by performing an initial expansion culture of a first TIL population in a first cell culture medium, wherein the second TIL population is at least five times larger in number than the first TIL population, the first cell culture medium contains IL-2, at least one adenosine 2A receptor (A2aR) antagonist and a tumor necrosis factor receptor superfamily (TNFRSF) agonist, and the initial expansion culture is performed for a period of 21 days or less; (d) A step of obtaining a third TIL population by performing rapid expansion culture of a second TIL population in a second cell culture medium, wherein seven days after the start of rapid expansion culture, the third TIL population is at least 50 times larger in number than the second TIL population, the second cell culture medium contains IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally a TNFRSF agonist, and the rapid expansion culture is performed for a period of 14 days or less; (e) the step of recovering the third TIL group; and (f) A step of administering the therapeutically effective portion of a third TIL population to a patient with cancer, wherein IL-21 is present in the first cell culture medium. This provides a method that includes [something].

[0117]

[0117] In one embodiment, the present invention treats cancer in a tumor-infiltrating lymphocyte (TIL) population. A method of placement, (a) The step of removing the tumor from the patient; (b) Steps to obtain a first TIL population from the tumor; (c) A step of obtaining a second TIL population by performing an initial expansion culture of a first TIL population in a first cell culture medium, wherein the second TIL population is at least five times larger in number than the first TIL population, the first cell culture medium contains IL-2, at least one adenosine 2A receptor (A2aR) antagonist and a tumor necrosis factor receptor superfamily (TNFRSF) agonist, and the initial expansion culture is performed for a period of 21 days or less. Step; (d) A step of obtaining a third TIL population by performing rapid expansion culture of a second TIL population in a second cell culture medium, wherein seven days after the start of rapid expansion culture, the third TIL population is at least 50 times larger in number than the second TIL population, the second cell culture medium contains IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally a TNFRSF agonist, and the rapid expansion culture is performed for a period of 14 days or less; (e) the step of recovering the third TIL group; and (f) A step of administering the therapeutically effective portion of a third TIL population to a patient with cancer, wherein IL-21 is present in the first cell culture medium at an initial concentration of about 5 ng / mL to about 20 ng / mL. This provides a method that includes [something].

[0118]

[0118] In one embodiment, the present invention treats cancer in a tumor-infiltrating lymphocyte (TIL) population. A method of placement, (a) The step of removing the tumor from the patient; (b) Steps to obtain a first TIL population from the tumor; (c) A step of obtaining a second TIL population by performing an initial expansion culture of a first TIL population in a first cell culture medium, wherein the second TIL population is at least five times larger in number than the first TIL population, the first cell culture medium contains IL-2, at least one adenosine 2A receptor (A2aR) antagonist and a tumor necrosis factor receptor superfamily (TNFRSF) agonist, and the initial expansion culture is performed for a period of 21 days or less; (d) A step of obtaining a third TIL population by performing rapid expansion culture of a second TIL population in a second cell culture medium, wherein seven days after the start of rapid expansion culture, the third TIL population is at least 50 times larger in number than the second TIL population, the second cell culture medium contains IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally a TNFRSF agonist, and the rapid expansion culture is performed for a period of 14 days or less; (e) the step of recovering the third TIL group; and (f) A step of administering the therapeutically effective portion of a third TIL population to a patient with cancer, wherein IL-21 is present in a second cell culture medium. This provides a method that includes [something].

[0119]

[0119] In one embodiment, the present invention treats cancer in a tumor-infiltrating lymphocyte (TIL) population. A method of placement, (a) The step of removing the tumor from the patient; (b) Steps to obtain a first TIL population from the tumor; (c) A step of obtaining a second TIL population by performing an initial expansion culture of a first TIL population in a first cell culture medium, wherein the second TIL population is at least five times larger in number than the first TIL population, the first cell culture medium contains IL-2, at least one adenosine 2A receptor (A2aR) antagonist and a tumor necrosis factor receptor superfamily (TNFRSF) agonist, and the initial expansion culture is performed for a period of 21 days or less; (d) A step of obtaining a third TIL population by performing rapid expansion culture of a second TIL population in a second cell culture medium, wherein seven days after the start of rapid expansion culture, the third TIL population is at least 50 times larger in number than the second TIL population, the second cell culture medium contains IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally a TNFRSF agonist, and the rapid expansion culture is performed for a period of 14 days or less; (e) the step of recovering the third TIL group; and (f) A step of administering the therapeutically effective portion of a third TIL population to a patient with cancer, wherein IL-21 is present in the second cell culture medium at an initial concentration of approximately 5 ng / mL to approximately 20 ng / mL. This provides a method that includes [something].

[0120]

[0120] In one embodiment, the present invention treats cancer in a tumor-infiltrating lymphocyte (TIL) population. A method of placement, (a) The step of removing the tumor from the patient; (b) Steps to obtain a first TIL population from the tumor; (c) A step of obtaining a second TIL population by performing an initial expansion culture of a first TIL population in a first cell culture medium, wherein the second TIL population is at least five times larger in number than the first TIL population, the first cell culture medium contains IL-2, at least one adenosine 2A receptor (A2aR) antagonist and a tumor necrosis factor receptor superfamily (TNFRSF) agonist, and the initial expansion culture is performed for a period of 21 days or less; (d) A step of obtaining a third TIL population by performing rapid expansion culture of a second TIL population in a second cell culture medium, wherein seven days after the start of rapid expansion culture, the third TIL population is at least 50 times larger in number than the second TIL population, the second cell culture medium contains IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally a TNFRSF agonist, and the rapid expansion culture is performed for a period of 14 days or less; (e) the step of recovering the third TIL group; and (f) A step of administering the therapeutically effective portion of a third TIL population to a patient with cancer, wherein the OKT-3 antibody is present in the second cell culture medium at an initial concentration of approximately 10 ng / mL to approximately 60 ng / mL. This provides a method that includes [something].

[0121]

[0121] In one embodiment, the present invention treats cancer in a tumor-infiltrating lymphocyte (TIL) population. A method of placement, (a) The step of removing the tumor from the patient; (b) Steps to obtain a first TIL population from the tumor; (c) A step of obtaining a second TIL population by performing an initial expansion culture of a first TIL population in a first cell culture medium, wherein the second TIL population is at least five times larger in number than the first TIL population, the first cell culture medium contains IL-2, at least one adenosine 2A receptor (A2aR) antagonist and a tumor necrosis factor receptor superfamily (TNFRSF) agonist, and the initial expansion culture is performed for a period of 21 days or less; (d) A step of obtaining a third TIL population by performing rapid expansion culture of a second TIL population in a second cell culture medium, wherein seven days after the start of rapid expansion culture, the third TIL population is at least 50 times larger in number than the second TIL population, the second cell culture medium contains IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally a TNFRSF agonist, and the rapid expansion culture is performed for a period of 14 days or less; (e) the step of recovering the third TIL group; and (f) A step of administering the therapeutically effective portion of a third TIL population to a patient with cancer, wherein the OKT-3 antibody is present in the second cell culture medium at an initial concentration of approximately 30 ng / mL. This provides a method that includes [something].

[0122]

[0122] In one embodiment, the present invention treats cancer in a tumor-infiltrating lymphocyte (TIL) population. A method of placement, (a) The step of removing the tumor from the patient; (b) Steps to obtain a first TIL population from the tumor; (c) A step of obtaining a second TIL population by performing an initial expansion culture of a first TIL population in a first cell culture medium, wherein the second TIL population is at least five times larger in number than the first TIL population, the first cell culture medium contains IL-2, at least one adenosine 2A receptor (A2aR) antagonist and a tumor necrosis factor receptor superfamily (TNFRSF) agonist, and the initial expansion culture is performed for a period of 21 days or less; (d) A step of obtaining a third TIL population by performing rapid expansion culture of a second TIL population in a second cell culture medium, wherein seven days after the start of rapid expansion culture, the third TIL population is at least 50 times larger in number than the second TIL population, the second cell culture medium contains IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally a TNFRSF agonist, and the rapid expansion culture is performed for a period of 14 days or less; (e) the step of recovering the third TIL group; and (f) A step of administering the therapeutically effective portion of a third TIL population to a patient with cancer, wherein the initial expansion culture is carried out using a gas-permeable container. This provides a method that includes [something].

[0123]

[0123] In one embodiment, the present invention treats cancer in a tumor-infiltrating lymphocyte (TIL) population. A method of placement, (a) The step of removing the tumor from the patient; (b) Steps to obtain a first TIL population from the tumor; (c) A step of obtaining a second TIL population by performing an initial expansion culture of a first TIL population in a first cell culture medium, wherein the second TIL population is at least five times larger in number than the first TIL population, the first cell culture medium contains IL-2, at least one adenosine 2A receptor (A2aR) antagonist and a tumor necrosis factor receptor superfamily (TNFRSF) agonist, and the initial expansion culture is performed for a period of 21 days or less; (d) A step of obtaining a third TIL population by performing rapid expansion culture of a second TIL population in a second cell culture medium, wherein seven days after the start of rapid expansion culture, the third TIL population is at least 50 times larger in number than the second TIL population, the second cell culture medium contains IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally a TNFRSF agonist, and the rapid expansion culture is performed for a period of 14 days or less; (e) the step of recovering the third TIL group; and (f) A step of administering the therapeutically effective portion of a third TIL population to a patient with cancer, wherein rapid expansion culture is carried out using a gas-permeable container. This provides a method that includes [something].

[0124]

[0124] In one embodiment, the present invention treats cancer in a tumor-infiltrating lymphocyte (TIL) population. A method of placement, (a) The step of removing the tumor from the patient; (b) Steps to obtain a first TIL population from the tumor; (c) A step of obtaining a second TIL population by performing an initial expansion culture of the first TIL population in a first cell culture medium, wherein the second TIL population is at least five times larger in number than the first TIL population, and the first cell culture medium contains IL-2, at least one adenosine 2A receptor (A2aR) antagonist and tumor necrosis factor receptor superfamily (TNF The initial expansion culture, containing an RSF agonist, is carried out over a period of 21 days or less; (d) A step of obtaining a third TIL population by performing rapid expansion culture of a second TIL population in a second cell culture medium, wherein seven days after the start of rapid expansion culture, the third TIL population is at least 50 times larger in number than the second TIL population, the second cell culture medium contains IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally a TNFRSF agonist, and the rapid expansion culture is performed for a period of 14 days or less; (e) the step of recovering the third TIL group; and (f) A step of administering the therapeutic active portion of a third TIL population to a patient having cancer, further comprising the step of treating the patient with a non-myeloablative lymphoid depletion regimen prior to administering the third TIL population to the patient. This provides a method that includes [something].

[0125]

[0125] In one embodiment, the present invention treats cancer in a tumor-infiltrating lymphocyte (TIL) population. A method of placement, (a) The step of removing the tumor from the patient; (b) Steps to obtain a first TIL population from the tumor; (c) A step of obtaining a second TIL population by performing an initial expansion culture of a first TIL population in a first cell culture medium, wherein the second TIL population is at least five times larger in number than the first TIL population, the first cell culture medium contains IL-2, at least one adenosine 2A receptor (A2aR) antagonist and a tumor necrosis factor receptor superfamily (TNFRSF) agonist, and the initial expansion culture is performed for a period of 21 days or less; (d) A step of obtaining a third TIL population by performing rapid expansion culture of a second TIL population in a second cell culture medium, wherein seven days after the start of rapid expansion culture, the third TIL population is at least 50 times larger in number than the second TIL population, the second cell culture medium contains IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally a TNFRSF agonist, and the rapid expansion culture is performed for a period of 14 days or less; (e) the step of recovering the third TIL group; and (f) A step of administering the therapeutic active portion of a third TIL population to a patient with cancer, further comprising the step of treating the patient with a non-myeloablative lymphoid depletion regimen prior to administering the third TIL population to the patient, the non-myeloablative lymphoid depletion regimen being 60 mg / m² 2 Administer cyclophosphamide at a daily dose for two days, followed by 25 mg / m². 2 The step includes administering fludarabine at a dose of / day over a period of 5 days. This provides a method that includes [something].

[0126]

[0126] In one embodiment, the present invention treats cancer in a tumor-infiltrating lymphocyte (TIL) population. A method of placement, (a) The step of removing the tumor from the patient; (b) Steps to obtain a first TIL population from the tumor; (c) A step of obtaining a second TIL population by performing an initial expansion culture of a first TIL population in a first cell culture medium, wherein the second TIL population is at least five times larger in number than the first TIL population, the first cell culture medium contains IL-2, at least one adenosine 2A receptor (A2aR) antagonist and a tumor necrosis factor receptor superfamily (TNFRSF) agonist, and the initial expansion culture is performed for a period of 21 days or less; (d) A step of obtaining a third TIL population by performing rapid expansion culture of the second TIL population in a second cell culture medium, wherein seven days after the start of rapid expansion culture, the third TIL population is number In the second TIL population, the second cell culture medium contains at least 50 times more IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally a TNFRSF agonist, and rapid expansion culture is carried out for a period of 14 days or less; step; (e) the step of recovering the third TIL group; and (f) A step of administering the therapeutic active portion of a third TIL population to a patient with cancer, further comprising treating the patient with a tapering IL-2 regimen starting the day following the administration of the third TIL population to the patient, the tapering IL-2 regimen being 18,000,000 IU / m² on day 1. 2 On the second day, the reading was 9,000,000 IU / m³. 2 Furthermore, on the 3rd and 4th days, the levels were 4,500,000 IU / m³. 2 A step containing aldesleukin administered intravenously in the following doses. This provides a method that includes [something].

[0127]

[0127] In one embodiment, the present invention treats cancer in a tumor-infiltrating lymphocyte (TIL) population. A method of placement, (a) The step of removing the tumor from the patient; (b) Steps to obtain a first TIL population from the tumor; (c) A step of obtaining a second TIL population by performing an initial expansion culture of a first TIL population in a first cell culture medium, wherein the second TIL population is at least five times larger in number than the first TIL population, the first cell culture medium contains IL-2, at least one adenosine 2A receptor (A2aR) antagonist and a tumor necrosis factor receptor superfamily (TNFRSF) agonist, and the initial expansion culture is performed for a period of 21 days or less; (d) A step of obtaining a third TIL population by performing rapid expansion culture of a second TIL population in a second cell culture medium, wherein seven days after the start of rapid expansion culture, the third TIL population is at least 50 times larger in number than the second TIL population, the second cell culture medium contains IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally a TNFRSF agonist, and the rapid expansion culture is performed for a period of 14 days or less; (e) the step of recovering the third TIL group; and (f) A step of administering the therapeutically effective portion of a third TIL population to a patient with cancer, further comprising the step of administering the third TIL population to the patient at a dose of 0.10 mg / day to 50 mg / day, followed by treating the patient with pegylated IL-2. This provides a method that includes [something].

[0128]

[0128] In one embodiment, the present invention treats cancer in a tumor-infiltrating lymphocyte (TIL) population. A method of placement, (a) The step of removing the tumor from the patient; (b) Steps to obtain a first TIL population from the tumor; (c) A step of obtaining a second TIL population by performing an initial expansion culture of a first TIL population in a first cell culture medium, wherein the second TIL population is at least five times larger in number than the first TIL population, the first cell culture medium contains IL-2, at least one adenosine 2A receptor (A2aR) antagonist and a tumor necrosis factor receptor superfamily (TNFRSF) agonist, and the initial expansion culture is performed for a period of 21 days or less; (d) A step of obtaining a third TIL population by performing rapid expansion culture of a second TIL population in a second cell culture medium, wherein seven days after the start of rapid expansion culture, the third TIL population is at least 50 times larger in number than the second TIL population, the second cell culture medium contains IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally a TNFRSF agonist, and the rapid expansion culture is performed for a period of 14 days or less; (e) the step of recovering the third TIL group; and (f) A step of administering the therapeutic active portion of a third TIL population to a patient with cancer, further comprising the step of treating the patient with a high-dose IL-2 regimen starting the day following the administration of the third TIL population to the patient. This provides a method that includes [something].

[0129]

[0129] In one embodiment, the present invention treats cancer in a tumor-infiltrating lymphocyte (TIL) population. A method of placement, (a) The step of removing the tumor from the patient; (b) Steps to obtain a first TIL population from the tumor; (c) A step of obtaining a second TIL population by performing an initial expansion culture of a first TIL population in a first cell culture medium, wherein the second TIL population is at least five times larger in number than the first TIL population, the first cell culture medium contains IL-2, at least one adenosine 2A receptor (A2aR) antagonist and a tumor necrosis factor receptor superfamily (TNFRSF) agonist, and the initial expansion culture is performed for a period of 21 days or less; (d) A step of obtaining a third TIL population by performing rapid expansion culture of a second TIL population in a second cell culture medium, wherein seven days after the start of rapid expansion culture, the third TIL population is at least 50 times larger in number than the second TIL population, the second cell culture medium contains IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally a TNFRSF agonist, and the rapid expansion culture is performed for a period of 14 days or less; (e) the step of recovering the third TIL group; and (f) A step of administering the therapeutic active portion of a third TIL population to a patient with cancer, further comprising treating the patient with a high-dose IL-2 regimen, which is initiated the day following the administration of the third TIL population to the patient, the high-dose IL-2 regimen comprising 600,000 or 720,000 IU / kg of aldesleukin or its biosimilar or variant, administered as a 15-minute bolus intravenous infusion every 8 hours up to a tolerable dose. This provides a method that includes [something].

[0130]

[0130] In one embodiment, the present invention treats cancer in a tumor-infiltrating lymphocyte (TIL) population. A method of placement, (a) The step of removing the tumor from the patient; (b) Steps to obtain a first TIL population from the tumor; (c) A step of obtaining a second TIL population by performing an initial expansion culture of a first TIL population in a first cell culture medium, wherein the second TIL population is at least five times larger in number than the first TIL population, the first cell culture medium contains IL-2, at least one adenosine 2A receptor (A2aR) antagonist and a tumor necrosis factor receptor superfamily (TNFRSF) agonist, and the initial expansion culture is performed for a period of 21 days or less; (d) A step of obtaining a third TIL population by performing rapid expansion culture of a second TIL population in a second cell culture medium, wherein seven days after the start of rapid expansion culture, the third TIL population is at least 50 times larger in number than the second TIL population, the second cell culture medium contains IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally a TNFRSF agonist, and the rapid expansion culture is performed for a period of 14 days or less; (e) the step of recovering the third TIL group; and (f) A step of administering the therapeutic active portion of a third TIL population to a patient having cancer, wherein the cancer is selected from the group consisting of melanoma, ovarian cancer, cervical cancer, lung cancer, bladder cancer, breast cancer, head and neck cancer, renal cell carcinoma, acute myeloid leukemia, colorectal cancer, cholangiocarcinoma and sarcoma. This provides a method that includes [something].

[0131]

[0131] In one embodiment, the present invention treats cancer in a tumor-infiltrating lymphocyte (TIL) population. A method of placement, (a) The step of removing the tumor from the patient; (b) Steps to obtain a first TIL population from the tumor; (c) A step of obtaining a second TIL population by performing an initial expansion culture of a first TIL population in a first cell culture medium, wherein the second TIL population is at least five times larger in number than the first TIL population, the first cell culture medium contains IL-2, at least one adenosine 2A receptor (A2aR) antagonist and a tumor necrosis factor receptor superfamily (TNFRSF) agonist, and the initial expansion culture is performed for a period of 21 days or less; (d) A step of obtaining a third TIL population by performing rapid expansion culture of a second TIL population in a second cell culture medium, wherein seven days after the start of rapid expansion culture, the third TIL population is at least 50 times larger in number than the second TIL population, the second cell culture medium contains IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally a TNFRSF agonist, and the rapid expansion culture is performed for a period of 14 days or less; (e) the step of recovering the third TIL group; and (f) A step of administering the therapeutic active portion of a third TIL population to a patient having cancer, wherein the cancer is selected from the group consisting of non-small cell lung cancer (NSCLC), triple-negative breast cancer, double-resistance melanoma and uveal (intraocular) melanoma. This provides a method that includes [something].

[0132]

[0132] In one embodiment, the present invention treats cancer in a tumor-infiltrating lymphocyte (TIL) population. A method of placement, (a) The step of removing the tumor from the patient; (b) Steps to obtain a first TIL population from the tumor; (c) A step of obtaining a second TIL population by performing an initial expansion culture of a first TIL population in a first cell culture medium, wherein the second TIL population is at least five times larger in number than the first TIL population, the first cell culture medium contains IL-2, at least one adenosine 2A receptor (A2aR) antagonist and a tumor necrosis factor receptor superfamily (TNFRSF) agonist, and the initial expansion culture is performed for a period of 21 days or less; (d) A step of obtaining a third TIL population by performing rapid expansion culture of a second TIL population in a second cell culture medium, wherein seven days after the start of rapid expansion culture, the third TIL population is at least 50 times larger in number than the second TIL population, the second cell culture medium contains IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally a TNFRSF agonist, and the rapid expansion culture is performed for a period of 14 days or less; (e) the step of recovering the third TIL group; and (f) A step of administering the therapeutic active portion of a third TIL population to a patient having cancer, further comprising the step of treating the patient with a PD-1 inhibitor or a PD-L1 inhibitor before surgically removing the tumor from the patient. This provides a method that includes [something].

[0133]

[0133] In one embodiment, the present invention treats cancer in a tumor-infiltrating lymphocyte (TIL) population. A method of placement, (a) The step of removing the tumor from the patient; (b) Steps to obtain a first TIL population from the tumor; (c) A step of obtaining a second TIL population by performing an initial expansion culture of a first TIL population in a first cell culture medium, wherein the second TIL population is at least five times larger in number than the first TIL population, the first cell culture medium contains IL-2, at least one adenosine 2A receptor (A2aR) antagonist and a tumor necrosis factor receptor superfamily (TNFRSF) agonist, and the initial expansion culture is performed for a period of 21 days or less; (d) A step of obtaining a third TIL population by performing rapid expansion culture of a second TIL population in a second cell culture medium, wherein seven days after the start of rapid expansion culture, the third TIL population is at least 50 times larger in number than the second TIL population, the second cell culture medium contains IL-2, OKT-3 (anti-CD3 antibody), peripheral blood mononuclear cells (PBMCs), and optionally a TNFRSF agonist, and the rapid expansion culture is performed for a period of 14 days or less; (e) the step of recovering the third TIL group; and (f) A step of administering the therapeutic active portion of a third TIL population to a patient having cancer, further comprising the step of treating the patient with a PD-1 inhibitor or a PD-L1 inhibitor before resecting the tumor from the patient, wherein the PD-1 inhibitor or PD-L1 inhibitor is selected from the group consisting of nivolumab, pembrolizumab, durvalumab, atezolizumab, avelumab and their fragments, derivatives, variants, biosimilars and combinations. This provides a method that includes [something].

[0134]

[0134] In one embodiment, the present invention treats cancer in a tumor-infiltrating lymphocyte (TIL) population. A method of placement, (a) The step of removing the tumor from the patient; (b) Steps to obtain a first TIL population from the tumor; (c) A step of obtaining a second TIL population by performing an initial expansion culture of a first TIL population in a first cell culture medium, wherein the second TIL population is at least five times larger in number than the first TIL population, the first cell culture medium contains IL-2, at least one adenosine 2A receptor (A2aR) antagonist and a tumor necrosis factor receptor superfamily (TNFRSF) agonist, and the initial expansion culture is performed for a period of 21 days or less; (d) A step of obtaining a third TIL population by performing rapid expansion culture of a second TIL population in a second cell culture medium, wherein seven days after the start of rapid expansion culture, the third TIL population is at least 50 times larger in number than the second TIL population, the second cell culture medium contains IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally a TNFRSF agonist, and the rapid expansion culture is performed for a period of 14 days or less; (e) the step of recovering the third TIL group; and (f) A step of administering the therapeutic active portion of a third TIL population to a patient having cancer, further comprising the step of treating the patient with an adenosine 2a receptor (A2aR) antagonist after surgically removing a tumor from the patient. This provides a method that includes [something].

[0135]

[0135] In one embodiment, the present invention treats cancer in a tumor-infiltrating lymphocyte (TIL) population. A method of placement, (a) The step of removing the tumor from the patient; (b) Steps to obtain a first TIL population from the tumor; (c) A step of obtaining a second TIL population by performing an initial expansion culture of the first TIL population in a first cell culture medium, wherein the second TIL population is at least five times larger in number than the first TIL population, and the first cell culture medium contains IL-2, at least one adenosine 2A receptor (A2aR) antagonist and tumor necrosis factor receptor superfamily (TNF The initial expansion culture, containing an RSF agonist, is carried out over a period of 21 days or less; (d) A step of obtaining a third TIL population by performing rapid expansion culture of a second TIL population in a second cell culture medium, wherein seven days after the start of rapid expansion culture, the third TIL population is at least 50 times larger in number than the second TIL population, the second cell culture medium contains IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally a TNFRSF agonist, and the rapid expansion culture is performed for a period of 14 days or less; (e) the step of recovering the third TIL group; and (f) A step of administering the therapeutic active portion of a third TIL population to a patient having cancer, further comprising the step of treating the patient with (1) a PD-1 inhibitor or PD-L1 inhibitor and (2) an adenosine 2A receptor (A2aR) antagonist after surgically removing a tumor from the patient. This provides a method that includes [something].

[0136]

[0136] In one embodiment, the present invention treats cancer in a tumor-infiltrating lymphocyte (TIL) population. A method of placement, (a) The step of removing the tumor from the patient; (b) Steps to obtain a first TIL population from the tumor; (c) A step of obtaining a second TIL population by performing an initial expansion culture of a first TIL population in a first cell culture medium, wherein the second TIL population is at least five times larger in number than the first TIL population, the first cell culture medium contains IL-2, at least one adenosine 2A receptor (A2aR) antagonist and a tumor necrosis factor receptor superfamily (TNFRSF) agonist, and the initial expansion culture is performed for a period of 21 days or less; (d) A step of obtaining a third TIL population by performing rapid expansion culture of a second TIL population in a second cell culture medium, wherein seven days after the start of rapid expansion culture, the third TIL population is at least 50 times larger in number than the second TIL population, the second cell culture medium contains IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally a TNFRSF agonist, and the rapid expansion culture is performed for a period of 14 days or less; (e) the step of recovering the third TIL group; and (f) A step of administering the therapeutic active portion of a third TIL population to a patient having cancer, further comprising the step of treating the patient with a PD-1 inhibitor or PD-L1 inhibitor after resecting the tumor from the patient, wherein the PD-1 inhibitor or PD-L1 inhibitor is selected from the group consisting of nivolumab, pembrolizumab, durvalumab, atezolizumab, avelumab and their fragments, derivatives, variants, biosimilars and combinations. This provides a method that includes [something].

[0137]

[0137] In one embodiment, the present invention treats cancer in a tumor-infiltrating lymphocyte (TIL) population. A method of placement, (a) The step of removing the tumor from the patient; (b) Steps to obtain a first TIL population from the tumor; (c) A step of obtaining a second TIL population by performing an initial expansion culture of a first TIL population in a first cell culture medium, wherein the second TIL population is at least five times larger in number than the first TIL population, the first cell culture medium contains IL-2, at least one adenosine 2A receptor (A2aR) antagonist and a tumor necrosis factor receptor superfamily (TNFRSF) agonist, and the initial expansion culture is performed for a period of 21 days or less; (d) Rapid expansion culture of the second TIL population in the second cell culture medium to produce a third TIL Step 1: Obtaining a population, where 7 days after the start of rapid expansion culture, the third TIL population is at least 50 times larger in number than the second TIL population, the second cell culture medium contains IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally a TNFRSF agonist, and the rapid expansion culture is carried out for a period of 14 days or less; (e) the step of recovering the third TIL group; and (f) A step of administering the therapeutically effective portion of a third TIL population to a patient having cancer, further comprising the step of treating the patient with a PD-1 inhibitor or a PD-L1 inhibitor after administering the third TIL population to the patient. This provides a method that includes [something].

[0138]

[0138] In one embodiment, the present invention treats cancer in a tumor-infiltrating lymphocyte (TIL) population. A method of placement, (a) The step of removing the tumor from the patient; (b) Steps to obtain a first TIL population from the tumor; (c) A step of obtaining a second TIL population by performing an initial expansion culture of a first TIL population in a first cell culture medium, wherein the second TIL population is at least five times larger in number than the first TIL population, the first cell culture medium contains IL-2, at least one adenosine 2A receptor (A2aR) antagonist and a tumor necrosis factor receptor superfamily (TNFRSF) agonist, and the initial expansion culture is performed for a period of 21 days or less; (d) A step of obtaining a third TIL population by performing rapid expansion culture of a second TIL population in a second cell culture medium, wherein seven days after the start of rapid expansion culture, the third TIL population is at least 50 times larger in number than the second TIL population, the second cell culture medium contains IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs), and optionally a TNFRSF agonist, and the rapid expansion culture is performed for a period of 14 days or less; (e) the step of recovering the third TIL group; and (f) A step of administering the therapeutic active portion of a third TIL population to a patient having cancer, further comprising the step of treating the patient with a PD-1 inhibitor or a PD-L1 inhibitor after administering the third TIL population to the patient, wherein the PD-1 inhibitor or PD-L1 inhibitor is selected from the group consisting of nivolumab, pembrolizumab, durvalumab, atezolizumab, avelumab and their fragments, derivatives, variants, biosimilars and combinations. This provides a method that includes [something].

[0139]

[0139] In one embodiment, the present invention prepares a population of tumor-infiltrating lymphocytes (TILs). It is a process for that purpose. (b) Step of obtaining the first TIL group; (c) A step of obtaining a second TIL population by performing an initial expansion culture of a first TIL population in a first cell culture medium, wherein the second TIL population is at least five times larger in number than the first TIL population, the first cell culture medium contains IL-2, at least one adenosine 2A receptor (A2aR) antagonist and a tumor necrosis factor receptor superfamily (TNFRSF) agonist, and the initial expansion culture is performed for a period of 21 days or less; (d) A step of obtaining a third TIL population by performing rapid expansion culture of a second TIL population in a second cell culture medium, wherein seven days after the start of rapid expansion culture, the third TIL population is at least 50 times larger in number than the second TIL population, the second cell culture medium comprises IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs) and optionally a TNFRSF agonist, and the rapid expansion culture is performed for a period of 14 days or less; and (e) Step of recovering the third TIL group It provides a process that includes this.

[0140]

[0140] In one embodiment, the present invention is (b) Step of obtaining the first TIL group; (c) A step of obtaining a second TIL population by performing an initial expansion culture of a first TIL population in a first cell culture medium, wherein the second TIL population is at least five times larger in number than the first TIL population, the first cell culture medium contains IL-2, at least one adenosine 2A receptor (A2aR) antagonist and a tumor necrosis factor receptor superfamily (TNFRSF) agonist, and the initial expansion culture is performed for a period of 21 days or less; (d) A step of obtaining a third TIL population by performing rapid expansion culture of a second TIL population in a second cell culture medium, wherein seven days after the start of rapid expansion culture, the third TIL population is at least 50 times larger in number than the second TIL population, the second cell culture medium comprises IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs) and optionally a TNFRSF agonist, and the rapid expansion culture is performed for a period of 14 days or less; and (e) Step of recovering the third TIL group This provides a population of tumor-infiltrating lymphocytes (TILs) that can be obtained from a process including the following.

[0141]

[0141] In one embodiment, the present invention relates to a TIL population for use in the treatment of cancer. The present invention provides a pharmaceutical composition comprising a tumor-infiltrating lymphocyte (TIL) population for use in the treatment of cancer, wherein the tumor-infiltrating lymphocyte (TIL) population is (b) Step of obtaining the first TIL group; (c) A step of obtaining a second TIL population by performing an initial expansion culture of a first TIL population in a first cell culture medium, wherein the second TIL population is at least five times larger in number than the first TIL population, the first cell culture medium contains IL-2, at least one adenosine 2A receptor (A2aR) antagonist and a tumor necrosis factor receptor superfamily (TNFRSF) agonist, and the initial expansion culture is performed for a period of 21 days or less; (d) A step of obtaining a third TIL population by performing rapid expansion culture of a second TIL population in a second cell culture medium, wherein seven days after the start of rapid expansion culture, the third TIL population is at least 50 times larger in number than the second TIL population, the second cell culture medium comprises IL-2, OKT-3 (anti-CD3 antibody), at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs) and optionally a TNFRSF agonist, and the rapid expansion culture is performed for a period of 14 days or less; and (e) Step of recovering the third TIL group It can be obtained through a process that includes this.

[0142]

[0142] In one embodiment, the first TIL population is obtained from a tumor. In this process, the tumor is first removed from the patient. In one embodiment, the first TIL population is obtained from the tumor removed from the patient. In one embodiment, the TIL population is intended to be administered to a patient with cancer in a therapeutically effective dose.

[0143]

[0143] In one embodiment, the present invention expands the tumor-infiltrating lymphocyte (TIL) population. A method of nourishment, (a) The step of removing the tumor from the patient; (b) Steps to obtain a first TIL population from the tumor; (c) Perform initial expansion culture of the first TIL population in the first cell culture medium to produce the second TIL A step to obtain a population, wherein the second TIL population is at least five times larger in number than the first TIL population, the first cell culture medium contains IL-2, and the initial expansion culture is carried out for a period of 11 days or less; (d) A step of obtaining a third TIL population by performing rapid expansion culture of a second TIL population in a second cell culture medium, wherein seven days after the start of rapid expansion culture, the third TIL population is at least 50 times larger in number than the second TIL population, the second cell culture medium contains IL-2, OKT-3 (anti-CD3) antibody, at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs) and TNFRSF agonist, and the rapid expansion culture is performed for a period of 11 days or less; (e) the step of recovering the third TIL group; and (f) Optionally, cryopreserve a third TIL population in a dimethyl sulfoxide-based medium. This provides a method that includes [something].

[0144]

[0144] In one embodiment, the present invention treats cancer in a tumor-infiltrating lymphocyte (TIL) population. A method of placement, (a) The step of removing the tumor from the patient; (b) Steps to obtain a first TIL population from the tumor; (c) A step of obtaining a second TIL population by performing an initial expansion culture of a first TIL population in a first cell culture medium, wherein the second TIL population is at least five times larger in number than the first TIL population, the first cell culture medium contains IL-2 and at least one adenosine 2A receptor (A2aR) antagonist, and the initial expansion culture is performed for a period of 11 days or less; (d) A step of obtaining a third TIL population by performing rapid expansion culture of a second TIL population in a second cell culture medium, wherein seven days after the start of rapid expansion culture, the third TIL population is at least 50 times larger in number than the second TIL population, the second cell culture medium contains IL-2, OKT-3 (anti-CD3) antibody, at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs) and TNFRSF agonist, and the rapid expansion culture is performed for a period of 11 days or less; (e) the step of recovering the third TIL group; and (f) The step of administering the therapeutically effective portion of the third TIL population to the patient. This provides a method that includes [something].

[0145]

[0145] In one embodiment, the present invention treats cancer in a tumor-infiltrating lymphocyte (TIL) population. A method of placement, (a) The step of removing the tumor from the patient; (b) Steps to obtain a first TIL population from the tumor; (c) A step of obtaining a second TIL population by performing an initial expansion culture of a first TIL population in a first cell culture medium, wherein the second TIL population is at least five times larger in number than the first TIL population, the first cell culture medium contains IL-2 and at least one adenosine 2A receptor (A2aR) antagonist, and the initial expansion culture is performed for a period of 11 days or less; (d) A step of obtaining a third TIL population by performing rapid expansion culture of a second TIL population in a second cell culture medium, wherein seven days after the start of rapid expansion culture, the third TIL population is at least 50 times larger in number than the second TIL population, the second cell culture medium contains IL-2, OKT-3 (anti-CD3) antibody, at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs) and TNFRSF agonist, and the rapid expansion culture is performed for a period of 11 days or less; (e) the step of recovering the third TIL group; and (f) The step of administering the therapeutically effective portion of the third TIL population to the patient. The present invention provides a method in which the TNFRSF agonist is selected from the group consisting of 4-1BB agonists, OX40 agonists, and combinations thereof.

[0146]

[0146] In one embodiment, the present invention treats cancer in a tumor-infiltrating lymphocyte (TIL) population. A method of placement, (a) The step of removing the tumor from the patient; (b) Steps to obtain a first TIL population from the tumor; (c) A step of obtaining a second TIL population by performing an initial expansion culture of a first TIL population in a first cell culture medium, wherein the second TIL population is at least five times larger in number than the first TIL population, the first cell culture medium contains IL-2 and at least one adenosine 2A receptor (A2aR) antagonist, and the initial expansion culture is performed for a period of 11 days or less; (d) A step of obtaining a third TIL population by performing rapid expansion culture of a second TIL population in a second cell culture medium, wherein seven days after the start of rapid expansion culture, the third TIL population is at least 50 times larger in number than the second TIL population, the second cell culture medium contains IL-2, OKT-3 (anti-CD3) antibody, at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs) and TNFRSF agonist, and the rapid expansion culture is performed for a period of 11 days or less; (e) the step of recovering the third TIL group; and (f) The step of administering the therapeutically effective portion of the third TIL population to the patient. Includes, The TNFRSF agonist is selected from the group consisting of 4-1BB agonists, OX40 agonists, and combinations thereof. The present invention provides a method in which a TNFRSF agonist is a 4-1BB agonist, and the 4-1BB agonist is selected from the group consisting of urelumab, utomirumab, EU-101, fusion proteins, and their fragments, derivatives, variants, biosimilars, and combinations.

[0147]

[0147] In one embodiment, the present invention treats cancer in a tumor-infiltrating lymphocyte (TIL) population. A method of placement, (a) The step of removing the tumor from the patient; (b) Steps to obtain a first TIL population from the tumor; (c) A step of obtaining a second TIL population by performing an initial expansion culture of a first TIL population in a first cell culture medium, wherein the second TIL population is at least five times larger in number than the first TIL population, the first cell culture medium contains IL-2 and at least one adenosine 2A receptor (A2aR) antagonist, and the initial expansion culture is performed for a period of 11 days or less; (d) A step of obtaining a third TIL population by performing rapid expansion culture of a second TIL population in a second cell culture medium, wherein seven days after the start of rapid expansion culture, the third TIL population is at least 50 times larger in number than the second TIL population, the second cell culture medium contains IL-2, OKT-3 (anti-CD3) antibody, at least one adenosine 2A receptor (A2aR) antagonist, peripheral blood mononuclear cells (PBMCs) and TNFRSF agonist, and the rapid expansion culture is performed for a period of 11 days or less; (e) the step of recovering the third TIL group; and (f) The step of administering the therapeutically effective portion of the third TIL population to the patient. Includes, The TNFRSF agonist is selected from the group consisting of 4-1BB agonists, OX40 agonists, and combinations thereof. TNFRSF agonists are OX40 agonists, and OX40 agonists include tavorixizumab, GSK3174998, MEDI6469, MEDI6383, MOXR0916, PF-04518600, Creative Biolabs MOM-18455, and their fragments, inducers Selected from the group consisting of conductors, mutants, biosimilars, and combinations, The method provides a concentration of 1 μg / mL to 30 μg / mL of OX4 agonist at the start of step (d).

[0148]

[0148] In one embodiment, the present invention provides a method of any of the embodiments described above. Here, the TNFRSF agonist is present at a concentration of 5 μg / mL to 20 μg / mL at the start of step (d).

[0149]

[0149] In one embodiment, the present invention provides a method from any of the embodiments described above. Here, the TNFRSF agonist is present at a concentration of approximately 10 μg / mL at the start of step (d).

[0150]

[0150] In one embodiment, the present invention provides a method from any of the embodiments described above. Here, the TNFRSF agonist is maintained at a concentration of 1 μg / mL to 30 μg / mL throughout step (d).

[0151]

[0151] In one embodiment, the present invention provides a method from any of the embodiments described above. Here, the TNFRSF agonist is maintained at a concentration of 5 μg / mL to 20 μg / mL throughout step (d).

[0152]

[0152] In one embodiment, the present invention provides a method for any of the embodiments described above. Here, the TNFRSF agonist is maintained at a concentration of approximately 10 μg / mL throughout step (d).

[0153]

[0153] In one embodiment, the present invention provides a method for any of the embodiments described above. Here, one adenosine 2A receptor (A2aR) antagonist is present throughout step (d) at least 1 nM, about 10 nM, about 50 nM, about 60 nM, about 70 nM, about 80 nM, about 85 nM, about 90 nM, about 95 nM, about 100 nM, about 1 uM, about 10 uM, about 25 uM, about 50 uM, about 75 uM, about 80 The concentrations are maintained at approximately uM, 90uM, 100uM, 125uM, 150uM, 175uM, 200uM, 225uM, 250uM, 280uM, 275uM, 290uM, 300uM, less than 500uM, less than 1000uM, less than 2000uM, and around the solubility limit of a specific A2aR antagonist.

[0154]

[0154] In one embodiment, the present invention provides a method from any of the embodiments described above. Here, the third TIL population is CD4 in the second TIL population. + CD8 for TIL + Compared to the TIL reference ratio, CD4 + CD8 for TIL + This shows the increased ratio of TIL. In one embodiment, the increased ratio is selected from the group consisting of at least 1% greater than the reference ratio, at least 2% greater than the reference ratio, at least 5% greater than the reference ratio, at least 10% greater than the reference ratio, at least 15% greater than the reference ratio, at least 20% greater than the reference ratio, at least 25% greater than the reference ratio, at least 30% greater than the reference ratio, at least 35% greater than the reference ratio, at least 40% greater than the reference ratio, at least 45% greater than the reference ratio, and at least 50% greater than the reference ratio. In one embodiment, the increased ratio is 5% to 80% greater than the reference ratio. In one embodiment, the increased ratio is 10% to 70% greater than the reference ratio. In one embodiment, the increased ratio is 15% to 60% greater than the reference ratio. In one of the embodiments described above, the reference ratio is obtained from a third TIL population that is a responder to the TNFRSF agonist.

[0155]

[0155] In one embodiment, the present invention provides a method from any of the embodiments described above. Here, cancers include melanoma, uveal (intraocular) melanoma, ovarian cancer, cervical cancer, lung cancer, bladder cancer, and breast cancer. , selected from the group consisting of head and neck cancer (head and neck squamous cell carcinoma), renal cell carcinoma, colorectal cancer, pancreatic cancer, glioblastoma, cholangiocarcinoma, and sarcoma. In one embodiment, the present invention provides a method according to any of the above embodiments, wherein the cancer is selected from the group consisting of cutaneous melanoma, uveal (intraocular) melanoma, platinum-resistant ovarian cancer, pancreatic ductal adenocarcinoma, osteosarcoma, triple-negative breast cancer, and non-small cell lung cancer.

[0156]

[0156] In one embodiment, any of the above embodiments is replaced with any of the following embodiments It can be combined with that.

[0157]

[0157] In one embodiment, the process is an in vitro or ex vivo process. be.

[0158]

[0158] In one embodiment, the TNFRSF agonist is a 4-1BB agonist, The agonist is selected from the group consisting of OX40 agonists, CD27 agonists, GITR agonists, HVEM agonists, CD95 agonists, and combinations thereof.

[0159]

[0159] In one embodiment, the TNFRSF agonist is a 4-1BB agonist. be.

[0160]

[0160] In one embodiment, the TNFRSF agonist is a 4-1BB agonist. The 4-1BB agonist is selected from the group consisting of urelumab, utomirumab, EU-101, and their fragments, derivatives, variants, biosimilars, and combinations.

[0161]

[0161] In one embodiment, the TNFRSF agonist is a 4-1BB agonist. Yes, and a 4-1BB agonist is a 4-1BB agonist fusion protein.

[0162]

[0162] In one embodiment, the TNFRSF agonist is fused with the 4-1BB agonist. The fusion protein, which is a 4-1BB agonist fusion protein, comprises (i) a first soluble 4-1BB binding domain, (ii) a first peptide linker, (iii) a second soluble 4-1BB binding domain, (iv) a second peptide linker, and (v) a third soluble 4-1BB binding domain, and further comprises additional domains at the N-terminus and / or C-terminus, the additional domains comprising an Fc fragment domain and a hinge domain, and the fusion protein has a dimeric structure according to structure IA or structure IB.

[0163]

[0163] In one embodiment, the TNFRSF agonist is an OX40 agonist. ru.

[0164]

[0164] In one embodiment, the TNFRSF agonist is an OX40 agonist. Furthermore, the OX40 agonist is selected from the group consisting of tavorixizumab, GSK3174998, MEDI6469, MEDI6383, MOXR0916, PF-04518600, Creative Biolabs MOM-18455, and their fragments, derivatives, variants, biosimilars, and combinations.

[0165]

[0165] In one embodiment, the TNFRSF agonist is an OX40 agonist. Furthermore, OX40 agonists are OX40 agonist fusion proteins.

[0166]

[0166] In one embodiment, the TNFRSF agonist is fused with the OX40 agonist. A protein that is also an OX40 agonist fusion protein comprises (i) a first soluble OX40 binding domain, (ii) a first peptide linker, (iii) a second soluble OX40 binding domain, (iv) a second peptide linker, and (v) a third soluble OX40 binding domain. The fusion protein contains a domain, further containing additional domains at the N-terminus and / or C-terminus, the additional domains comprising an Fc fragment domain and a hinge domain, and the fusion protein has a dimeric structure according to structure IA or structure IB.

[0167]

[0167] In one embodiment, the TNFRSF agonist is a CD27 agonist. ru.

[0168]

[0168] In one embodiment, the TNFRSF agonist is a CD27 agonist. Furthermore, the CD27 agonist is valrirumab or a fragment, derivative, variant, or biosimilar thereof.

[0169]

[0169] In one embodiment, the TNFRSF agonist is a CD27 agonist. Furthermore, CD27 agonists are CD27 agonist fusion proteins.

[0170]

[0170] In one embodiment, the TNFRSF agonist is a CD27 agonist. Furthermore, the CD27 agonist fusion protein comprises (i) a first soluble CD27 binding domain, (ii) a first peptide linker, (iii) a second soluble CD27 binding domain, (iv) a second peptide linker, and (v) a third soluble CD27 binding domain, and further comprises additional domains at the N-terminus and / or C-terminus, the additional domains comprising an Fc fragment domain and a hinge domain, and the fusion protein has a dimeric structure according to structure IA or structure IB.

[0171]

[0171] In one embodiment, the TNFRSF agonist is a GITR agonist. ru.

[0172]

[0172] In one embodiment, the TNFRSF agonist is a GITR agonist. Furthermore, the GITR agonist is selected from the group consisting of TRX518, 6C8, 36E5, 3D6, 61G6, 6H6, 61F6, 1D8, 17F10, 35D8, 49A1, 9E5, 31H6, 2155, 698, 706, 827, 1649, 1718, 1D7, 33C9, 33F6, 34G4, 35B10, 41E11, 41G5, 42A11, 44C1, 45A8, 46E11, 48H12, 48H7, 49D9, 49E2, 48A9, 5H7, 7A10, 9H6 and their fragments, derivatives, variants, biosimilars and combinations.

[0173]

[0173] In one embodiment, the TNFRSF agonist is a GITR agonist. Furthermore, GITR agonists are GITR agonist fusion proteins.

[0174]

[0174] In one embodiment, the TNFRSF agonist is fused with the GITR agonist. A protein that is also a GITR agonist fusion protein comprises (i) a first soluble GITR binding domain, (ii) a first peptide linker, (iii) a second soluble GITR binding domain, (iv) a second peptide linker, and (v) a third soluble GITR binding domain, further comprising additional domains at the N-terminus and / or C-terminus, the additional domains comprising an Fc fragment domain and a hinge domain, and the fusion protein has a dimeric structure according to structure IA or structure IB.

[0175]

[0175] In one embodiment, the TNFRSF agonist is an HVEM agonist. ru.

[0176]

[0176] In one embodiment, the TNFRSF agonist is an HVEM agonist. Furthermore, HVEM agonists are HVEM agonist fusion proteins.

[0177]

[0177] In one embodiment, the TNFRSF agonist is fused with the HVEM agonist. A protein and HVEM agonist fusion protein comprises (i) a first soluble HVEM binding domain, (ii) a first peptide linker, (iii) a second soluble HVEM binding domain, (iv) a second peptide linker, and (v) a third soluble HVEM binding domain, further comprising additional domains at the N-terminus and / or C-terminus, the additional domains comprising an Fc fragment domain and a hinge domain, and the fusion protein has a dimeric structure according to structure IA or structure IB.

[0178]

[0178] In one embodiment, the TNFRSF agonist is urelumab, utomirma The selection is made from the group consisting of , EU-101, tavorixizumab, Creative Biolabs MOM-18455, and their fragments, derivatives, variants, biosimilars, and combinations.

[0179]

[0179] In one embodiment, the first cell culture medium is the second TNFRSF agonis Includes "t".

[0180]

[0180] In one embodiment, the TNFRSF agonist is used daily during the initial expansion culture. It is added to the first cell culture medium at intervals selected from the group consisting of every 2 days, every 3 days, every 4 days, every 5 days, every 6 days, every 7 days, and every 2 weeks.

[0181]

[0181] In one embodiment, the TNFRSF agonist is used daily during rapid expansion culture. It is added to the second cell culture medium at intervals selected from the group consisting of every 2 days, every 3 days, every 4 days, every 5 days, every 6 days, every 7 days, and every 2 weeks.

[0182]

[0182] In one embodiment, the TNFRSF agonist is in the cell culture medium. It is added at a concentration sufficient to achieve a concentration of 0.1 μg / mL to 100 μg / mL.

[0183]

[0183] In one embodiment, the TNFRSF agonist is in the cell culture medium. It is added at a concentration sufficient to achieve a concentration of 20 μg / mL to 40 μg / mL.

[0184]

[0184] Further details of the TNFRSF agonist are provided herein.

[0185]

[0185] In one embodiment, IL-2 is added to the first cell culture medium in a quantity of about 10 to about 60 It is present at an initial concentration of 00 IU / mL.

[0186]

[0186] In one embodiment, IL-2 is added in a first cell culture medium at a concentration of approximately 3000 IU. It exists at an initial concentration of / mL.

[0187]

[0187] In one embodiment, IL-2 is added to the first cell culture medium at a concentration of approximately 800 IU / It is present at an initial concentration of approximately 1100 IU / mL.

[0188]

[0188] In one embodiment, IL-2 is added in a first cell culture medium at a concentration of approximately 1000 IU. It exists at an initial concentration of / mL.

[0189]

[0189] In one embodiment, IL-2 is added to the second cell culture medium in a quantity of about 10 to 60 units. It is present at an initial concentration of 00 IU / mL.

[0190]

[0190] In one embodiment, IL-2 is added in a second cell culture medium at a concentration of approximately 3000 IU. It exists at an initial concentration of / mL.

[0191]

[0191] In one embodiment, IL-2 is added to the second cell culture medium at a concentration of approximately 800 IU / It is present at an initial concentration of approximately 1100 IU / mL.

[0192]

[0192] In one embodiment, IL-2 is added in a second cell culture medium at a concentration of approximately 1000 IU. It exists at an initial concentration of / mL.

[0193]

[0193] In one embodiment, IL-15 is present in the first cell culture medium.

[0194]

[0194] In one embodiment, IL-15 is added to the first cell culture medium at a concentration of approximately 5 ng / m³. It is present at an initial concentration of approximately 20 ng / mL per L.

[0195]

[0195] In one embodiment, IL-15 is present in a second cell culture medium.

[0196]

[0196] In one embodiment, IL-15 is added to the second cell culture medium at a concentration of approximately 5 ng / m³. It is present at an initial concentration of approximately 20 ng / mL per L.

[0197]

[0197] In one embodiment, IL-21 is present in a first cell culture medium.

[0198]

[0198] In one embodiment, IL-21 is added to the first cell culture medium at a concentration of approximately 5 ng / m³. It is present at an initial concentration of approximately 20 ng / mL per L.

[0199]

[0199] In one embodiment, IL-21 is present in a second cell culture medium.

[0200]

[0200] In one embodiment, IL-21 is added to the second cell culture medium at a concentration of approximately 5 ng / m³. It is present at an initial concentration of approximately 20 ng / mL per L.

[0201]

[0201] In one embodiment, the OKT-3 antibody is added to the second cell culture medium at a concentration of approximately 10 nucleotides. It exists at an initial concentration of g / mL to approximately 60 ng / mL.

[0202]

[0202] In one embodiment, the OKT-3 antibody is added to the second cell culture medium in a quantity of approximately 30 nucleotides. It exists at an initial concentration of g / mL.

[0203]

[0203] In one embodiment, initial expansion culture is carried out using a gas-permeable container. ru.

[0204]

[0204] In one embodiment, rapid expansion culture is carried out using a gas-permeable container. ru.

[0205]

[0205] In one embodiment, the present invention relates to tumor infiltration for use in the treatment of cancer. A population of tumor-infiltrating lymphocytes (TILs) is provided, which can be obtained by the process of the present invention as described herein.

[0206]

[0206] In one embodiment, the present invention relates to a method for treating cancer. The present invention provides a pharmaceutical composition comprising a tumor-infiltrating lymphocyte (TIL) population, wherein the tumor-infiltrating lymphocyte (TIL) population can be obtained by a process of the present invention as described herein.

[0207]

[0207] In one embodiment, the TIL group and / or pharmaceutical composition is TNFRSF and It is intended for use in combination cancer treatments.

[0208]

[0208] In one embodiment, the present invention is described herein as a prototyping of the present invention. This provides a combination of TIL populations obtainable by Seth and TNFRSF for use in cancer treatment.

[0209]

[0209] In one embodiment, the TIL group and / or pharmaceutical composition is TNFRSF For use in the treatment of cancer in combination with a gonist, the TNFRSF agonist is to be administered the day after the administration of the third TIL population to the patient, and the TNFRSF agonist is administered intravenously at doses of 0.1 mg / kg to 50 mg / kg every four weeks for up to eight cycles.

[0210]

[0210] In one embodiment, the TIL group and / or pharmaceutical composition is TNFRSF This is intended for use in the treatment of cancer in combination with a gonist, where the TNFRSF agonist is to be administered prior to the step of tumor resection from the patient, and the TNFRSF agonist is to be administered intravenously at doses of 0.1 mg / kg to 50 mg / kg every 4 weeks for up to 8 cycles.

[0211]

[0211] In one embodiment, the TIL population and / or pharmaceutical composition is a non-myeloablative lithotripsy It is intended for use in the treatment of cancer in combination with a cytoplasmic rehydration regimen.

[0212]

[0212] In one embodiment, the TIL group and / or pharmaceutical composition is a third TIL group This is intended for use in the treatment of cancer in combination with a non-myeloablative lymphoid depletion regimen prior to administration of a pharmaceutical composition containing the group and / or a third TIL group to the patient.

[0213]

[0213] In one embodiment, the TIL group and / or pharmaceutical composition is a third TIL group This is for use in the treatment of cancer in combination with a non-myeloablative lymphoid depletion regimen prior to administration to the patient of a pharmaceutical composition containing the group and / or a third TIL group, wherein the non-myeloablative lymphoid depletion regimen is 60 mg / m². 2 Administer cyclophosphamide at a daily dose for two days, followed by 25 mg / m². 2The procedure includes administering fludarabine at a dose of / day over a period of 5 days. Further details of the non-myeloablative lymphodepletion regimen are provided herein, for example, under the heading "Non-myeloablative lymphodepletion by chemotherapy."

[0214]

[0214] In one embodiment, the TIL group and / or pharmaceutical composition is IL-2 regimen It is intended for use in the treatment of cancer in combination with [another substance].

[0215]

[0215] In one embodiment, the IL-2 regimen is a tapering IL-2 regimen. .

[0216]

[0216] In one embodiment, the TIL group and / or pharmaceutical composition is a third TIL group This is intended for use in the treatment of cancer in combination with a tapering IL-2 regimen, which is initiated the day after administration of a pharmaceutical composition containing the group and / or a third TIL group to the patient, where the tapering IL-2 regimen is 18,000,000 IU / m³ on day 1. 2 On the second day, the reading was 9,000,000 IU / m³. 2 Furthermore, on the 3rd and 4th days, the levels were 4,500,000 IU / m³. 2 Contains aldezleukin administered intravenously at the specified dose.

[0217]

[0217] In one embodiment, the TIL group and / or pharmaceutical composition is pegylated IL-2 It is intended for use in combination with other cancer treatments.

[0218]

[0218] In one embodiment, the TIL group and / or pharmaceutical composition is 0.10 mg / At a dose of 50 mg / day, the third TIL population and / or medical patients including the third TIL population This is intended for use in a method of treating cancer in combination with pegylated IL-2, which is administered to the patient after the drug composition has been administered.

[0219]

[0219] In one embodiment, the TIL group and / or pharmaceutical composition is high dose IL-2 It is intended for use in methods of treating cancer in combination with regimens.

[0220]

[0220] In one embodiment, the TIL group and / or pharmaceutical composition is a third TIL group It is intended for use in a method of treating cancer in combination with a high-dose IL-2 regimen initiated the day after administering a pharmaceutical composition containing the group and / or a third TIL group to the patient.

[0221]

[0221] In one embodiment, the TIL group and / or pharmaceutical composition is a third TIL group For use in the treatment of cancer in combination with a high-dose IL-2 regimen initiated the day following administration of a pharmaceutical composition containing the group and / or a third TIL group to the patient, wherein the high-dose IL-2 regimen comprises 600,000 or 720,000 IU / kg of aldesleukin or its biosimilar or variant, administered as a 15-minute bolus intravenous infusion every 8 hours up to a tolerable dose.

[0222]

[0222] In one embodiment, the TIL group and / or pharmaceutical composition is used in the treatment of cancer. It is intended for use in which cancer is selected from the group consisting of melanoma, ovarian cancer, cervical cancer, lung cancer, bladder cancer, breast cancer, head and neck cancer, renal cell carcinoma, acute myeloid leukemia, colorectal cancer, bile duct cancer, and sarcoma.

[0223]

[0223] In one embodiment, the TIL group and / or pharmaceutical composition is used in the treatment of cancer. For use in this regard, cancer is selected from the group consisting of non-small cell lung cancer (NSCLC), triple-negative breast cancer, double-resistance melanoma, and uveal (intraocular) melanoma.

[0224]

[0224] In one embodiment, the TIL population and / or pharmaceutical composition is a PD-1 inhibitor Alternatively, it is intended for use in the treatment of cancer in combination with PD-L1 inhibitors.

[0225]

[0225] In one embodiment, the TIL population and / or pharmaceutical composition is a PD-1 inhibitor Alternatively, it may be used in combination with a PD-L1 inhibitor for the treatment of cancer, where the PD-1 inhibitor or PD-L1 inhibitor is selected from the group consisting of nivolumab, pembrolizumab, durvalumab, atezolizumab, avelumab, and their fragments, derivatives, variants, biosimilars, and combinations.

[0226]

[0226] In one embodiment, the TIL population and / or pharmaceutical composition is a PD-1 inhibitor Alternatively, it is intended for use in the treatment of cancer in combination with a PD-L1 inhibitor, where the PD-1 inhibitor or PD-L1 inhibitor is to be administered before the tumor is removed from the patient.

[0227]

[0227] In one embodiment, the TIL population and / or pharmaceutical composition remove tumors from patients For use in combination with a PD-1 inhibitor or PD-L1 inhibitor prior to resection of cancer, wherein the PD-1 inhibitor or PD-L1 inhibitor is selected from the group consisting of nivolumab, pembrolizumab, durvalumab, atezolizumab, avelumab, and their fragments, derivatives, variants, biosimilars, and combinations.

[0228]

[0228] In one embodiment, the TIL population and / or pharmaceutical composition is a PD-1 inhibitor Alternatively, it is intended for use in methods of treating cancer in combination with PD-L1 inhibitors.

[0229]

[0229] In one embodiment, the TIL population and / or pharmaceutical composition is a PD-1 inhibitor Alternatively, it may be used in combination with a PD-L1 inhibitor for the treatment of cancer, where the PD-1 inhibitor or PD-L1 inhibitor is selected from the group consisting of nivolumab, pembrolizumab, durvalumab, atezolizumab, avelumab, and their fragments, derivatives, variants, biosimilars, and combinations.

[0230]

[0230] In one embodiment, the TIL population and / or pharmaceutical composition remove tumors from patients It is intended for use in methods of treating cancer after resection, in combination with PD-1 inhibitors or PD-L1 inhibitors.

[0231]

[0231] In one embodiment, the TIL population and / or pharmaceutical composition remove tumors from patients For use in combination with a PD-1 inhibitor or PD-L1 inhibitor after resection of cancer, wherein the PD-1 inhibitor or PD-L1 inhibitor is selected from the group consisting of nivolumab, pembrolizumab, durvalumab, atezolizumab, avelumab, and their fragments, derivatives, variants, biosimilars, and combinations.

[0232]

[0232] In one embodiment, the TIL population and / or pharmaceutical composition is a PD-1 inhibitor Alternatively, it is intended for use in the treatment of cancer in combination with a PD-L1 inhibitor, where the PD-1 or PD-L1 inhibitor is intended for administration to the patient after administration of a pharmaceutical composition containing a third TIL population and / or a third TIL population.

[0233]

[0233] In one embodiment, a TIL group and / or pharmaceutical composition is used to deliver a third T to a patient. For use in the treatment of cancer in combination with a PD-1 inhibitor or PD-L1 inhibitor for administration after administration of the IL population, wherein the PD-1 inhibitor or PD-L1 inhibitor is selected from the group consisting of nivolumab, pembrolizumab, durvalumab, atezolizumab, avelumab and their fragments, derivatives, variants, biosimilars and combinations. Further details of the PD-1 inhibitor and PD-L1 inhibitor are described herein, for example, under the heading "Combinations with PD-1 and PD-L1 Inhibitors". In some embodiments, the TIL population and / or pharmaceutical composition containing the TIL population further includes one or more features as described herein, for example, under the headings "Pharmaceutical Compositions, Dosages and Dosage Regimen of TIL" and "Pharmaceutical Compositions, Dosages and Dosage Regimen of TNFRSF Agonists".

[0234] Brief explanation of the drawing

[0234] The above summary and the following detailed description of the invention should be read in conjunction with the attached drawings. It will be better understood. [Brief explanation of the drawing]

[0235] [Figure 1]

[0235] The TIL expansion culture and treatment process is illustrated. The A2AR antagonist (labeled "A2AR" in Figure 1) or TNFRSF agonist of the present invention can be used in both the pre-REP stage (upper half of the figure) or the REP stage (lower half of the figure) and can be added when IL-2 is added to each cell culture. Step 1 refers to the addition of approximately 4 tumor fragments to 10 G-Rex 10 flasks. In Step 2, approximately 40 × 10⁶ TILs or more are obtained. In Step 3, the fragmentation into 36 G-Rex 100 flasks occurs for REP. In Step 4, the TILs are recovered by centrifugation. The fresh TIL product is obtained in Step 5 after a total process time of approximately 43 days, at which point the TILs can be injected into the patient. [Figure 2]

[0236] This disclosure provides a treatment protocol for use with TILs grown with the A2AR antagonist. The TNFRSF agonist may be used in treatment as described herein, either after administration of TILs or during the expansion culture process. [Figure 3]

[0237] An exemplary TIL expansion culture and manufacturing protocol (Process 2A) is shown. [Figure 4]

[0238] The steps of an exemplary method performed in Process 2A are shown below. [Figure 5]

[0239] An exemplary TIL expansion culture protocol is shown. [Figure 6]

[0240] This study evaluates the binding affinity to Creative Biolabs (CB) and BPS Biosciences (BPS) 4-1BB agonist antibodies, as assessed by the percentage of 4-1BB+ cells obtained by flow cytometry. The CB 4-1BB agonist showed the highest binding affinity. [Figure 7]

[0241] This shows the binding affinity to Creative Biolabs (CB) and BPS Biosciences (BPS) 4-1BB agonist antibodies, evaluated by mean fluorescence intensity (MFI). The CB 4-1BB agonist showed the highest binding affinity. [Figure 8]

[0242] The results of the evaluation of NF-κB pathway activation by anti-4-1BB agonist antibodies are shown. [Figure 9]

[0243] This indicates the binding affinity to the Creative Biolabs OX40 agonist antibody, as assessed by the percentage of OX40+ cells obtained by flow cytometry. [Figure 10]

[0244] This indicates the binding affinity to the Creative Biolabs OX40 agonist antibody, as evaluated by mean fluorescence intensity (MFI). [Figure 11]

[0245] Creative Biolabs anti-OX40 agonist antibody (at the five concentrations shown) exhibits equivalent binding affinity to the commercially available anti-OX40 (clone Ber-ACT35) agonist. The first letter of each tumor name indicates histology: C=cervix; H=head and neck (head and neck squamous cell carcinoma); L=lung; and M=melanoma. [Figure 12]

[0246] The results of the evaluation of NF-κB pathway activation by anti-OX40 agonist antibodies are presented. OX40 reporter cells were treated for 24 hours with either anti-OX40 alone or an isotype control at concentrations of 1, 2, 4, 8, and 16 μg / mL, with or without PBMC feeder cells. The cells were lysed using a one-step luciferase reagent, and luciferase activity was measured using a luminometer. [Figure 13]

[0247] This document presents the experimental design for experiments using 4-1BB and OX40 agonists during the pre-REP phase. [Figure 14]

[0248] The tumor histology used in the experimental design shown in Figure 23 is presented. [Figure 15]

[0249] This document presents a data analysis strategy used to evaluate the impact of 4-1BB and anti-OX40 agonists used during pre-REP on TIL performance and characteristics. [Figure 16]

[0250] The results for total cell count in cell expansion cultures using CB 4-1BB agonist are shown (N=3). NT = no test (control). The p-value was >0.99. [Figure 17]

[0251] The results for total cell count in cell expansion cultures using CB OX40 agonist are shown (N=5). NT=not tested (control). The p-value was 0.06. [Figure 18]

[0252] The results for total cell count in cell expansion cultures using CB 4-1BB agonist and OX-40 agonist are shown (N=2). NT = No test (control). [Figure 19]

[0253] The results for the total CD8+ cell count in cell expansion cultures using CB 4-1BB agonist are shown (N=3). The p-value was 0.5. [Figure 20]

[0254] The results for total CD8+ cell count in cell expansion cultures using CB OX40 agonist are shown (N=5). The p-value was 0.03. [Figure 21]

[0255] The results for total CD8+ cell counts in cell expansion cultures using CB 4-1BB agonist and OX-40 agonist are shown (N=2). NT = not tested (control). [Figure 22]

[0256] The results for the total CD8+ / CD4+ cell count ratio in cell expansion cultures using CB 4-1BB agonist are shown (N=3). The p-value was 0.2. [Figure 23]

[0257] The results for the total CD8+ / CD4+ cell count ratio in cell expansion cultures using CB OX40 agonist are shown (N=5). The p-value was 0.12. [Figure 24]

[0258] The results for the total CD8+ / CD4+ cell count ratio in cell expansion cultures using CB 4-1BB agonist and OX-40 agonist are shown (N=2). NT = not tested (control). [Figure 25]

[0259] The experimental scheme for REP proliferation of pre-REP TILs cultured in the presence of 4-1BB or OX40 agonist is shown. [Figure 26]

[0260] This shows the magnification factor of pre-REP TILs cultured in the presence of CB 4-1BB agonist compared to TILs not treated with pre-REP(NT), and TILs cultured with REP. [Figure 27]

[0261] This shows the magnification factor of pre-REP TILs cultured in the presence of CB OX40 agonist compared to TILs not treated with pre-REP(NT), and TILs cultured with REP. [Figure 28]

[0262] This shows the magnification factor of pre-REP TILs cultured in the presence of CB 4-1BB agonist and CB OX40 agonist compared to TILs not treated with pre-REP(NT), and TILs cultured with REP. [Figure 29]

[0263] Histology of 21 TIL strains used for evaluation of CB OX40 agonists during the REP phase is shown. [Figure 30]

[0264] This document presents an experimental scheme for evaluating CB OX40 agonists during the REP phase. [Figure 31]

[0265] The presence of the OX40 agonist antibody indicates that CD8+ TILs are preferentially expanded during REP (shown as a percentage of CD3+CD4+ cells). [Figure 32]

[0266] The presence of the OX40 agonist antibody indicates that CD8+ TILs are preferentially expanded during REP (shown as a percentage of CD3+CD8+ cells). [Figure 33]

[0267] This indicates that in non-responder TIL lines, no downregulation of OX40 was observed in the CD4+ subset after anti-OX40 treatment. [Figure 34]

[0268] This document presents experimental details of CB OX40 agonist dose titration in non-responder and responder TIL systems. [Figure 35]

[0269] The results of CB OX40 agonist dose titration in the Responder TIL system are shown. [Figure 36]

[0270] The results of CB OX40 agonist dose titration in non-responder TIL systems are shown. [Figure 37]

[0271] This shows a comparable TCRvb repertoire profile for the responder L4005. [Figure 38]

[0272] This shows a comparable TCRvb repertoire profile for responder H3005. [Figure 39]

[0273] This shows a comparable TCRvb repertoire profile for the M1022 responder. [Figure 40]

[0274] The cell count results for melanoma TILs obtained after the addition of A2AR antagonists to pre-REP and REP cultures under various conditions are shown. [Figure 41]

[0275] The cell count results for lung TILs (first tumors) obtained after the addition of A2AR antagonists to pre-REP and REP cultures under various conditions are shown. [Figure 42]

[0276] The cell count results for lung TILs (secondary tumors) obtained after the addition of A2AR antagonists to pre-REP and REP cultures under various conditions are shown. [Figure 43]

[0277] Flow cytometry analysis of CD8+ and CD4+ subsets of melanoma TILs obtained after the addition of A2AR antagonists to pre-REP and REP cultures under various conditions is shown. [Figure 44]

[0278] Flow cytometry analysis of CD8+ and CD4+ subsets of pulmonary TILs (primary tumors) obtained after the addition of A2AR antagonists to pre-REP and REP cultures under various conditions is shown. [Figure 45]

[0279] Flow cytometry analysis of CD8+ and CD4+ subsets of pulmonary TILs (secondary tumors) obtained after the addition of A2AR antagonists to pre-REP and REP cultures under various conditions is shown. [Figure 46]

[0280] The results of ELISA and ELIspot obtained from melanoma TILs after the addition of A2AR antagonists to pre-REP and REP cultures under various conditions are shown. [Figure 47]

[0281] The results of ELISA and ELIspot obtained from lung TILs (first tumors) after the addition of A2AR antagonists to pre-REP and REP cultures under various conditions are shown. [Figure 48]

[0282] The results of ELISA and ELIspot obtained from lung TILs (secondary tumors) after the addition of A2AR antagonists to pre-REP and REP cultures under various conditions are shown. [Figure 49]

[0283] This disclosure provides a treatment protocol for use with TILs grown with the A2AR antagonist. The TNFRSF agonist may be used in treatment as described herein, either after administration of TILs or during the expansion culture process. [Modes for carrying out the invention]

[0236] A brief explanation of sequence listings

[0284] Sequence ID 1 is the amino acid sequence of the heavy chain of muromonab.

[0285] Sequence ID 2 is the amino acid sequence of the light chain of muromonab.

[0286] Sequence ID 3 is the amino acid sequence of recombinant human IL-2 protein.

[0287] Sequence ID 4 is the amino acid sequence of aldethleukin.

[0288] Sequence ID 5 is the amino acid sequence of recombinant human IL-4 protein.

[0289] Sequence ID 6 is the amino acid sequence of recombinant human IL-7 protein.

[0290] Sequence ID 7 is the amino acid sequence of recombinant human IL-15 protein.

[0291] Sequence ID 8 is the amino acid sequence of recombinant human IL-21 protein.

[0292] Sequence ID 9 is the amino acid sequence of human 4-1BB.

[0293] Sequence ID 10 is the amino acid sequence of mouse 4-1BB.

[0294] Sequence ID 11 is utomirumab, a 4-1BB agonist monoclonal antibody. This is the heavy chain of PF-05082566.

[0295] Sequence ID 12 is utomirumab, a 4-1BB agonist monoclonal antibody. This is a light chain (PF-05082566).

[0296] Sequence ID 13 is utomirumab, a 4-1BB agonist monoclonal antibody. This is the heavy-chain variable region (VH) of PF-05082566.

[0297] Sequence ID 14 is a 4-1BB agonist monoclonal antibody, utomirumab. This is the light chain variable region (VL) of PF-05082566.

[0298] Sequence ID 15 is utomirumab, a 4-1BB agonist monoclonal antibody. This is the heavy-chain CDR1 of PF-05082566.

[0299] Sequence ID 16 is a 4-1BB agonist monoclonal antibody, utomirumab. This is the heavy-chain CDR2 of PF-05082566.

[0300] Sequence ID 17 is a 4-1BB agonist monoclonal antibody, utomirumab. This is the heavy-chain CDR3 of PF-05082566.

[0301] Sequence ID 18 is a 4-1BB agonist monoclonal antibody, utomirumab. This is the light chain CDR1 of PF-05082566.

[0302] Sequence ID 19 is a 4-1BB agonist monoclonal antibody, utomirumab. This is the light chain CDR2 of PF-05082566.

[0303] Sequence ID No. 20 is a 4-1BB agonist monoclonal antibody, utomirumab. This is the light chain CDR3 of PF-05082566.

[0304] Sequence ID 21 is a 4-1BB agonist monoclonal antibody, urelumab (B This is the heavy chain of MS-663513.

[0305] Sequence ID 22 is a 4-1BB agonist monoclonal antibody, urelumab (B This is a light chain (MS-663513).

[0306] Sequence ID 23 is a 4-1BB agonist monoclonal antibody, urelumab (B This is the heavy-chain variable region (VH) of MS-663513.

[0307] Sequence ID No. 24 is a 4-1BB agonist monoclonal antibody, urelumab (B This is the light chain variable region (VL) of MS-663513.

[0308] Sequence ID 25 is a 4-1BB agonist monoclonal antibody, urelumab (B This is the heavy-chain CDR1 of MS-663513.

[0309] Sequence ID 26 is a 4-1BB agonist monoclonal antibody, urelumab (B This is the heavy-chain CDR2 of MS-663513.

[0310] Sequence ID 27 is a 4-1BB agonist monoclonal antibody, urelumab (B This is the heavy-chain CDR3 of MS-663513.

[0311] Sequence ID No. 28 is a 4-1BB agonist monoclonal antibody, urelumab (B This is the light chain CDR1 of MS-663513.

[0312] Sequence ID 29 is a 4-1BB agonist monoclonal antibody, urelumab (B This is the light chain CDR2 of MS-663513.

[0313] Sequence ID 30 is a 4-1BB agonist monoclonal antibody, urelumab (B This is the light chain CDR3 of MS-663513.

[0314] Sequence ID 31 is the Fc domain of the TNFRSF agonist fusion protein. be.

[0315] Sequence ID 32 is the linker of the TNFRSF agonist fusion protein. .

[0316] Sequence ID 33 is the linker of the TNFRSF agonist fusion protein. .

[0317] Sequence ID 34 is the linker of the TNFRSF agonist fusion protein. .

[0318] Sequence ID 35 is the linker of the TNFRSF agonist fusion protein. .

[0319] Sequence ID 36 is the linker of the TNFRSF agonist fusion protein. .

[0320] Sequence ID 37 is the linker of the TNFRSF agonist fusion protein. .

[0321] Sequence ID 38 is the linker of the TNFRSF agonist fusion protein. .

[0322] Sequence ID 39 is the linker of the TNFRSF agonist fusion protein. .

[0323] Sequence ID 40 is the linker of the TNFRSF agonist fusion protein. .

[0324] Sequence ID 41 is the linker of the TNFRSF agonist fusion protein. .

[0325] Sequence ID 42 is the Fc domain of the TNFRSF agonist fusion protein. be.

[0326] Sequence ID 43 is the linker of the TNFRSF agonist fusion protein. .

[0327] Sequence ID 44 is the linker of the TNFRSF agonist fusion protein. .

[0328] Sequence ID 45 is the linker of the TNFRSF agonist fusion protein. .

[0329] Sequence ID 46 is the amino acid sequence of the 4-1BB ligand (4-1BBL). .

[0330] Sequence ID No. 47 is the soluble portion of the 4-1BBL polypeptide.

[0331] Sequence ID 48 is a 4-1BB agonist antibody, version 1 of 4B4-1-1. This is the heavy chain variable region (VH).

[0332] Sequence ID 49 is for the 4-1BB agonist antibody 4B4-1-1 version 1. This is the light chain variable region (VL).

[0333] Sequence ID 50 is a 4-1BB agonist antibody, version 2 of 4B4-1-1. This is the heavy chain variable region (VH).

[0334] Sequence ID 51 is for the 4-1BB agonist antibody 4B4-1-1 version 2. This is the light chain variable region (VL).

[0335] Sequence ID 52 is the heavy chain variable region of the 4-1BB agonist antibody H39E3-2. (VH)

[0336] Sequence ID 53 is the light chain variable region of the 4-1BB agonist antibody H39E3-2. (VL)

[0337] Sequence ID 54 is the amino acid sequence of human OX40.

[0338] Sequence ID 55 is the amino acid sequence of mouse OX40.

[0339] Sequence ID No. 56 is tavorixizumab, an OX40 agonist monoclonal antibody. This is the heavy chain of (MEDI-0562).

[0340] Sequence ID No. 57 is tavorixizumab, an OX40 agonist monoclonal antibody. This is the light chain of (MEDI-0562).

[0341] Sequence ID No. 58 is tavorixizumab, an OX40 agonist monoclonal antibody. This is the heavy chain variable region (VH) of (MEDI-0562).

[0342] Sequence ID No. 59 is tavorixizumab, an OX40 agonist monoclonal antibody. This is the light chain variable region (VL) of (MEDI-0562).

[0343] SEQ ID NO: 60 is tavorixizumab, an OX40 agonist monoclonal antibody. This is the heavy-chain CDR1 of (MEDI-0562).

[0344] Sequence ID No. 61 is tavorixizumab, an OX40 agonist monoclonal antibody. This is the heavy-chain CDR2 of (MEDI-0562).

[0345] Sequence ID No. 62 is tavorixizumab, an OX40 agonist monoclonal antibody. This is the heavy-chain CDR3 of (MEDI-0562).

[0346] Sequence ID No. 63 is tavorixizumab, an OX40 agonist monoclonal antibody. This is the light chain CDR1 of (MEDI-0562).

[0347] Sequence ID No. 64 is tavorixizumab, an OX40 agonist monoclonal antibody. This is the light chain CDR2 of (MEDI-0562).

[0348] Sequence ID No. 65 is tavorixizumab, an OX40 agonist monoclonal antibody. This is the light chain CDR3 of (MEDI-0562).

[0349] Sequence ID 66 is the heavy chain of the OX40 agonist monoclonal antibody 11D4. be.

[0350] Sequence ID 67 is the light chain of the OX40 agonist monoclonal antibody 11D4. be.

[0351] SEQ ID NO: 68 is a heavy chain of the OX40 agonist monoclonal antibody 11D4. This is a variable region (VH).

[0352] Sequence ID 69 is a light chain oxidative of the OX40 agonist monoclonal antibody 11D4. It is a variable region (VL).

[0353] SEQ ID NO: 70 is the heavy chain C of the OX40 agonist monoclonal antibody 11D4. It's DR1.

[0354] SEQ ID NO: 71 is the heavy chain C of the OX40 agonist monoclonal antibody 11D4. It's DR2.

[0355] SEQ ID NO: 72 is the heavy chain C of the OX40 agonist monoclonal antibody 11D4. It's DR3.

[0356] SEQ ID NO: 73 is the light chain C of the OX40 agonist monoclonal antibody 11D4. It's DR1.

[0357] SEQ ID NO: 74 is the light chain C of the OX40 agonist monoclonal antibody 11D4. It's DR2.

[0358] SEQ ID NO: 75 is the light chain C of the OX40 agonist monoclonal antibody 11D4. It's DR3.

[0359] Sequence ID 76 is the heavy chain of the OX40 agonist monoclonal antibody 18D8. be.

[0360] Sequence ID 77 is the light chain of the OX40 agonist monoclonal antibody 18D8. be.

[0361] SEQ ID NO: 78 is a heavy chain of the OX40 agonist monoclonal antibody 18D8. This is a variable region (VH).

[0362] Sequence ID 79 is a light chain assay for the OX40 agonist monoclonal antibody 18D8. It is a variable region (VL).

[0363] SEQ ID NO: 80 is the heavy chain C of the OX40 agonist monoclonal antibody 18D8. It's DR1.

[0364] SEQ ID NO: 81 is the heavy chain C of the OX40 agonist monoclonal antibody 18D8. It's DR2.

[0365] SEQ ID NO: 82 is the heavy chain C of the OX40 agonist monoclonal antibody 18D8. It's DR3.

[0366] Sequence ID 83 is the light chain C of the OX40 agonist monoclonal antibody 18D8. It's DR1.

[0367] SEQ ID NO: 84 is the light chain C of the OX40 agonist monoclonal antibody 18D8. It's DR2.

[0368] SEQ ID NO: 85 is the light chain C of the OX40 agonist monoclonal antibody 18D8. It's DR3.

[0369] Sequence ID 86 is an OX40 agonist monoclonal antibody, Hu119-12 This is the heavy chain variable region (VH) of 2.

[0370] Sequence ID 87 is an OX40 agonist monoclonal antibody, Hu119-12 This is the variable light chain region (VL) of 2.

[0371] Sequence ID 88 is an OX40 agonist monoclonal antibody, Hu119-12 This is a heavy-chain CDR1 of type 2.

[0372] Sequence ID 89 is an OX40 agonist monoclonal antibody, Hu119-12 This is a heavy-chain CDR2 of type 2.

[0373] Sequence ID 90 is an OX40 agonist monoclonal antibody, Hu119-12 It is a heavy-chain CDR3 of type 2.

[0374] Sequence ID 91 is an OX40 agonist monoclonal antibody, Hu119-12 It is a light chain CDR1 of type 2.

[0375] Sequence ID 92 is an OX40 agonist monoclonal antibody, Hu119-12 It is a light chain CDR2 of type 2.

[0376] Sequence ID 93 is an OX40 agonist monoclonal antibody, Hu119-12 It is a light chain CDR3 of type 2.

[0377] Sequence ID 94 is an OX40 agonist monoclonal antibody, Hu106-22. This is the heavy chain variable region (VH) of 2.

[0378] Sequence ID 95 is an OX40 agonist monoclonal antibody, Hu106-22. This is the variable light chain region (VL) of 2.

[0379] Sequence ID 96 is an OX40 agonist monoclonal antibody, Hu106-22. This is a heavy-chain CDR1 of type 2.

[0380] Sequence ID 97 is an OX40 agonist monoclonal antibody, Hu106-22. This is a heavy-chain CDR2 of type 2.

[0381] Sequence ID 98 is an OX40 agonist monoclonal antibody, Hu106-22. It is a heavy-chain CDR3 of type 2.

[0382] Sequence ID 99 is an OX40 agonist monoclonal antibody, Hu106-22. It is a light chain CDR1 of type 2.

[0383] Sequence ID No. 100 is an OX40 agonist monoclonal antibody, Hu106-2 It is a light chain CDR2 with 22 units.

[0384] Sequence ID 101 is an OX40 agonist monoclonal antibody, Hu106-2 It is a 22-unit light chain CDR3.

[0385] Sequence ID 102 is the amino acid sequence of the OX40 ligand (OX40L).

[0386] Sequence ID No. 103 is the soluble portion of the OX40L polypeptide.

[0387] Sequence ID No. 104 is an alternative soluble moiety of the OX40L polypeptide.

[0388] SEQ ID NO: 105 is a heavy chain of OX40 agonist monoclonal antibody 008. This is a variable region (VH).

[0389] Sequence ID 106 is a light chain capacitating agent of OX40 agonist monoclonal antibody 008. It is a variable region (VL).

[0390] Sequence ID 107 is a heavy chain of OX40 agonist monoclonal antibody 011. This is a variable region (VH).

[0391] Sequence ID 108 is a light chain of OX40 agonist monoclonal antibody 011. It is a variable region (VL).

[0392] SEQ ID NO: 109 is a heavy chain of OX40 agonist monoclonal antibody 021. This is a variable region (VH).

[0393] Sequence ID 110 is a light chain oxidizer for OX40 agonist monoclonal antibody 021. It is a variable region (VL).

[0394] Sequence ID 111 is a heavy chain of OX40 agonist monoclonal antibody 023. This is a variable region (VH).

[0395] Sequence ID 112 is a light chain of OX40 agonist monoclonal antibody 023. It is a variable region (VL).

[0396] Sequence ID 113 is the heavy chain variable region of the OX40 agonist monoclonal antibody. (VH)

[0397] Sequence ID 114 is the light chain variable region of the OX40 agonist monoclonal antibody. (VL)

[0398] Sequence ID 115 is the heavy chain variable region of the OX40 agonist monoclonal antibody. (VH)

[0399] Sequence ID 116 is the light chain variable region of the OX40 agonist monoclonal antibody. (VL)

[0400] Sequence ID 117 is a heavy chain of humanized OX40 agonist monoclonal antibody. This is a variable region (VH).

[0401] SEQ ID NO: 118 is a heavy chain-capable humanized OX40 agonist monoclonal antibody. This is a variable region (VH).

[0402] Sequence ID 119 is a light chain antibody for humanized OX40 agonist monoclonal antibody. It is a variable region (VL).

[0403] Sequence ID No. 120 is a light chain antibody for humanized OX40 agonist monoclonal antibody. It is a variable region (VL).

[0404] Sequence ID 121 is a heavy chain of humanized OX40 agonist monoclonal antibody. This is a variable region (VH).

[0405] Sequence ID 122 is a heavy chain of humanized OX40 agonist monoclonal antibody. This is a variable region (VH).

[0406] Sequence ID 123 is a light chain of a humanized OX40 agonist monoclonal antibody. It is a variable region (VL).

[0407] Sequence ID 124 is a light chain antibody of a humanized OX40 agonist monoclonal antibody. It is a variable region (VL).

[0408] Sequence ID 125 is the heavy chain variable region of the OX40 agonist monoclonal antibody. (VH)

[0409] Sequence ID 126 is the light chain variable region of the OX40 agonist monoclonal antibody. (VL)

[0410] Sequence ID 127 is the amino acid sequence of human CD27.

[0411] Sequence ID 128 is the amino acid sequence of macaque CD27.

[0412] Sequence ID 129 is the heavy chain of the CD27 agonist monoclonal antibody varylumab (CDX-1127).

[0413] Sequence ID 130 is the light chain of the CD27 agonist monoclonal antibody varylumab (CDX-1127).

[0414] Sequence ID 131 is the heavy chain variable region (V) of the CD27 agonist monoclonal antibody varylumab (CDX-1127). H )

[0415] Sequence ID 132 is the light chain variable region (V) of the CD27 agonist monoclonal antibody varylumab (CDX-1127). L )

[0416] Sequence ID 133 is the heavy chain CDR1 of the CD27 agonist monoclonal antibody varrilumab (CDX-1127).

[0417] Sequence ID 134 is the heavy chain CDR2 of the CD27 agonist monoclonal antibody varrilumab (CDX-1127).

[0418] Sequence ID 135 is the heavy chain CDR3 of the CD27 agonist monoclonal antibody varrilumab (CDX-1127).

[0419] Sequence ID 136 is the light chain CDR1 of the CD27 agonist monoclonal antibody varrilumab (CDX-1127).

[0420] Sequence ID 137 is the light chain CDR2 of the CD27 agonist monoclonal antibody varrilumab (CDX-1127).

[0421] Sequence ID 138 is the light chain CDR3 of the CD27 agonist monoclonal antibody varrilumab (CDX-1127).

[0422] Sequence ID 139 is the amino acid sequence of the CD27 ligand (CD70).

[0423] Sequence ID 140 is the soluble portion of the CD70 polypeptide.

[0424] Sequence ID 141 is an alternative soluble moiety of the CD70 polypeptide.

[0425] Sequence ID 142 is human GITR (human tumor necrosis factor receptor superfamiliar This is the amino acid sequence of the Remember 18 (TNFRSF18) protein.

[0426] Sequence ID 143 is mouse GITR (mouse tumor necrosis factor receptor superfluid). This is the amino acid sequence of Family Member 18 (TNFRSF18 protein).

[0427] Sequence ID 144 corresponds to Sequence ID 60 of U.S. Patent No. 7,812,135. This is the amino acid sequence of HuN6C8 (glycosylated), a heavy chain variant of the 6C8 humanized GITR agonist monoclonal antibody that has N (asparagine) in CDR2.

[0428] Sequence ID 145 corresponds to Sequence ID 61 of U.S. Patent No. 7,812,135. This is the amino acid sequence of HuN6C8 (non-glycosylated), a heavy chain variant of the 6C8 humanized GITR agonist monoclonal antibody that has N (asparagine) in CDR2.

[0429] Sequence ID 146 corresponds to Sequence ID 62 of U.S. Patent No. 7,812,135. This is the amino acid sequence of HuQ6C8 (glycosylated), a heavy chain mutant of the 6C8 humanized GITR agonist monoclonal antibody that has Q (glutamine) in CDR2.

[0430] Sequence ID 147 corresponds to Sequence ID 63 of U.S. Patent No. 7,812,135. This is the amino acid sequence of HuQ6C8 (non-glycosylated), a heavy chain mutant of a 6C8 humanized GITR agonist monoclonal antibody that has Q (glutamine) in CDR2.

[0431] Sequence ID 148 corresponds to Sequence ID 58 of U.S. Patent No. 7,812,135. This is the amino acid sequence of the light chain of a 6C8 humanized GITR agonist monoclonal antibody.

[0432] Sequence ID No. 149 is the sequence number for GITR agonist monoclonal antibodies. This is a leader sequence amino acid sequence that may be optionally included along with the amino acid sequences of sequence number 144, sequence number 145, sequence number 146, or sequence number 147.

[0433] Sequence ID No. 150 is the sequence number for GITR agonist monoclonal antibodies. The amino acid sequence of the leader sequence, which may be included by optional selection along with the amino acid sequence of number 148. That is the case.

[0434] Sequence ID 151 corresponds to Sequence ID 1 of U.S. Patent No. 7,812,135. This is the amino acid sequence of the heavy chain variable region of a 6C8 humanized GITR agonist monoclonal antibody.

[0435] Sequence ID 152 corresponds to Sequence ID 66 of U.S. Patent No. 7,812,135. This is the amino acid sequence of the heavy chain variable region of a 6C8 humanized GITR agonist monoclonal antibody.

[0436] Sequence ID 153 corresponds to Sequence ID 2 of U.S. Patent No. 7,812,135. This is the amino acid sequence of the light chain variable region of a 6C8 humanized GITR agonist monoclonal antibody.

[0437] Sequence ID 154 corresponds to Sequence ID 3 of U.S. Patent No. 7,812,135. This is the amino acid sequence of the heavy chain CDR1 region of a 6C8 humanized GITR agonist monoclonal antibody.

[0438] Sequence ID 155 corresponds to Sequence ID 4 of U.S. Patent No. 7,812,135. This is the amino acid sequence of the heavy chain CDR2 region of a 6C8 humanized GITR agonist monoclonal antibody.

[0439] Sequence ID 156 corresponds to Sequence ID 19 of U.S. Patent No. 7,812,135. This is the amino acid sequence of the heavy chain CDR2 region of a 6C8 humanized GITR agonist monoclonal antibody.

[0440] Sequence ID 157 corresponds to Sequence ID 5 of U.S. Patent No. 7,812,135. This is the amino acid sequence of the heavy chain CDR3 region of a 6C8 humanized GITR agonist monoclonal antibody.

[0441] Sequence ID 158 corresponds to Sequence ID 6 of U.S. Patent No. 7,812,135. This is the amino acid sequence of the heavy chain CDR1 region of a 6C8 humanized GITR agonist monoclonal antibody.

[0442] Sequence ID 159 corresponds to Sequence ID 7 of U.S. Patent No. 7,812,135. This is the amino acid sequence of the heavy chain CDR2 region of a 6C8 humanized GITR agonist monoclonal antibody.

[0443] Sequence ID 160 corresponds to Sequence ID 8 of U.S. Patent No. 7,812,135. This is the amino acid sequence of the heavy chain CDR3 region of a 6C8 humanized GITR agonist monoclonal antibody.

[0444] Sequence ID 161 corresponds to Sequence ID 23 of U.S. Patent No. 7,812,135. This is the amino acid sequence of HuN6C8 (glycosylated), a heavy chain mutant of a 6C8 chimeric GITR agonist monoclonal antibody that has N (asparagine) in CDR2.

[0445] Sequence ID 162 corresponds to Sequence ID 24 of U.S. Patent No. 7,812,135. This is the amino acid sequence of HuQ6C8 (non-glycosylated), a heavy chain mutant of a 6C8 chimeric GITR agonist monoclonal antibody that has Q (glutamine) in CDR2.

[0446] Sequence ID 163 corresponds to Sequence ID 22 of U.S. Patent No. 7,812,135. This is the amino acid sequence of the light chain of a 6C8 chimeric GITR agonist monoclonal antibody.

[0447] Sequence ID 164 is a GITR agonist under U.S. Patent No. 8,709,424. This is the amino acid sequence of the 36E5 heavy chain variable region.

[0448] Sequence ID No. 165 is a GITR agonist under U.S. Patent No. 8,709,424. This is the amino acid sequence of the 36E5 light chain variable region.

[0449] Sequence ID No. 166 is a GITR agonist under U.S. Patent No. 8,709,424. This is the amino acid sequence of the 3D6 heavy chain variable region.

[0450] Sequence ID No. 167 is a GITR agonist under U.S. Patent No. 8,709,424. This is the amino acid sequence of the 3D6 light chain variable region.

[0451] Sequence ID No. 168 is a GITR agonist under U.S. Patent No. 8,709,424. This is the amino acid sequence of the 61G6 heavy chain variable region.

[0452] Sequence ID 169 is a GITR agonist under U.S. Patent No. 8,709,424. This is the amino acid sequence of the 61G6 light chain variable region.

[0453] Sequence ID No. 170 is a GITR agonist under U.S. Patent No. 8,709,424. This is the amino acid sequence of the 6H6 heavy chain variable region.

[0454] Sequence ID No. 171 is a GITR agonist under U.S. Patent No. 8,709,424. This is the amino acid sequence of the 6H6 light chain variable region.

[0455] Sequence ID 172 is a GITR agonist under U.S. Patent No. 8,709,424. This is the amino acid sequence of the 61F6 heavy chain variable region.

[0456] Sequence ID No. 173 is a GITR agonist under U.S. Patent No. 8,709,424. This is the amino acid sequence of the 61F6 light chain variable region.

[0457] Sequence ID No. 174 is a GITR agonist under U.S. Patent No. 8,709,424. This is the amino acid sequence of the 1D8 heavy chain variable region.

[0458] Sequence ID No. 175 is a GITR agonist under U.S. Patent No. 8,709,424. This is the amino acid sequence of the 1D8 light chain variable region.

[0459] Sequence ID No. 176 is a GITR agonist under U.S. Patent No. 8,709,424. This is the amino acid sequence of the 17F10 heavy chain variable region.

[0460] Sequence ID No. 177 is a GITR agonist under U.S. Patent No. 8,709,424. This is the amino acid sequence of the 17F10 light chain variable region.

[0461] Sequence ID No. 178 is a GITR agonist under U.S. Patent No. 8,709,424. This is the amino acid sequence of the 35D8 heavy chain variable region.

[0462] Sequence ID No. 179 is a GITR agonist under U.S. Patent No. 8,709,424. This is the amino acid sequence of the 35D8 light chain variable region.

[0463] Sequence ID No. 180 is a GITR agonist under U.S. Patent No. 8,709,424. This is the amino acid sequence of the 49A1 heavy chain variable region.

[0464] Sequence ID No. 181 is a GITR agonist under U.S. Patent No. 8,709,424. This is the amino acid sequence of the 49A1 light chain variable region.

[0465] Sequence ID 182 is a GITR agonist under U.S. Patent No. 8,709,424. This is the amino acid sequence of the 9E5 heavy chain variable region.

[0466] Sequence ID 183 is a GITR agonist under U.S. Patent No. 8,709,424. This is the amino acid sequence of the 9E5 light chain variable region.

[0467] Sequence ID 184 is a GITR agonist under U.S. Patent No. 8,709,424. This is the amino acid sequence of the 31H6 heavy chain variable region.

[0468] Sequence ID No. 185 is a GITR agonist under U.S. Patent No. 8,709,424. This is the amino acid sequence of the 31H6 light chain variable region.

[0469] Sequence ID No. 186 is a humanized GITR jaw, U.S. Patent No. 8,709,424. This is the amino acid sequence of the 36E5 heavy chain variable region.

[0470] Sequence ID No. 187 is a humanized GITR jaw, U.S. Patent No. 8,709,424. This is the amino acid sequence of the 36E5 light chain variable region.

[0471] Sequence ID No. 188 is a humanized GITR jaw, U.S. Patent No. 8,709,424. This is the amino acid sequence of the nist3D6 heavy chain variable region.

[0472] Sequence ID No. 189 is a humanized GITR jaw, U.S. Patent No. 8,709,424. This is the amino acid sequence of the nist3D6 light chain variable region.

[0473] Sequence ID No. 190 is a humanized GITR jaw, U.S. Patent No. 8,709,424. This is the amino acid sequence of the 61G6 heavy chain variable region.

[0474] Sequence ID No. 191 is a humanized GITR jaw, U.S. Patent No. 8,709,424. This is the amino acid sequence of the 61G6 light chain variable region.

[0475] Sequence ID No. 192 is a humanized GITR jaw, U.S. Patent No. 8,709,424. This is the amino acid sequence of the nist 6H6 heavy chain variable region.

[0476] Sequence ID No. 193 is a humanized GITR jaw, U.S. Patent No. 8,709,424. This is the amino acid sequence of the nist 6H6 light chain variable region.

[0477] Sequence ID No. 194 is a humanized GITR jaw, U.S. Patent No. 8,709,424. This is the amino acid sequence of the nist61F6 heavy chain variable region.

[0478] Sequence ID No. 195 is a humanized GITR jaw, U.S. Patent No. 8,709,424. This is the amino acid sequence of the nisto 61F6 light chain variable region.

[0479] Sequence ID No. 196 is a humanized GITR jaw, U.S. Patent No. 8,709,424. This is the amino acid sequence of the 1D8 heavy chain variable region.

[0480] Sequence ID No. 197 is a humanized GITR jaw, U.S. Patent No. 8,709,424. This is the amino acid sequence of the 1D8 light chain variable region.

[0481] Sequence ID No. 198 is a humanized GITR jaw, U.S. Patent No. 8,709,424. This is the amino acid sequence of the nist 17F10 heavy chain variable region.

[0482] Sequence ID No. 199 is a humanized GITR jaw, U.S. Patent No. 8,709,424. This is the amino acid sequence of the variable region of the light chain of Nist17F10.

[0483] Sequence ID No. 200 is a humanized GITR jaw, U.S. Patent No. 8,709,424. This is the amino acid sequence of the 35D8 heavy chain variable region.

[0484] Sequence ID No. 201 is a humanized GITR jaw, U.S. Patent No. 8,709,424. This is the amino acid sequence of the nist35D8 light chain variable region.

[0485] Sequence ID No. 202 is a humanized GITR jaw, U.S. Patent No. 8,709,424. This is the amino acid sequence of the nist49A1 heavy chain variable region.

[0486] Sequence ID No. 203 is a humanized GITR jaw, U.S. Patent No. 8,709,424. This is the amino acid sequence of the nist49A1 light chain variable region.

[0487] Sequence ID No. 204 is a humanized GITR jaw, U.S. Patent No. 8,709,424. This is the amino acid sequence of the 9E5 heavy chain variable region.

[0488] Sequence ID No. 205 is a humanized GITR jaw, U.S. Patent No. 8,709,424. This is the amino acid sequence of the 9E5 light chain variable region.

[0489] Sequence ID No. 206 is a humanized GITR jaw, U.S. Patent No. 8,709,424. This is the amino acid sequence of the 31H6 heavy chain variable region.

[0490] Sequence ID No. 207 is a humanized GITR jaw, U.S. Patent No. 8,709,424. This is the amino acid sequence of the 31H6 light chain variable region.

[0491] Sequence ID No. 208 corresponds to U.S. Patent Application Publication No. 2013 / 0108641 A1. This is the amino acid sequence of the GITR agonist 2155 variable heavy chain.

[0492] Sequence ID No. 209 corresponds to U.S. Patent Application Publication No. 2013 / 0108641 A1. This is the amino acid sequence of the GITR agonist 2155 variable light chain.

[0493] Sequence ID No. 210 corresponds to U.S. Patent Application Publication No. 2013 / 0108641 A1. This is the amino acid sequence of the GITR agonist 2155 humanized (HC1) heavy chain.

[0494] Sequence ID No. 211 corresponds to U.S. Patent Application Publication No. 2013 / 0108641 A1. This is the amino acid sequence of the GITR agonist 2155 humanized (HC2) heavy chain.

[0495] Sequence ID No. 212 corresponds to U.S. Patent Application Publication No. 2013 / 0108641 A1. This is the amino acid sequence of the heavy chain of the GITR agonist 2155 humanized (HC3a).

[0496] Sequence ID No. 213 corresponds to U.S. Patent Application Publication No. 2013 / 0108641 A1. This is the amino acid sequence of the humanized (HC3b) GITR agonist heavy chain.

[0497] Sequence ID No. 214 corresponds to U.S. Patent Application Publication No. 2013 / 0108641 A1. This is the amino acid sequence of the humanized (HC4) GITR agonist heavy chain.

[0498] Sequence ID No. 215 corresponds to U.S. Patent Application Publication No. 2013 / 0108641 A1. This is the amino acid sequence of the 2155 humanized (LC1) GITR agonist light chain.

[0499] Sequence ID No. 216 corresponds to U.S. Patent Application Publication No. 2013 / 0108641 A1. This is the amino acid sequence of the 2155 humanized (LC2a) GITR agonist light chain.

[0500] Sequence ID No. 217 corresponds to U.S. Patent Application Publication No. 2013 / 0108641 A1. This is the amino acid sequence of the 2155 humanized (LC2b) GITR agonist light chain.

[0501] Sequence ID No. 218 corresponds to U.S. Patent Application Publication No. 2013 / 0108641 A1. This is the amino acid sequence of the 2155 humanized (LC3) GITR agonist light chain.

[0502] Sequence ID No. 219 corresponds to U.S. Patent Application Publication No. 2013 / 0108641 A1. This is the amino acid sequence of the GITR agonist 698 variable heavy chain.

[0503] Sequence ID No. 220 corresponds to U.S. Patent Application Publication No. 2013 / 0108641 A1. This is the amino acid sequence of the GITR agonist 698 variable light chain.

[0504] Sequence ID No. 221 corresponds to U.S. Patent Application Publication No. 2013 / 0108641 A1. This is the amino acid sequence of the GITR agonist 706 variable heavy chain.

[0505] Sequence ID No. 222 corresponds to U.S. Patent Application Publication No. 2013 / 0108641 A1. This is the amino acid sequence of the GITR agonist 706 variable light chain.

[0506] Sequence ID No. 223 corresponds to U.S. Patent Application Publication No. 2013 / 0108641 A1. This is the amino acid sequence of the GITR agonist 827 variable heavy chain.

[0507] Sequence ID No. 224 corresponds to U.S. Patent Application Publication No. 2013 / 0108641 A1. This is the amino acid sequence of the GITR agonist 827 variable light chain.

[0508] Sequence ID No. 225 corresponds to U.S. Patent Application Publication No. 2013 / 0108641 A1. This is the amino acid sequence of the GITR agonist 1718 variable heavy chain.

[0509] Sequence ID No. 226 corresponds to U.S. Patent Application Publication No. 2013 / 0108641 A1. This is the amino acid sequence of the GITR agonist 1718 variable light chain.

[0510] Sequence ID No. 227 corresponds to U.S. Patent Application Publication No. 2013 / 0108641 A1. This is the amino acid sequence of the GITR agonist 2155 heavy chain CDR3.

[0511] Sequence ID No. 228 corresponds to U.S. Patent Application Publication No. 2013 / 0108641 A1. This is the amino acid sequence of the GITR agonist 2155 heavy chain CDR2.

[0512] Sequence ID No. 229 corresponds to U.S. Patent Application Publication No. 2013 / 0108641 A1. This is the amino acid sequence of the GITR agonist 2155 heavy chain CDR1.

[0513] Sequence ID No. 230 corresponds to U.S. Patent Application Publication No. 2013 / 0108641 A1. This is the amino acid sequence of the GITR agonist 2155 light chain CDR3.

[0514] Sequence ID No. 231 corresponds to U.S. Patent Application Publication No. 2013 / 0108641 A1. This is the amino acid sequence of the GITR agonist 2155 light chain CDR2.

[0515] Sequence ID No. 232 corresponds to U.S. Patent Application Publication No. 2013 / 0108641 A1. This is the amino acid sequence of the GITR agonist 2155 light chain CDR1.

[0516] Sequence ID No. 233 corresponds to U.S. Patent Application Publication No. 2013 / 0108641 A1. These are the amino acid sequences of the GITR agonists 698 and 706 heavy chain CDR3.

[0517] Sequence ID No. 234 corresponds to U.S. Patent Application Publication No. 2013 / 0108641 A1. These are the amino acid sequences of the GITR agonists 698 and 706 heavy chain CDR2.

[0518] Sequence ID No. 235 corresponds to U.S. Patent Application Publication No. 2013 / 0108641 A1. These are the amino acid sequences of the GITR agonists 698 and 706 heavy chain CDR1.

[0519] Sequence ID No. 236 corresponds to U.S. Patent Application Publication No. 2013 / 0108641 A1. This is the amino acid sequence of the GITR agonist 698 light chain CDR3.

[0520] Sequence ID No. 237 corresponds to U.S. Patent Application Publication No. 2013 / 0108641 A1. These are the amino acid sequences of the GITR agonists 698, 706, 827, and 1649 light chain CDR2.

[0521] Sequence ID No. 238 corresponds to U.S. Patent Application Publication No. 2013 / 0108641 A1. These are the amino acid sequences of the GITR agonists 698, 706, 827, and 1649 light chain CDR1.

[0522] Sequence ID No. 239 corresponds to U.S. Patent Application Publication No. 2013 / 0108641 A1. These are the amino acid sequences of the GITR agonists 706, 827, and 1649 light chain CDR3.

[0523] Sequence ID No. 240 corresponds to U.S. Patent Application Publication No. 2013 / 0108641 A1. These are the amino acid sequences of the GITR agonist 827 and the 1649 heavy chain CDR3.

[0524] Sequence ID No. 241 corresponds to U.S. Patent Application Publication No. 2013 / 0108641 A1. This is the amino acid sequence of the GITR agonist 827 heavy chain CDR2.

[0525] Sequence ID No. 242 corresponds to U.S. Patent Application Publication No. 2013 / 0108641 A1. This is the amino acid sequence of the GITR agonist 1649 heavy chain CDR2.

[0526] Sequence ID No. 243 corresponds to U.S. Patent Application Publication No. 2013 / 0108641 A1. This is the amino acid sequence of the GITR agonist 1718 heavy chain CDR3.

[0527] Sequence ID No. 244 corresponds to U.S. Patent Application Publication No. 2013 / 0108641 A1. This is the amino acid sequence of the GITR agonist 1718 heavy chain CDR2.

[0528] Sequence ID No. 245 corresponds to U.S. Patent Application Publication No. 2013 / 0108641 A1. This is the amino acid sequence of the GITR agonist 1718 heavy chain CDR1.

[0529] Sequence ID No. 246 corresponds to U.S. Patent Application Publication No. 2013 / 0108641 A1. This is the amino acid sequence of the GITR agonist 1718 light chain CDR3.

[0530] Sequence ID No. 247 corresponds to U.S. Patent Application Publication No. 2013 / 0108641 A1. This is the amino acid sequence of the GITR agonist 1718 light chain CDR2.

[0531] Sequence ID No. 248 corresponds to U.S. Patent Application Publication No. 2013 / 0108641 A1. This is the amino acid sequence of the GITR agonist 1718 light chain CDR1.

[0532] Sequence ID No. 249 corresponds to U.S. Patent Application Publication No. 2013 / 0108641 A1. These are the amino acid sequences of the GITR agonist 827 and the 1649 heavy chain CDR1.

[0533] Sequence ID No. 250 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 1D7 heavy chain.

[0534] Sequence ID No. 251 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 1D7 light chain.

[0535] Sequence ID No. 252 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 1D7 variable heavy chain.

[0536] Sequence ID No. 253 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 1D7 variable light chain.

[0537] Sequence ID No. 254 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 1D7 heavy chain CDR1.

[0538] Sequence ID No. 255 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 1D7 heavy chain CDR2.

[0539] Sequence ID No. 256 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 1D7 heavy chain CDR3.

[0540] Sequence ID No. 257 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 1D7 light chain CDR1.

[0541] Sequence ID No. 258 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 1D7 light chain CDR2.

[0542] Sequence ID No. 259 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 1D7 light chain CDR3.

[0543] Sequence ID No. 260 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 33C9 heavy chain.

[0544] Sequence ID No. 261 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 33C9 light chain.

[0545] Sequence ID No. 262 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 33C9 variable heavy chain.

[0546] Sequence ID No. 263 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 33C9 variable light chain.

[0547] Sequence ID No. 264 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 33C9 heavy chain CDR1.

[0548] Sequence ID No. 265 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 33C9 heavy chain CDR2.

[0549] Sequence ID No. 266 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 33C9 heavy chain CDR3.

[0550] Sequence ID No. 267 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 33C9 light chain CDR1.

[0551] Sequence ID No. 268 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 33C9 light chain CDR2.

[0552] Sequence ID No. 269 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 33C9 light chain CDR3.

[0553] Sequence ID No. 270 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 33F6 heavy chain.

[0554] Sequence ID No. 271 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 33F6 light chain.

[0555] Sequence ID No. 272 ​​corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 33F6 variable heavy chain.

[0556] Sequence ID No. 273 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 33F6 variable light chain.

[0557] Sequence ID No. 274 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 33F6 heavy chain CDR1.

[0558] Sequence ID No. 275 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 33F6 heavy chain CDR2.

[0559] Sequence ID No. 276 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 33F6 heavy chain CDR3.

[0560] Sequence ID No. 277 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 33F6 light chain CDR1.

[0561] Sequence ID No. 278 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 33F6 light chain CDR2.

[0562] Sequence ID No. 279 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 33F6 light chain CDR3.

[0563] Sequence ID No. 280 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 34G quadrilateral.

[0564] Sequence ID No. 281 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 34G4 light chain.

[0565] Sequence ID No. 282 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 34G4 variable heavy chain.

[0566] Sequence ID No. 283 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 34G4 variable light chain.

[0567] Sequence ID No. 284 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 34G4 heavy chain CDR1.

[0568] Sequence ID No. 285 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 34G4 heavy chain CDR2.

[0569] Sequence ID No. 286 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 34G4 heavy chain CDR3.

[0570] Sequence ID No. 287 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 34G4 light chain CDR1.

[0571] Sequence ID No. 288 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 34G4 light chain CDR2.

[0572] Sequence ID No. 289 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 34G4 light chain CDR3.

[0573] Sequence ID No. 290 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 35B10 heavy chain.

[0574] Sequence ID No. 291 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 35B10 light chain.

[0575] Sequence ID No. 292 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 35B10 variable heavy chain.

[0576] Sequence ID No. 293 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 35B10 variable light chain.

[0577] Sequence ID No. 294 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 35B10 heavy chain CDR1.

[0578] Sequence ID No. 295 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 35B10 heavy chain CDR2.

[0579] Sequence ID No. 296 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 35B10 heavy chain CDR3.

[0580] Sequence ID No. 297 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 35B10 light chain CDR1.

[0581] Sequence ID No. 298 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 35B10 light chain CDR2.

[0582] Sequence ID No. 299 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 35B10 light chain CDR3.

[0583] Sequence ID No. 300 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 41E11 heavy chain.

[0584] Sequence ID No. 301 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 41E11 light chain.

[0585] Sequence ID No. 302 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 41E11 variable heavy chain.

[0586] Sequence ID No. 303 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 41E11 variable light chain.

[0587] Sequence ID No. 304 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 41E11 heavy chain CDR1.

[0588] Sequence ID No. 305 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 41E11 heavy chain CDR2.

[0589] Sequence ID No. 306 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 41E11 heavy chain CDR3.

[0590] Sequence ID No. 307 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 41E11 light chain CDR1.

[0591] Sequence ID No. 308 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 41E11 light chain CDR2.

[0592] Sequence ID No. 309 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 41E11 light chain CDR3.

[0593] Sequence ID No. 310 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 41G5 heavy chain.

[0594] Sequence ID No. 311 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 41G5 light chain.

[0595] Sequence ID No. 312 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 41G5 variable heavy chain.

[0596] Sequence ID No. 313 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 41G5 variable light chain.

[0597] Sequence ID No. 314 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 41G5 heavy chain CDR1.

[0598] Sequence ID No. 315 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 41G5 heavy chain CDR2.

[0599] Sequence ID No. 316 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 41G5 heavy chain CDR3.

[0600] Sequence ID No. 317 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 41G5 light chain CDR1.

[0601] Sequence ID No. 318 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 41G5 light chain CDR2.

[0602] Sequence ID No. 319 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 41G5 light chain CDR3.

[0603] Sequence ID No. 320 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 42A11 heavy chain.

[0604] Sequence ID No. 321 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 42A11 light chain.

[0605] Sequence ID No. 322 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 42A11 variable heavy chain.

[0606] Sequence ID No. 323 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 42A11 variable light chain.

[0607] Sequence ID No. 324 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 42A11 heavy chain CDR1.

[0608] Sequence ID No. 325 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 42A11 heavy chain CDR2.

[0609] Sequence ID No. 326 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 42A11 heavy chain CDR3.

[0610] Sequence ID No. 327 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 42A11 light chain CDR1.

[0611] Sequence ID No. 328 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 42A11 light chain CDR2.

[0612] Sequence ID No. 329 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 42A11 light chain CDR3.

[0613] Sequence ID No. 330 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 44C1 heavy chain.

[0614] Sequence ID No. 331 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 44C1 light chain.

[0615] Sequence ID No. 332 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 44C1 variable heavy chain.

[0616] Sequence ID No. 333 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 44C1 variable light chain.

[0617] Sequence ID No. 334 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 44C1 heavy chain CDR1.

[0618] Sequence ID No. 335 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 44C1 heavy chain CDR2.

[0619] Sequence ID No. 336 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 44C1 heavy chain CDR3.

[0620] Sequence ID No. 337 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 44C1 light chain CDR1.

[0621] Sequence ID No. 338 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 44C1 light chain CDR2.

[0622] Sequence ID No. 339 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 44C1 light chain CDR3.

[0623] Sequence ID No. 340 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 45A8 heavy chain.

[0624] Sequence ID No. 341 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 45A8 light chain.

[0625] Sequence ID No. 342 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 45A8 variable heavy chain.

[0626] Sequence ID No. 343 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 45A8 variable light chain.

[0627] Sequence ID No. 344 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 45A8 heavy chain CDR1.

[0628] Sequence ID No. 345 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 45A8 heavy chain CDR2.

[0629] Sequence ID No. 346 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 45A8 heavy chain CDR3.

[0630] Sequence ID No. 347 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 45A8 light chain CDR1.

[0631] Sequence ID No. 348 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 45A8 light chain CDR2.

[0632] Sequence ID No. 349 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 45A8 light chain CDR3.

[0633] Sequence ID No. 350 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 46E11 heavy chain.

[0634] Sequence ID No. 351 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 46E11 light chain.

[0635] Sequence ID No. 352 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 46E11 variable heavy chain.

[0636] Sequence ID No. 353 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 46E11 variable light chain.

[0637] Sequence ID No. 354 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 46E11 heavy chain CDR1.

[0638] Sequence ID No. 355 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 46E11 heavy chain CDR2.

[0639] Sequence ID No. 356 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 46E11 heavy chain CDR3.

[0640] Sequence ID No. 357 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 46E11 light chain CDR1.

[0641] Sequence ID No. 358 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 46E11 light chain CDR2.

[0642] Sequence ID No. 359 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 46E11 light chain CDR3.

[0643] Sequence ID 360 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 48H12 heavy chain.

[0644] Sequence ID No. 361 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 48H12 light chain.

[0645] Sequence ID No. 362 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 48H12 variable heavy chain.

[0646] Sequence ID No. 363 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 48H12 variable light chain.

[0647] Sequence ID No. 364 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 48H12 heavy chain CDR1.

[0648] Sequence ID No. 365 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 48H12 heavy chain CDR2.

[0649] Sequence ID 366 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 48H12 heavy chain CDR3.

[0650] Sequence ID No. 367 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 48H12 light chain CDR1.

[0651] Sequence ID No. 368 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 48H12 light chain CDR2.

[0652] Sequence ID No. 369 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 48H12 light chain CDR3.

[0653] Sequence ID No. 370 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 48H7 heavy chain.

[0654] Sequence ID No. 371 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 48H7 light chain.

[0655] Sequence ID No. 372 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 48H7 variable heavy chain.

[0656] Sequence ID No. 373 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 48H7 variable light chain.

[0657] Sequence ID No. 374 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 48H7 heavy chain CDR1.

[0658] Sequence ID No. 375 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 48H7 heavy chain CDR2.

[0659] Sequence ID No. 376 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 48H7 heavy chain CDR3.

[0660] Sequence ID No. 377 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 48H7 light chain CDR1.

[0661] Sequence ID No. 378 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 48H7 light chain CDR2.

[0662] Sequence ID No. 379 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 48H7 light chain CDR3.

[0663] Sequence ID No. 380 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 49D9 heavy chain.

[0664] Sequence ID No. 381 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 49D9 light chain.

[0665] Sequence ID No. 382 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 49D9 variable heavy chain.

[0666] Sequence ID No. 383 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 49D9 variable light chain.

[0667] Sequence ID No. 384 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 49D9 heavy chain CDR1.

[0668] Sequence ID No. 385 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 49D9 heavy chain CDR2.

[0669] Sequence ID No. 386 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 49D9 heavy chain CDR3.

[0670] Sequence ID No. 387 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 49D9 light chain CDR1.

[0671] Sequence ID No. 388 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 49D9 light chain CDR2.

[0672] Sequence ID No. 389 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 49D9 light chain CDR3.

[0673] Sequence ID No. 390 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 49E2 heavy chain.

[0674] Sequence ID No. 391 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 49E2 light chain.

[0675] Sequence ID No. 392 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 49E2 variable heavy chain.

[0676] Sequence ID No. 393 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 49E2 variable light chain.

[0677] Sequence ID No. 394 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 49E2 heavy chain CDR1.

[0678] Sequence ID No. 395 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 49E2 heavy chain CDR2.

[0679] Sequence ID No. 396 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 49E2 heavy chain CDR3.

[0680] Sequence ID No. 397 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 49E2 light chain CDR1.

[0681] Sequence ID No. 398 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 49E2 light chain CDR2.

[0682] Sequence ID No. 399 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 49E2 light chain CDR3.

[0683] Sequence ID No. 400 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 48A9 heavy chain.

[0684] Sequence ID No. 401 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 48A9 light chain.

[0685] Sequence ID No. 402 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 48A9 variable heavy chain.

[0686] Sequence ID No. 403 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 48A9 variable light chain.

[0687] Sequence ID No. 404 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 48A9 heavy chain CDR1.

[0688] Sequence ID No. 405 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 48A9 heavy chain CDR2.

[0689] Sequence ID No. 406 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 48A9 heavy chain CDR3.

[0690] Sequence ID No. 407 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 48A9 light chain CDR1.

[0691] Sequence ID No. 408 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 48A9 light chain CDR2.

[0692] Sequence ID No. 409 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 48A9 light chain CDR3.

[0693] Sequence ID No. 410 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 5H7 heavy chain.

[0694] Sequence ID No. 411 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 5H7 light chain.

[0695] Sequence ID No. 412 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 5H7 variable heavy chain.

[0696] Sequence ID No. 413 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 5H7 variable light chain.

[0697] Sequence ID No. 414 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 5H7 heavy chain CDR1.

[0698] Sequence ID No. 415 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 5H7 heavy chain CDR2.

[0699] Sequence ID No. 416 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 5H7 heavy chain CDR3.

[0700] Sequence ID No. 417 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 5H7 light chain CDR1.

[0701] Sequence ID No. 418 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 5H7 light chain CDR2.

[0702] Sequence ID No. 419 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 5H7 light chain CDR3.

[0703] Sequence ID No. 420 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 7A10 heavy chain.

[0704] Sequence ID No. 421 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 7A10 light chain.

[0705] Sequence ID No. 422 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 7A10 variable heavy chain.

[0706] Sequence ID No. 423 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 7A10 variable light chain.

[0707] Sequence ID No. 424 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 7A10 heavy chain CDR1.

[0708] Sequence ID No. 425 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 7A10 heavy chain CDR2.

[0709] Sequence ID No. 426 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 7A10 heavy chain CDR3.

[0710] Sequence ID No. 427 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 7A10 light chain CDR1.

[0711] Sequence ID No. 428 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 7A10 light chain CDR2.

[0712] Sequence ID No. 429 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 7A10 light chain CDR3.

[0713] Sequence ID No. 430 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 9H6 heavy chain.

[0714] Sequence ID No. 431 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 9H6 light chain.

[0715] Sequence ID No. 432 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 9H6 variable heavy chain.

[0716] Sequence ID No. 433 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 9H6 variable light chain.

[0717] Sequence ID No. 434 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 9H6 heavy chain CDR1.

[0718] Sequence ID No. 435 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 9H6 heavy chain CDR2.

[0719] Sequence ID No. 436 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 9H6 heavy chain CDR3.

[0720] Sequence ID No. 437 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 9H6 light chain CDR1.

[0721] Sequence ID No. 438 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 9H6 light chain CDR2.

[0722] Sequence ID No. 439 corresponds to U.S. Patent Application Publication No. 2015 / 0064204 A1. This is the amino acid sequence of the GITR agonist 9H6 light chain CDR3.

[0723] Sequence ID 440 is the amino acid sequence of the GITR ligand (GITRL).

[0724] Sequence ID 441 is the soluble portion of the GITRL polypeptide.

[0725] Sequence ID 442 is the amino acid sequence of human HVEM (CD270).

[0726] Sequence ID 443 is the amino acid sequence for the HVEM ligand (LIGHT).

[0727] Sequence ID 444 is the soluble portion of the LIGHT polypeptide.

[0728] Sequence ID No. 445 is an alternative soluble moiety of the LIGHT polypeptide.

[0729] Sequence ID 446 is an alternative soluble moiety of the LIGHT polypeptide.

[0730] Sequence ID 447 is the amino acid sequence of human CD95 isoform 1.

[0731] Sequence ID 448 is the amino acid sequence of human CD95 isoform 2.

[0732] Sequence ID 449 is the amino acid sequence of human CD95 isoform 3.

[0733] Sequence ID 450 is the amino acid sequence of human CD95 isoform 4.

[0734] Sequence ID 451 is a heavy chain variant of the CD95 agonist monoclonal antibody E09. Variable region (V H )

[0735] Sequence ID 452 is a light chain antibody of the CD95 agonist monoclonal antibody E09. Variable region (V L )

[0736] SEQ ID NO: 453 is the heavy chain C of the CD95 agonist monoclonal antibody E09. It's DR1.

[0737] Sequence ID 454 is the heavy chain C of the CD95 agonist monoclonal antibody E09. It's DR2.

[0738] Sequence ID 455 is the heavy chain C of the CD95 agonist monoclonal antibody E09. It's DR3.

[0739] Sequence ID 456 is the light chain C of the CD95 agonist monoclonal antibody E09. It's DR1.

[0740] Sequence ID 457 is the light chain C of the CD95 agonist monoclonal antibody E09. It's DR2.

[0741] Sequence ID 458 is the light chain C of the CD95 agonist monoclonal antibody E09. It's DR3.

[0742] Sequence ID 459 is the amino acid sequence of the CD95 ligand (CD95L).

[0743] Sequence ID 460 is the soluble portion of the CD95L polypeptide.

[0744] Sequence ID 461 is an alternative soluble moiety of the CD95L polypeptide.

[0745] Sequence ID 462 is an alternative soluble moiety of the CD95L polypeptide.

[0746] Sequence ID 463 is the heavy chain amino acid sequence of the PD-1 inhibitor nivolumab.

[0747] Sequence ID 464 is the light chain amino acid sequence of the PD-1 inhibitor nivolumab.

[0748] Sequence ID 465 is the heavy chain variable region (V) of the PD-1 inhibitor nivolumab. H ) Ami It is a no-acid sequence.

[0749] Sequence ID 466 is the light chain variable region (V) of the PD-1 inhibitor nivolumab. L ) Ami It is a no-acid sequence.

[0750] Sequence ID 467 is the heavy chain CDR1 amino acid sequence of the PD-1 inhibitor nivolumab. That is the case.

[0751] Sequence ID 468 is the heavy chain CDR2 amino acid sequence of the PD-1 inhibitor nivolumab. That is the case.

[0752] Sequence ID 469 is the heavy chain CDR3 amino acid sequence of the PD-1 inhibitor nivolumab. That is the case.

[0753] Sequence ID 470 is the light chain CDR1 amino acid sequence of the PD-1 inhibitor nivolumab. That is the case.

[0754] Sequence ID 471 is the light chain CDR2 amino acid sequence of the PD-1 inhibitor nivolumab. That is the case.

[0755] Sequence ID 472 is the light chain CDR3 amino acid sequence of the PD-1 inhibitor nivolumab. That is the case.

[0756] Sequence ID 473 is the heavy chain amino acid sequence of the PD-1 inhibitor pembrolizumab. be.

[0757] Sequence ID 474 is the light chain amino acid sequence of the PD-1 inhibitor pembrolizumab. be.

[0758] Sequence ID 475 is the heavy chain variable region (V) of the PD-1 inhibitor pembrolizumab. H ) This is the amino acid sequence.

[0759] Sequence ID 476 is the light chain variable region (V) of the PD-1 inhibitor pembrolizumab. L ) This is the amino acid sequence.

[0760] Sequence ID 477 is the heavy chain CDR1 amino acid of the PD-1 inhibitor pembrolizumab. It is an acid sequence.

[0761] Sequence ID 478 is the heavy chain CDR2 amino acid of the PD-1 inhibitor pembrolizumab. It is an acid sequence.

[0762] Sequence ID 479 is the heavy chain CDR3 amino acid of the PD-1 inhibitor pembrolizumab. It is an acid sequence.

[0763] Sequence ID 480 is the light chain CDR1 amino acid of the PD-1 inhibitor pembrolizumab. It is an acid sequence.

[0764] Sequence ID 481 is the light chain CDR2 amino acid of the PD-1 inhibitor pembrolizumab. It is an acid sequence.

[0765] Sequence ID 482 is the light chain CDR3 amino acid of the PD-1 inhibitor pembrolizumab. It is an acid sequence.

[0766] Sequence ID 483 is the heavy chain amino acid sequence of the PD-L1 inhibitor durvalumab. be.

[0767] Sequence ID 484 is the light chain amino acid sequence of the PD-L1 inhibitor durvalumab. be.

[0768] Sequence ID 485 is the heavy chain variable region (V) of the PD-L1 inhibitor durvalumab. H ) This is the amino acid sequence.

[0769] Sequence ID 486 is the light chain variable region (V) of the PD-L1 inhibitor durvalumab. L ) This is the amino acid sequence.

[0770] Sequence ID 487 is the heavy chain CDR1 amino acid of the PD-L1 inhibitor durvalumab. It is an acid sequence.

[0771] Sequence ID 488 is the heavy chain CDR2 amino acid of the PD-L1 inhibitor durvalumab. It is an acid sequence.

[0772] Sequence ID 489 is the heavy chain CDR3 amino acid of the PD-L1 inhibitor durvalumab. It is an acid sequence.

[0773] Sequence ID 490 is the light chain CDR1 amino acid of the PD-L1 inhibitor durvalumab. It is an acid sequence.

[0774] Sequence ID 491 is the light chain CDR2 amino acid of the PD-L1 inhibitor durvalumab. It is an acid sequence.

[0775] Sequence ID 492 is the light chain CDR3 amino acid of the PD-L1 inhibitor durvalumab. It is an acid sequence.

[0776] Sequence ID 493 is the heavy chain amino acid sequence of the PD-L1 inhibitor avelumab. .

[0777] Sequence ID 494 is the light chain amino acid sequence of the PD-L1 inhibitor avelumab. .

[0778] Sequence ID 495 is the heavy chain variable region (V) of the PD-L1 inhibitor avelumab. H )a It is a mino acid sequence.

[0779] Sequence ID 496 is the light chain variable region (V) of the PD-L1 inhibitor avelumab. L )a It is a mino acid sequence.

[0780] Sequence ID 497 is a heavy chain CDR1 amino acid compound of the PD-L1 inhibitor avelumab. It is a row.

[0781] Sequence ID 498 is a heavy chain CDR2 amino acid compound of the PD-L1 inhibitor avelumab. It is a row.

[0782] Sequence ID 499 is a heavy chain CDR3 amino acid compound of the PD-L1 inhibitor avelumab. It is a row.

[0783] Sequence ID 500 is the light chain CDR1 amino acid compound of the PD-L1 inhibitor avelumab. It is a row.

[0784] Sequence ID 501 is a light chain CDR2 amino acid compound of the PD-L1 inhibitor avelumab. It is a row.

[0785] Sequence ID 502 is a light chain CDR3 amino acid compound of the PD-L1 inhibitor avelumab. It is a row.

[0786] Sequence ID 503 is the heavy chain amino acid sequence of the PD-L1 inhibitor atezolizumab. be.

[0787] Sequence ID 504 is the light chain amino acid sequence of the PD-L1 inhibitor atezolizumab. be.

[0788] Sequence ID 505 is the heavy chain variable region (V) of the PD-L1 inhibitor atezolizumab. H ) This is the amino acid sequence.

[0789] Sequence ID 506 is the light chain variable region (V) of the PD-L1 inhibitor atezolizumab. L ) This is the amino acid sequence.

[0790] Sequence ID 507 is the heavy chain CDR1 amino acid of the PD-L1 inhibitor atezolizumab. It is an acid sequence.

[0791] Sequence ID 508 is the heavy chain CDR2 amino acid of the PD-L1 inhibitor atezolizumab. It is an acid sequence.

[0792] Sequence ID 509 is the heavy chain CDR3 amino acid of the PD-L1 inhibitor atezolizumab. It is an acid sequence.

[0793] Sequence ID 510 is the light chain CDR1 amino acid of the PD-L1 inhibitor atezolizumab. It is an acid sequence.

[0794] Sequence ID 511 is the light chain CDR2 amino acid of the PD-L1 inhibitor atezolizumab. It is an acid sequence.

[0795] Sequence ID 512 is the light chain CDR3 amino acid of the PD-L1 inhibitor atezolizumab. It is an acid sequence.

[0237] Detailed description of the invention

[0796] Unless otherwise defined, all technical and scientific terms used herein The terms have the same meaning as those generally understood by those skilled in the art to which this invention pertains. All patents and publications referenced herein are incorporated herein by reference in their entirety.

[0238] definition

[0797] The terms "co-administration," "to co-administer," and "combined with" as used in this specification are used in this document. The terms "administered in combination with," "administered in combination with," "simultaneous," and "concurrent" encompass the administration of two or more active pharmaceutical ingredients (in a preferred embodiment of the present invention, for example, at least one TNFRSF agonist and multiple TILs) to a subject so that both active pharmaceutical ingredients and / or their metabolites are present in the subject at the same time. Co-administration includes simultaneous administration in separate compositions, administration at different time points in separate compositions, or administration in a composition containing two or more active pharmaceutical ingredients. Simultaneous administration in separate compositions and administration in a composition containing both drugs are preferred.

[0239]

[0798] The term "rapid expansion culture" refers to a culture that grows at least three times over a period of one week (or This means an increase in the number of antigen-specific TILs of at least about 10 times (or 20 times, 30 times, 40 times, 50 times, 60 times, 70 times, 80 times, or 90 times) over a period of 1 week, more preferably at least about 100 times over a period of 1 week. Several rapid expansion culture protocols are described herein.

[0240]

[0799] In this specification, "tumor-infiltrating lymphocytes" or "TILs" refers to the target blood flow This refers to a group of cells that migrated from a detached location into the tumor and were initially obtained as leukocytes. While not limited to these, TILs include CD8+ cytotoxic T cells (lymphocytes), Th1 and Th17 CD4+ T cells, natural killer cells, dendritic cells, and M1 macrophages. TILs include both primary and secondary TILs. "Primary TILs" are obtained from patient tissue samples as outlined herein (sometimes referred to as "freshly recovered"), and "secondary TILs" are any TIL cell populations that have been cultured or grown as discussed herein, including but not limited to bulk TILs and expanded cultured TILs ("REP TILs" or "post-REP TILs").

[0241]

[0800] In this specification, “cell population” (including TIL) refers to a group of cells that share common characteristics. It means a large number of cells. Generally, a population is roughly 1 x 10⁻¹⁶ 6 ~1 × 10 10 This is a range of individuals, and different TIL populations contain different numbers. For example, the initial growth of primary TILs in the presence of IL-2 is approximately 1 × 10⁻⁶. 8 This yields a bulk TIL population of individual cells. REP expansion cultures generally yield 1.5 × 10⁶ cells. 9 ~1.5×10 10 This is done so that individual cell populations for injection are provided.

[0242]

[0801] The term "central memory T cell" is CD45R0+ in humans, and This refers to a subset of T cells that constitutively express CCR7 (CCR7hi) and CD62L (CD62hi). The surface phenotype of central memory T cells also includes TCR, CD3, CD127 (IL-7R), and IL-15R. The transcription factors of central memory T cells include BCL-6, BCL-6B, MBD2, and BMI1. After TCR induction, central memory T cells mainly secrete IL-2 and CD40L as effector molecules. Central memory T cells are dominant in the CD4 compartment of the blood and are proportionally concentrated in lymph nodes and tonsils in humans.

[0243]

[0802] The term "anti-CD3 antibody" refers to an antibody or its variant, such as a monoclonal antibody. This refers to human, humanized, chimeric, or mouse antibodies targeted against the CD3 receptor on the T cell antigen receptor of mature T cells. Anti-CD3 antibodies include OKT-3, also known as muromonab. Anti-CD3 antibodies also include UHCT1 clones, also known as T3 and CD3ε. Other anti-CD3 antibodies include, for example, otelixizumab, teprizumab, and vizilizumab.

[0244]

[0803] The term "OKT-3" (also referred to as "OKT3" in this specification) refers to mature T This refers to monoclonal antibodies or biosimilars or their variants, including human, humanized, chimeric, or mouse antibodies targeted against the CD3 receptor in the T cell antigen receptor of cells, such as OKT-3 (30 ng / mL, MACS GMP CD3 pure, Miltenyi Biotech, Inc., San Diego, CA, USA) and muromonab or their variants, conservative amino acid substitutions, and glycoforms. This also includes commercially available forms such as biosimilars. The amino acid sequences of the heavy and light chains of muromonab are shown in Table 1 (SEQ ID NO: 1 and SEQ ID NO: 2).

[0245] [Table 1]

[0246]

[0804] The term "IL-2" (also referred to as "IL2" in this specification) is an interlocutor. This refers to the T cell growth factor known as IL-2, and includes all forms of IL-2, including human and mammalian forms, conserved amino acid substitutions, glycoforms, biosimilars, and their variants. IL-2 is discussed, for example, in Nelson, J. Immunol. 2004, 172, 3983-88 and Malek, This information is described in Annu. Rev. Immunol. 2008, 26, 453-79, and its disclosure is referred to herein by reference. It is incorporated into. Table 2 shows the amino acid sequence of recombinant human IL-2 suitable for use in the present invention (SEQ ID NO: 3). For example, the term IL-2 is derived from aldethleukin (PROLEUKIN). This includes human recombinant forms of IL-2, such as those commercially available from multiple suppliers at 22 million IU per single-use vial, as well as recombinant IL-2 forms commercially supplied by CellGenix, Inc., Portsmouth, NH, USA (CELLGRO GMP) or ProSpec-Tany TechnoGene Ltd., East Brunswick, NJ, USA (catalog number CYT-209-b), and other commercially available equivalents from other distributors. Aldesleukin (des-alanil-1, serine-125 human IL-2) is a non-glycosylated human recombinant IL-2 with a molecular weight of approximately 15 kDa. The amino acid sequence of aldesleukin suitable for use in this invention is shown in Table 2 (SEQ ID NO: 4). The term IL-2, as described herein, includes the pegylated IL-2 prodrug NKTR-214 available from Nektar Therapeutics, South San Francisco, CA, USA. This also includes pegylated IL-2. NKTR-214 and pegylated IL-2 suitable for use in the present invention are described in U.S. Patent Publication No. 2014 / 0328791 A1 and International Publication No. 2012 / 065086 A1 (these disclosures are incorporated herein by reference). Alternative forms of conjugated IL-2 suitable for use in the present invention are described in U.S. Patents No. 4,766,106, 5,206,344, 5,089,261 and 4902,502, the disclosures of which are incorporated herein by reference. Formulations of IL-2 suitable for use in the present invention are described in U.S. Patent No. 6,706,289, the disclosures of which are incorporated herein by reference.

[0247] [Table 2]

[0248]

[0805] The term "IL-4" (also referred to as "IL4" in this specification) refers to interlo This refers to a cytokine known as IL-4, which is produced by Th2 T cells, as well as by eosinophils, basophils, and mast cells. IL-4 regulates the differentiation of naive helper T cells (Th0 cells) into Th2 T cells. (Steinke and Borish, Respir. Res. 2001, 2, 66-70). Upon activation by IL-4, Th2 T cells subsequently become positive. In the feedback loop, further IL-4 is produced. IL-4 also stimulates B cell expansion culture and class II MHC expression, inducing class switching from B cells to IgE and IgG1 expression. Recombinant human IL-4 suitable for use in this invention is available from ProSpec-Tany TechnoGene Ltd., East Brunswick, NJ, USA (catalog number CYT-211) and ThermoFisher Scientific, Inc., Waltham, MA, USA (Human IL-15 Recombinant Protein) It is commercially available from several suppliers, including Gibco (catalog number CTP0043). The amino acid sequence of recombinant human IL-4 suitable for use in this invention is shown in Table 2 (SEQ ID NO: 5).

[0249]

[0806] The term "IL-7" (also referred to as "IL7" in this specification) refers to interlo This refers to glycosylated tissue-derived cytokines known as Ikin 7, which can be obtained from stromal and epithelial cells as well as dendritic cells. Fry and Mackall, Blood 2002, 99, 3892-904. IL-7 can stimulate T cell development. IL-7 binds to the IL-7 receptor, a heterodimer consisting of IL-7 receptor alpha and a common gamma chain receptor, in a series of signals crucial for T cell development in the thymus and survival in the periphery. Recombinant human IL-7 suitable for use in this invention is commercially available from several suppliers, including ProSpec-Tany TechnoGene Ltd., East Brunswick, NJ, USA (catalog number CYT-254) and ThermoFisher Scientific, Inc., Waltham, MA, USA (human IL-7 recombinant protein, catalog number Gibco PHC0071). The amino acid sequence of recombinant human IL-7 suitable for use in this invention is shown in Table 2 (SEQ ID NO: 6).

[0250]

[0807] The term "IL-15" (also referred to as "IL15" in this specification) refers to an interface. - Refers to the T cell growth factor known as leukin-15, which is present in the morphology and storage of human and mammalian cells. This includes all forms of IL-15, including specific amino acid substitutions, glycoforms, biosimilars, and their variants. IL-15 is described, for example, in Fehniger and Caligiuri, Blood 2001, 97, 14-32, the disclosure of which is incorporated herein by reference. IL-15 is, It shares β and γ signaling receptor subunits with IL-2. Recombinant human IL-15 is a single non-glycosylated polypeptide chain containing 114 amino acids (and N-terminal methionine) with a molecular weight of 12.8 kDa. Recombinant human IL-15 is commercially available from several suppliers, including ProSpec-Tany TechnoGene Ltd., East Brunswick, NJ, USA (catalog no. CYT-230-b) and ThermoFisher Scientific, Inc., Waltham, MA, USA (recombinant human IL-15 protein, catalog no. 34-8159-82). The amino acid sequence of recombinant human IL-15 suitable for use in this invention is shown in Table 2 (SEQ ID NO: 7).

[0251]

[0808] The term "IL-21" (also referred to as "IL21" in this specification) refers to the internet. - This refers to the pleomorphic cytokine protein known as leukin-21, and includes all forms of IL-21, including human and mammalian forms, conserved amino acid substitutions, glycoforms, biosimilars and their variants. IL-21 is, for example, described by Spolski and Leonard. This information is described in Nat. Rev. Drug. Disc. 2014, 13, 379-95, and its disclosure is referenced in this specification. It is incorporated into the text. IL-21 is mainly used on natural killer T cells and activated human CD4+ It is produced by T cells. Recombinant human IL-21 is a single non-glycosylated polypeptide chain containing 132 amino acids with a molecular weight of 15.4 kDa. Recombinant human IL-21 is manufactured by ProSpec-Tany TechnoGene Ltd., East Brunswick, NJ, USA (Catalog No. CY). T-408-b) and ThermoFisher Scientific, Inc., Waltham, MA, USA (Human IL- Recombinant IL-21 (catalog number 14-8219-80) is commercially available from several suppliers. The amino acid sequence of recombinant human IL-21 suitable for use in the present invention is shown in Table 2 (SEQ ID NO: 8).

[0252]

[0809] Adenosine A2A receptor antagonists are "A2aR antagonists" and bi "A 2A These receptors are referred to as "AdoR antagonists." They belong to the G protein-coupled receptor family and are distinct from the adenosine A1, adenosine A2B, and adenosine A3 receptor subfamilies.

[0253]

[0810] The term "CPI-444" refers to a compound known as siphoradenanth. This refers to the compound 7-(5-methylfuran-2-yl)-3-[[6-[[(3S)-oxolan-3-yl]oxymethyl]pyridine-2-yl]methyl]triazolo[4,5-d]pyrimidine-5-amine. This compound is also known as "V81444". The molecular formula is C 20 H 21 It is N7O3. As used in this disclosure, the terms “CPI-444” or “siphoradenanth” encompass pharmaceutically acceptable salts, solvates, hydrates, cocrystals or prodrugs of 7-(5-methylfuran-2-yl)-3-[[6-[[(3S)-oxolan-3-yl]oxymethyl]pyridine-2-yl]methyl]triazolo[4,5-d]pyrimidine-5-amine, respectively.

[0254]

[0811] The term "SCH58261" refers to the molecular formula C 18 H 15 Containing N7O, The compound 2-(furan-2-yl)-7-phenethyl-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine-5-amine. As used in this disclosure, the term "SCH58261" encompasses pharmaceutically acceptable salts, solvates, hydrates, cocrystals, or prodrugs of 2-(furan-2-yl)-7-phenethyl-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine-5-amine.

[0255]

[0812] The term "SYN115" refers to the molecular formula C 19 H 26 Having N4O4S, Compound 4-hydroxy-N-[4-methoxy-7-(4-morpholinyl)-2-benzoth [Azolyl]-4-methyl-1-piperidinecarboxamide. As used in this disclosure, the term "SYN115" encompasses pharmaceutically acceptable salts, solvates, hydrates, cocrystals, or prodrugs of 4-hydroxy-N-[4-methoxy-7-(4-morpholinyl)-2-benzothiazolyl]-4-methyl-1-piperidinecarboxamide.

[0256]

[0813] The term "ZM241385" refers to the molecular formula C 16 H 15 Contains N7O2 , refers to the compound 4-(-2-[7-amino-2-{2-furyl}{1,2,4}triazolo{2,3-a}{1,3,5}triazine-5-yl-amino]ethyl)phenol. As used in this disclosure, the term "ZM241385" encompasses pharmaceutically acceptable salts, solvates, hydrates, cocrystals, or prodrugs of 4-(-2-[7-amino-2-{2-furyl}{1,2,4}triazolo{2,3-a}{1,3,5}triazine-5-yl-amino]ethyl)phenol.

[0257]

[0814] The term "7MMB" refers to a family of compounds defined in the template. This refers to a group where X is C and R is selected from the group consisting of para-F, meta-F, para-CH3, 2,4-difluoro, 2,6-difluoro, 3,4-difluoro, 3,4-dimethoxy, meta-(2-methoxyethoxy), meta-(1,3-benzodioxole), para-Cl, para-CF3, para-CN and para-tert-butyl; where X is N and R is selected from the group consisting of para-F, meta-F, ortho-F, para-Cl, meta-CF3, 2,4-difluoro, 2,6-difluoro, 3,4-difluoro, meta-(2-methoxyethoxy), meta-(1,3-benzodioxole), para-CH3 and meta-OCH3. The term "7MMB" encompasses pharmaceutically acceptable salts, solvates, hydrates, cocrystals, or prodrugs of the genus disclosed in this template and in the following section on adenosine 2A receptor antagonists "7MMG".

[0258]

[0815] The term "in vivo" refers to events that occur within the body of mammals.

[0259]

[0816] The term "exvivo" refers to the external environment of mammalian subjects in an artificial environment. It refers to an event that occurs.

[0260]

[0817] The term "in vitro" refers to events that occur in a test system. The term "Say" encompasses cell-based assays in which viable or dead cells may be used, and may also encompass cell-free assays in which intact cells are not used.

[0261]

[0818] The terms "effective dose" or "therapeutic effective dose" include, but are not limited to, disease treatment. This refers to the amount of a compound or combination of compounds described herein that is sufficient to achieve the intended use, and is not specified. The therapeutically effective dose may vary depending on the intended use (in vitro or in vivo), the subject and disease state being treated (e.g., the subject's weight, age, and sex), the severity of the disease state, or the method of administration. This term also applies to doses that induce a specific response in target cells (e.g., reduced platelet adhesion and / or cell migration). The specific dose will vary depending on the specific compound selected, the administration regimen to be followed, whether the compound is administered in combination with other compounds, the timing of administration, the tissue to which it is administered, and the physical delivery system through which the compound is carried.

[0262]

[0819] When the term "therapeutic effect" is used herein, it refers to the therapeutic benefit and / or includes preventive benefits. Preventive effects include delaying or eliminating the onset of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, stopping, or reversing the progression of a disease or condition, or any combination thereof.

[0263]

[0820] The terms "QD", "qd", or "qd" are used once a day, once a day. Or it means once a day. The terms "BID", "bid", or "bid" mean twice a day, twice a day, or twice a day. The terms "TID", "tid", or "tid" mean three times a day, three times a day, or three times a day. The terms "QID", "qid", or "qid" mean four times a day, four times a day, or four times a day. The term "QW" means once a week. The term "Q2W" means once every two weeks. The term "Q3W" means once every three weeks. The term "Q4W" means once every four weeks.

[0264]

[0821] The term "pharmaceutically acceptable salt" is used in various fields known in the art. This refers to salts derived from organic and inorganic counterions. Pharmaceutically acceptable acid addition salts can be formed using inorganic and organic acids. Preferred inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Preferred organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. Pharmaceutically acceptable base addition salts can be formed using inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins. Specific examples include isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, pharmaceutically acceptable base addition salts are selected from ammonium salts, potassium salts, sodium salts, calcium salts, and magnesium salts. The term "cocrystal" refers to molecular complexes derived from several cocrystal-forming agents known in the art. Unlike salts, cocrystals typically do not involve hydrogen transfer between the cocrystal and the drug, but instead involve intermolecular interactions such as hydrogen bonding, aromatic ring stacking, or dispersion forces between the cocrystal-forming agent and the drug in the crystalline structure.

[0265]

[0822] The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" This includes all kinds of solvents, dispersants, coatings, antimicrobial and antifungal agents, isotonic and absorption retardants, and inert components. The use of such pharmaceutically acceptable carriers or pharmaceutically acceptable excipients for active pharmaceutical ingredients is well known in the art. Unless any conventional pharmaceutically acceptable carrier or pharmaceutically acceptable excipient is incompatible with the active pharmaceutical ingredient, its use in the therapeutic compositions of the present invention is intended. Additional active pharmaceutical ingredients, such as other drugs, can also be incorporated into the compositions, processes, and methods described.

[0266]

[0823] The term "antigen" refers to a substance that induces an immune response. In some embodiments, Here, an antigen is a molecule that, when presented by a major histocompatibility complex (MHC) molecule, can be bound by an antibody or a T cell receptor (TCR). As used herein, the term “antigen” also encompasses T cell epitopes. Antigens may be further recognized by the immune system. In some embodiments, an antigen can induce a humoral or cellular immune response that results in the activation of B lymphocytes and / or T lymphocytes. In some cases, this may require the antigen to contain or be bound to a Th cell epitope. An antigen may also have one or more epitopes (e.g., a B epitope and a T epitope). In some embodiments, an antigen preferably reacts with its corresponding antibody or TCR in a typically highly specific and selective manner, and does not react with a number of other antibodies or TCRs that may be induced by that antigen.

[0267]

[0824] The term "antibody" refers to one or more immunoglobulins and any antigens. The term "antibody" refers to a binding fragment ("antigen-binding region") or a single chain thereof. "Antibody" further refers to a glycoprotein or its antigen-binding region comprising at least two heavy (H) chains and two light (L) chains interconnected by disulfide bonds. Each heavy chain has a heavy chain variable region (V in this specification). HIt consists of a heavy chain constant region (abbreviated as CH1, CH2, and CH3). Each light chain is composed of a light chain variable region (V in this specification). L It consists of a (abbreviated as) and a light chain steady region. The light chain steady region is one domain, C L It is composed of the antibody V H and V L The region is called the Complementarity Determination Region (CDR) or the Hypervariability Region (HVR), and can be further subdivided into hypervariability regions that can be dispersed into more conserved regions (called framework regions (FR)). H and V L It consists of three CDRs and four FRs arranged in the order FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4 from the amino terminus to the carboxyl terminus. The variable regions of the heavy and light chains contain binding domains that interact with the antigen epitope. The constant region of the antibody can mediate the binding of immunoglobulins to various cells of the immune system (e.g., effector cells) and to host tissues or factors including the first component (Clq) of the classical complement system.

[0268]

[0825] "Monoclonal antibody," "mAb," "Monoclonal antibody composition" The terms or their plural forms refer to preparations of antibody molecules with a single molecular composition. Monoclonal antibody compositions exhibit a single binding specificity and affinity for a particular epitope. Monoclonal antibodies specific to the TNFRSF receptor can be produced using knowledge and techniques in the art, which involve injecting a suitable antigen into a test subject and then isolating hybridomas that express antibodies having the desired sequence or functional characteristics. The DNA encoding the monoclonal antibody is readily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes that can specifically bind to the genes encoding the heavy and light chains of the monoclonal antibody). Hybridoma cells serve as a preferred source of such DNA. Once isolated, the DNA can be placed in an expression vector, which can then be used to express E. coli (E. coli) cells, monkey COS cells, Chinese hamster ovary (CHO) cells, and other similar cells. The recombinant host cells, such as myeloma cells, which do not produce immunoglobulin proteins by other means, are transfected to obtain the synthesis of monoclonal antibodies in the recombinant host cells. Recombinant production of the antibody is described in more detail below.

[0269]

[0826] As used herein, the “antigen-binding portion” or “antigen-binding fragment” of an antibody The term (or simply “antibody moiety” or “fragment”) refers to one or more fragments of an antibody that retain the ability to specifically bind to an antigen. It has been shown that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody. Examples of binding fragments encompassed by the term “antigen-binding moiety” of an antibody include (i)V L , V H , C L (ii) a monovalent fragment consisting of the CH1 domain, the Fab fragment; (ii) a divalent fragment containing two Fab fragments linked by disulfide bridges in the hinge region, the F(ab')2 fragment; (iii) V H and Fd fragment consisting of CH1 domain; (iv) V of a single arm of antibody L and V H Fv fragment consisting of domains, (v)V H or V L It may consist of domain-based antibody (dAb) fragments (Ward, et al., Nature, 1989, 341, 544-546); and (vi) isolated complementarity-determining regions (CDRs). Furthermore, it includes two domains of the Fv fragment, V L and V H These are encoded by separate genes, but they can be synthesized using recombination. L and V HRegion pairs can be linked by synthetic linkers, which allow them to be constructed as a single protein chain forming a monovalent molecule known as a single-chain Fv (scFv); see, for example, Bird, et al., Science 1988, 242, 423-426; and Huston, et al., Proc.Natl.Acad.Sci.USA 1988, 85, 5879-5883). Such scFv antibodies are also intended to be encompassed within the terminology of the “antigen-binding portion” or “antigen-binding fragment” of an antibody. These antibody fragments are obtained using prior art known to those skilled in the art, and the fragments are screened for utility in the same manner as intact antibodies.

[0270]

[0827] As used herein, the term "human antibody" refers to the framework region and The present invention is intended to include antibodies in which both CDR regions have variable regions derived from human germline immunoglobulin sequences. Furthermore, if the antibody contains a constant region, the constant region also derives from a human germline immunoglobulin sequence. The human antibodies of the present invention may contain amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-directed mutagenesis in vitro or somatic mutation in vivo). As used herein, the term “human antibody” is not intended to include antibodies in which a CDR sequence derived from the germline of another mammalian species, such as mouse, has been transplanted into a human framework sequence.

[0271]

[0828] The term "human monoclonal antibody" is used in the framework area and CDR. This refers to a single binding-specific antibody having variable regions in both areas derived from human germline immunoglobulin sequences. In one embodiment, a human monoclonal antibody is obtained from a transgenic non-human animal, such as a transgenic mouse, and produced by a hybridoma containing B cells having a genome containing human heavy chain and light chain transgenes fused to immortalized cells.

[0272]

[0829] As used herein, the term “recombinant human antibody” means (a) human immunoglobulin The following are all human antibodies prepared, expressed, produced or isolated by recombinant means, including (b) antibodies isolated from animals (such as mice) that are transgenic or transchromosomes of the immunoglobulin gene, or hybridomas prepared therefrom (as further described below); (c) antibodies isolated from host cells transformed to express human antibodies, e.g., transfectomas; (d) antibodies isolated from recombinant combinatorial human antibody libraries; and (e) antibodies prepared, expressed, produced or isolated by any other means including splicing of the human immunoglobulin gene sequence to other DNA sequences. Such recombinant human antibodies have variable regions in which the framework region and CDR region are derived from the human germline immunoglobulin sequence. However, in certain embodiments, such recombinant human antibodies can be subjected to in vitro mutagenesis (or in vivo somatic mutagenesis, if using animals transgenic for the human Ig sequence), and therefore the recombinant antibody V H and V L The amino acid sequence of the region is from human germ cell line V H and V L While derived from and related to sequences, these sequences do not naturally exist within the in vivo human antibody germline repertoire.

[0273]

[0830] As used herein, "isotype" refers to a heavy chain constant region gene. Therefore, it refers to the encoded antibody class (e.g., IgM or IgG1).

[0274]

[0831] The phrases "antibody that recognizes an antigen" and "antibody that is specific to an antigen" are used in this specification. In this context, it is used interchangeably with the term "antibody that specifically binds to an antigen."

[0275]

[0832] The term "human antibody derivative" refers to a combination of an antibody and another active pharmaceutical ingredient or antibody. The term "conjugate" refers to any variant form of a human antibody, including conjugates. The terms "conjugate," "antibody-drug conjugate," "ADC," or "immunoconjugate" refer to an antibody or fragment thereof conjugated to another therapeutic portion, which can be conjugated to the antibodies described herein using methods available in the art.

[0276]

[0833] The terms "humanized antibody" and "humanization" refer to different mammalian species such as mice. This refers to antibodies in which a CDR sequence derived from the germline has been transplanted into a human framework sequence. Further modifications of the framework region may be made within the human framework sequence. Humanized non-human (e.g., mouse) antibodies are derived from non-human immunoglobulins. This...

Claims

1. A method of treating cancer with a tumor-infiltrating lymphocyte (TIL) population, (a) To obtain a first TIL population from tumors excised from a patient by processing tumor samples obtained from the patient into multiple tumor fragments; (b) Adding the tumor fragment to the closed system; (c) Performing a first expansion culture to produce a second TIL population by culturing the first TIL population in a cell culture medium containing IL-2 and optionally OKT-3, wherein the first expansion culture is performed in a closed container providing a first gas-permeable surface area, the first expansion culture is performed for about 3 to 14 days to obtain the second TIL population, the second TIL population being at least 50 times larger in number than the first TIL population, the transition from step (b) to step (c) occurring without opening the system, and optionally the medium containing an adenosine 2A receptor (A2aR) antagonist; (d) Producing a third TIL population by performing a second expansion culture of the cell culture medium of the second TIL population by supplementing it with additional IL-2, OKT-3 and antigen-presenting cells (APCs), wherein the second expansion culture is carried out for about 7 to 14 days to obtain the third TIL population, the third TIL population being a therapeutic TIL population, the second expansion culture is carried out in a closed container providing a second gas-permeable surface area, the transition from step (c) to step (d) occurs without opening the system, and optionally the medium contains an adenosine 2A receptor (A2aR) antagonist; (e) Recovering the therapeutic TIL population obtained from step (d), wherein the transition from step (d) to step (e) occurs without opening the system; and (f) transferring the recovered TIL population from step (e) to an infusion bag, the transfer from step (e) to (f) occurring without opening the system; and (g) administering the therapeutically effective portion of the final TIL population to the patient. A method that includes this.

2. The method according to claim 1, wherein the adenosine 2A receptor (A2aR) antagonist is selected from the group consisting of vipadenant, CPI-444 (siforadenant), SCH58261, ZM241385, SCH420814, SYN115, 8-CSC, KW-6002, A2A receptor antagonist 1, ADZ4635, ST4206, KF21213, SCH412348, 7MMG-49 or pharmaceutically acceptable salts, solvates, hydrates, cocrystals or prodrugs thereof and combinations thereof.

3. The method according to claim 1 or 2, wherein the A2aR antagonist is CPI-444 (siphoradenant) or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, or a combination thereof.

4. The method according to claim 1 or 2, wherein the A2aR antagonist is SCH58261 or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, or a combination thereof.

5. The method according to claim 1 or 2, wherein the A2aR antagonist is SYN115 or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, prodrug, or combination thereof.

6. The A2aR antagonist is ZM241385 or a pharmaceutically acceptable salt thereof. The method according to claim 1 or 2, wherein the solvate is a hydrate, a cocrystal, or a prodrug, or a combination thereof.

7. The method according to claim 1 or 2, wherein the A2aR antagonist is SCH420814 or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, or a combination thereof.

8. The method according to any one of claims 1 to 7, further comprising the step of treating the patient with the A2aR antagonist, wherein the first dose is administered to the patient on a day after administration of the third TIL population, selected from the group consisting of days 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, and 18.

9. The method according to any one of claims 1 to 8, further comprising the step of treating the patient with the A2aR antagonist before the step of excising the tumor from the patient.

10. The method according to any one of claims 1 to 9, wherein the first cell culture medium comprises an A2aR antagonist.

11. The method according to any one of claims 1 to 10, wherein the A2aR antagonist is CPI-444 (siphoradenant), and the A2aR antagonist is a xanthine family A2aR antagonist.

12. The method according to any one of claims 1 to 11, wherein the A2aR antagonist is added to the first cell culture medium at intervals selected from the group consisting of daily, every two days, every three days, every four days, every five days, every six days, every seven days, and every two weeks during the first expansion culture.

13. The method according to any one of claims 1 to 12, wherein the A2aR antagonist is added to the second cell culture medium at intervals selected from the group consisting of daily, every two days, every three days, every four days, every five days, every six days, every seven days, and every two weeks during the second expansion culture.

14. The method according to any one of claims 10 to 13, wherein the A2aR antagonist is added to the cell culture medium at a concentration sufficient to achieve a concentration of 0.01 μg / mL to 500 μg / mL.

15. The method according to claim 14, wherein the A2aR antagonist is added to the cell culture medium at a concentration sufficient to achieve a concentration of 1 μg / mL to 100 μg / mL.

16. The method according to any one of claims 1 to 15, wherein IL-2 is present in the first cell culture medium at an initial concentration of about 10 to about 6000 IU / mL.

17. The method according to claim 16, wherein IL-2 is present in the first cell culture medium at an initial concentration of about 3000 IU / mL.

18. The method according to claim 16, wherein IL-2 is present in the first cell culture medium at an initial concentration of about 800 to about 1100 IU / mL.

19. The method according to claim 16, wherein IL-2 is present in the first cell culture medium at an initial concentration of about 1000 IU / mL.

20. The method according to any one of claims 1 to 19, wherein IL-2 is present in the second cell culture medium at an initial concentration of about 10 to about 6000 IU / mL.

21. The method according to claim 20, wherein IL-2 is present in the second cell culture medium at an initial concentration of about 3000 IU / mL.

22. The method according to claim 20, wherein IL-2 is present in the second cell culture medium at an initial concentration of about 800 to about 1100 IU / mL.

23. The method according to claim 20, wherein IL-2 is present in the second cell culture medium at an initial concentration of about 1000 IU / mL.

24. The method according to any one of claims 1 to 23, wherein IL-15 is present in the first cell culture medium.

25. The method according to claim 24, wherein IL-15 is present in the first cell culture medium at an initial concentration of about 5 ng / mL to about 20 ng / mL.

26. The method according to any one of claims 1 to 25, wherein IL-15 is present in the second cell culture medium.

27. The method according to claim 26, wherein IL-15 is present in the second cell culture medium at an initial concentration of about 5 ng / mL to about 20 ng / mL.

28. The method according to any one of claims 1 to 27, wherein IL-21 is present in the first cell culture medium.

29. The method according to claim 28, wherein IL-21 is present in the first cell culture medium at an initial concentration of about 5 ng / mL to about 20 ng / mL.

30. The method according to any one of claims 1 to 29, wherein IL-21 is present in the second cell culture medium.

31. The method according to claim 30, wherein IL-21 is present in the second cell culture medium at an initial concentration of about 5 ng / mL to about 20 ng / mL.

32. The method according to any one of claims 1 to 31, wherein the OKT-3 antibody is present in the second cell culture medium at an initial concentration of about 10 ng / mL to about 60 ng / mL.

33. The method according to claim 32, wherein the OKT-3 antibody is present in the second cell culture medium at an initial concentration of about 30 ng / mL.

34. The method according to any one of claims 1 to 33, wherein the first expansion culture is carried out using a gas-permeable container.

35. The method according to any one of claims 1 to 34, wherein the second expansion culture is carried out using a gas-permeable container.

36. The method according to any one of claims 1 to 35, further comprising the step of treating the patient with a non-myeloablative lymphodepletion regimen before administering the third TIL population to the patient.

37. The aforementioned non-myeloablative lymphocyte depletion regimen is 60 mg / m². ２ Administer cyclophosphamide at a daily dose for two days, followed by 25 mg / m². ２ The method according to claim 36, comprising the step of administering fludarabine at a dose of / day over a period of 5 days.

38. The procedure further includes treating the patient with a tapering IL-2 regimen, which is initiated the day following the administration of the third TIL population to the patient, the tapering IL-2 regimen being 18,000,000 IU / m² on day 1. ２ On the second day, it reached 9,000,000 IU / m³. ２ Furthermore, on the third and fourth days, the levels reached 4,500,000 IU / m³. ２ The method according to any one of claims 1 to 37, comprising aldezleukin administered intravenously in the dose of [amount].

39. The method according to any one of claims 1 to 38, further comprising the step of administering the third TIL population to the patient at a dose of 0.10 mg / day to 50 mg / day, and then treating the patient with pegylated IL-2.

40. The method according to any one of claims 1 to 39, further comprising the step of treating the patient with a high-dose IL-2 regimen initiated the day following the administration of the third TIL population to the patient.

41. The method according to claim 40, wherein the high-dose IL-2 regimen comprises 600,000 or 720,000 IU / kg of aldesleukin or its biosimilar or variant, administered as a 15-minute bolus intravenous infusion every 8 hours until a tolerable dose is reached.

42. The method according to any one of claims 1 to 41, wherein the cancer is selected from the group consisting of melanoma, ovarian cancer, cervical cancer, lung cancer, bladder cancer, breast cancer, head and neck cancer, renal cell carcinoma, acute myeloid leukemia, colorectal cancer, bile duct cancer, and sarcoma.

43. The method according to any one of claims 1 to 42, wherein the cancer is selected from the group consisting of non-small cell lung cancer (NSCLC), triple-negative breast cancer, melanoma, head and neck cancer, bladder cancer, gastric cancer, microsatellite high instability (MSI-H) colorectal cancer, mismatch repair deficiency (dMMR) colorectal cancer, Hodgkin lymphoma, urothelial carcinoma, and hepatocellular carcinoma.

44. The method according to any one of claims 1 to 43, further comprising the step of treating the patient with a PD-1 inhibitor or a PD-L1 inhibitor before excising the tumor from the patient.

45. The method according to claim 44, wherein the PD-1 inhibitor or PD-L1 inhibitor is selected from the group consisting of nivolumab, pembrolizumab, durvalumab, atezolizumab, avelumab, and fragments, derivatives, variants, biosimilars, and combinations thereof.

46. The method according to any one of claims 1 to 45, further comprising the step of treating the patient with a PD-1 inhibitor or a PD-L1 inhibitor after excising the tumor from the patient.

47. The method according to claim 46, wherein the PD-1 inhibitor or PD-L1 inhibitor is selected from the group consisting of nivolumab, pembrolizumab, durvalumab, atezolizumab, avelumab, and fragments, derivatives, variants, biosimilars, and combinations thereof.

48. The method according to any one of claims 1 to 47, further comprising the step of administering the third TIL population to the patient, and then treating the patient with a PD-1 inhibitor or a PD-L1 inhibitor.

49. The PD-1 inhibitor or PD-L1 inhibitor mentioned above is nivolumab, pembrolizumab, dull The method according to claim 48, selected from the group consisting of valmab, atezolizumab, avelumab, and fragments, derivatives, variants, biosimilars, and combinations thereof.

50. The method according to any one of claims 1 to 49, wherein the first cell culture medium further comprises IL-4, IL-7, or a combination thereof.

51. The method according to any one of claims 1 to 50, wherein the second cell culture medium further comprises IL-4, IL-7, or a combination thereof.

52. The method according to any one of claims 1 to 51, wherein the first expansion culture is carried out over a period of 11 days or less.

53. The method according to any one of claims 1 to 52, wherein the second expansion culture is carried out over a period of 11 days or less.

54. A process for preparing a tumor-infiltrating lymphocyte (TIL) population, (a) A step of obtaining a first TIL population from a tumor resected from a patient by processing a tumor sample obtained from the patient into multiple tumor fragments; (b) Adding the tumor fragment to the closed system; (c) A step of performing a first expansion culture by culturing the first TIL population in a cell culture medium containing IL-2 to produce a second TIL population, wherein the first expansion culture is performed in a closed container providing a first gas-permeable surface area, the first expansion culture is performed for about 3 to 14 days to obtain the second TIL population, the second TIL population is at least 50 times larger in number than the first TIL population, the transition from step (b) to step (c) occurs without opening the system, and optionally the medium contains an adenosine 2A receptor (A2aR) antagonist; (d The step of generating a third TIL population by performing a second expansion culture of the cell culture medium of the second TIL population by supplementing it with additional IL-2, OKT-3, and antigen-presenting cells (APCs), wherein the second expansion culture is performed for approximately 7 to 14 days to obtain the third TIL population, the third TIL population is a therapeutic TIL population, the second expansion culture is performed in a closed container providing a second gas-permeable surface area, the transition from step (c) to step (d) occurs without opening the system, and optionally the medium contains an adenosine 2A receptor (A2aR) antagonist; (e) A step of collecting the therapeutic TIL population obtained from step (d), wherein the transition from step (d) to step (e) occurs without opening the system; and (f) a step of transferring the recovered TIL mass from step (e) to an infusion bag, wherein the transition from step (e) to (f) occurs without opening the system; and (g) The step of administering the therapeutically effective portion of the final TIL population to the patient. A process that includes this.

55. The process according to claim 54, wherein the first TIL population is obtained from tumors resected from a patient and treated in a culture medium containing an adenosine 2A receptor (A2aR) antagonist.

56. The adenosine 2A receptor (A2aR) antagonists mentioned above are CPI-444 (siphoradenanth), SCH58261, ZM241385, SCH420814, SYN115, 8-CSC, KW-6002, A2A receptor antagonist 1, ADZ4635, and VIPA The process according to claim 54 or 55, selected from the group consisting of Denant, ST4206, KF21213, SCH412348, 7MMG-49 or pharmaceutically acceptable salts, solvates, hydrates, cocrystals or prodrugs thereof and combinations thereof.

57. The process according to any one of claims 54 to 56, wherein the adenosine 2A receptor (A2aR) antagonist is CPI-444 (siphoradenant) or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal or prodrug thereof, or a combination thereof.

58. The process according to any one of claims 54 to 56, wherein the adenosine 2A receptor (A2aR) antagonist is SCH58261 or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, or a combination thereof.

59. The process according to any one of claims 54 to 56, wherein the A2aR antagonist is SYN115 or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, or a combination thereof.

60. The process according to any one of claims 54 to 56, wherein the A2aR antagonist is ZM241385 or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, or a combination thereof.

61. The process according to any one of claims 54 to 56, wherein the A2aR antagonist is SCH420814 or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, or a combination thereof.

62. The process according to any one of claims 54 to 61, wherein the first cell culture medium comprises a second adenosine 2A receptor (A2aR) antagonist.

63. The process according to any one of claims 54 to 62, wherein the adenosine 2A receptor (A2aR) antagonist is added to the first cell culture medium at intervals selected from the group consisting of daily, every two days, every three days, every four days, every five days, every six days, every seven days, and every two weeks during the first expansion culture.

64. The process according to any one of claims 54 to 63, wherein the adenosine 2A receptor (A2aR) antagonist is added to the second cell culture medium at intervals selected from the group consisting of daily, every two days, every three days, every four days, every five days, every six days, every seven days, and every two weeks during the second expansion culture.

65. The process according to any one of claims 54 to 64, wherein the adenosine 2A receptor (A2aR) antagonist is added to the cell culture medium at a concentration sufficient to achieve a concentration of 0.01 μM to 1000 μM.

66. The process according to any one of claims 54 to 65, wherein the adenosine 2A receptor (A2aR) antagonist is added to the cell culture medium at a concentration sufficient to achieve a concentration of 1 μg / mL to 100 μg / mL.

67. The process according to any one of claims 54 to 66, wherein IL-2 is present in the first cell culture medium at an initial concentration of about 10 to about 6000 IU / mL.

68. IL-2 is present in the first cell culture medium at an initial concentration of approximately 3000 IU / mL. or the process according to any one of claims 54 to 67.

69. The process according to any one of claims 54 to 68, wherein IL-2 is present in the first cell culture medium at an initial concentration of about 800 to about 1100 IU / mL.

70. The process according to any one of claims 54 to 69, wherein IL-2 is present in the first cell culture medium at an initial concentration of about 1000 IU / mL.

71. The process according to any one of claims 54 to 70, wherein IL-2 is present in the second cell culture medium at an initial concentration of about 10 to about 6000 IU / mL.

72. The process according to any one of claims 54 to 71, wherein IL-2 is present in the second cell culture medium at an initial concentration of about 3000 IU / mL.

73. The process according to any one of claims 54 to 72, wherein IL-2 is present in the second cell culture medium at an initial concentration of about 800 to about 1100 IU / mL.

74. The process according to any one of claims 54 to 73, wherein IL-2 is present in the second cell culture medium at an initial concentration of about 1000 IU / mL.

75. The process according to any one of claims 54 to 74, wherein IL-15 is present in the first cell culture medium.

76. The process according to any one of claims 54 to 75, wherein IL-15 is present in the first cell culture medium at an initial concentration of about 5 ng / mL to about 20 ng / mL.

77. The process according to any one of claims 54 to 76, wherein IL-15 is present in the second cell culture medium.

78. The process according to any one of claims 54 to 77, wherein IL-15 is present in the second cell culture medium at an initial concentration of about 5 ng / mL to about 20 ng / mL.

79. The process according to any one of claims 54 to 78, wherein IL-21 is present in the first cell culture medium.

80. The process according to any one of claims 54 to 79, wherein IL-21 is present in the first cell culture medium at an initial concentration of about 5 ng / mL to about 20 ng / mL.

81. The process according to any one of claims 54 to 80, wherein IL-21 is present in the second cell culture medium.

82. The process according to any one of claims 54 to 81, wherein IL-21 is present in the second cell culture medium at an initial concentration of about 5 ng / mL to about 20 ng / mL.

83. The process according to any one of claims 54 to 82, wherein the OKT-3 antibody is present in the second cell culture medium at an initial concentration of about 10 ng / mL to about 60 ng / mL.

84. The process according to any one of claims 54 to 83, wherein the OKT-3 antibody is present in the second cell culture medium at an initial concentration of about 30 ng / mL.

85. The process according to any one of claims 54 to 84, wherein the first expansion culture is carried out using a gas-permeable container.

86. The process according to any one of claims 54 to 85, wherein the second expansion culture is carried out using a gas-permeable container.

87. A tumor-infiltrating lymphocyte (TIL) population that can be obtained from the process described in any one of claims 54 to 86.

88. A pharmaceutical composition comprising a tumor-infiltrating lymphocyte (TIL) population for use in the treatment of cancer, wherein the tumor-infiltrating lymphocyte (TIL) population can be obtained by a process according to any one of claims 54 to 87, and the pharmaceutical composition comprises the third TIL population.

89. A pharmaceutical composition for use in the treatment of cancer according to claim 88, for use in combination with an adenosine 2A receptor (A2aR) antagonist.

90. A pharmaceutical composition for use in the treatment of cancer according to claim 88, for use in combination with an adenosine 2A receptor (A2aR) antagonist, wherein the adenosine 2A receptor (A2aR) antagonist is to be administered to the patient on the day following the administration of the third TIL population, and the adenosine 2A receptor (A2aR) antagonist is administered orally twice daily in each treatment cycle.

91. A pharmaceutical composition for use in the treatment of cancer according to claim 88, for use in combination with an adenosine 2A receptor (A2aR) antagonist, wherein the adenosine 2A receptor (A2aR) antagonist is to be administered prior to the step of tumor resection from the patient, and the adenosine 2A receptor (A2aR) antagonist is to be administered orally twice daily in each treatment cycle.

92. The pharmaceutical composition for use in the treatment of cancer according to claim 88, wherein the adenosine 2α receptor antagonist is CPI-444 (siforadenanth) or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal or prodrug thereof, or a combination thereof.

93. The pharmaceutical composition for use in the treatment of cancer according to claim 92, wherein the adenosine 2a receptor antagonist is administered twice daily for at least 14 days.

94. The pharmaceutical composition for use in the treatment of cancer according to claim 92, wherein the adenosine 2a receptor antagonist is administered twice daily in a total daily dose of about 100 mg to about 500 mg.

95. The pharmaceutical composition for use in the treatment of cancer according to claim 92, wherein the adenosine 2a receptor antagonist is administered twice daily at a total daily dose of about 200 mg for at least 14 days.

96. A pharmaceutical composition for use in the treatment of cancer according to claim 88, for use in combination with a non-myeloablative lymphocyte depletion regimen.

97. A pharmaceutical composition for use in the treatment of cancer according to claim 88, for use in combination with a myeloablative lymphoid depletion regimen prior to administration of the third TIL population to the patient.

98. It is intended for use in combination with a myeloablative lymph depletion regimen, the non-myeloablative lymph depletion regimen to be administered before administering the third TIL population to the patient, the non-myeloablative lymph depletion regimen is 60 mg / m² ２ Administer cyclophosphamide at a daily dose for two days, followed by 25 mg / m². ２ A pharmaceutical composition for use in the treatment of cancer according to claim 88, comprising the step of administering fludarabine at a dose of / day over a period of 5 days.

99. A pharmaceutical composition for use in the treatment of cancer according to claim 88, for use in combination with a tapering IL-2 regimen.

100. For use in combination with a tapered IL-2 regimen starting on the day after administration of the third TIL population to the patient, the tapered IL-2 regimen being 18,000,000 IU / m ２ on day 1, 9,000,000 IU / m ２ on day 2, and 4,500,000 IU / m ２ on days 3 and 4 by intravenous administration, the pharmaceutical composition for use in the treatment of cancer according to claim 88, comprising aldesleukin.

101. A pharmaceutical composition for use in the treatment of cancer according to claim 88, for use in combination with pegylated IL-2.

102. A pharmaceutical composition for use in the treatment of cancer according to claim 88, for use in combination with pegylated IL-2 administered to the patient after administration of the third TIL population at a dose of 0.10 mg / day to 50 mg / day.

103. A pharmaceutical composition for use in the treatment of cancer according to claim 88, intended for use in combination with a high-dose IL-2 regimen.

104. A pharmaceutical composition for use in the treatment of cancer according to claim 88, for use in combination with a high-dose IL-2 regimen initiated the day following the administration of the third TIL population to the patient.

105. A pharmaceutical composition for use in the treatment of cancer according to claim 88, for use in combination with a high-dose IL-2 regimen initiated the day following the administration of the third TIL population to the patient, wherein the high-dose IL-2 regimen comprises 600,000 or 720,000 IU / kg of aldesleukin or its biosimilar or variant, administered as a 15-minute bolus intravenous infusion every 8 hours up to a tolerable dose.

106. A pharmaceutical composition for use in the treatment of cancer according to claim 88, for use in combination with a PD-1 inhibitor or a PD-L1 inhibitor.

107. A pharmaceutical composition for use in the treatment of cancer according to claim 88, for use in combination with a PD-1 inhibitor or a PD-L1 inhibitor, wherein the PD-1 inhibitor or PD-L1 inhibitor is selected from the group consisting of nivolumab, pembrolizumab, durvalumab, atezolizumab, avelumab, and fragments, derivatives, variants, biosimilars and combinations thereof.

108. A pharmaceutical composition for use in the treatment of cancer according to claim 88, for use in combination with a PD-1 inhibitor or a PD-L1 inhibitor, wherein the PD-1 inhibitor or PD-L1 inhibitor is administered before the resection of the tumor from the patient.

109. A pharmaceutical composition for use in the treatment of cancer according to claim 88, for use in combination with a PD-1 inhibitor or PD-L1 inhibitor prior to resection of the tumor from the patient, wherein the PD-1 inhibitor or PD-L1 inhibitor is selected from the group consisting of nivolumab, pembrolizumab, durvalumab, atezolizumab, avelumab, and fragments, derivatives, variants, biosimilars and combinations thereof.

110. A pharmaceutical composition for use in the treatment of cancer according to claim 88, for use in combination with a PD-1 inhibitor or PD-L1 inhibitor after tumor resection from the patient.

111. A pharmaceutical composition for use in the treatment of cancer according to claim 88, for use in combination with a PD-1 inhibitor or PD-L1 inhibitor after resection of the tumor from the patient, wherein the PD-1 inhibitor or PD-L1 inhibitor is selected from the group consisting of nivolumab, pembrolizumab, durvalumab, atezolizumab, avelumab, and fragments, derivatives, variants, biosimilars and combinations thereof.

112. A pharmaceutical composition for use in the treatment of cancer according to claim 88, for use in combination with a PD-1 inhibitor or PD-L1 inhibitor to be administered to the patient after administering the third TIL population.

113. A pharmaceutical composition for use in the treatment of cancer according to claim 88, for use in combination with a PD-1 inhibitor or PD-L1 inhibitor to be administered to the patient after administration of the third TIL population, wherein the PD-1 inhibitor or PD-L1 inhibitor is selected from the group consisting of nivolumab, pembrolizumab, durvalumab, atezolizumab, avelumab and fragments, derivatives, variants, biosimilars and combinations thereof.

114. A pharmaceutical composition for use in the treatment of cancer according to any one of claims 88 to 109, wherein the cancer is selected from the group consisting of melanoma, ovarian cancer, cervical cancer, lung cancer, bladder cancer, breast cancer, head and neck cancer, renal cell carcinoma, acute myeloid leukemia, colorectal cancer, bile duct cancer, and sarcoma.

115. A pharmaceutical composition for use in the treatment of cancer according to any one of claims 88 to 110, wherein the cancer is selected from the group consisting of non-small cell lung cancer (NSCLC), triple-negative breast cancer, melanoma, head and neck cancer, bladder cancer, gastric cancer, microsatellite-high instability (MSI-H) colorectal cancer, mismatch repair deficiency (dMMR) colorectal cancer, Hodgkin lymphoma, urothelial carcinoma, and hepatocellular carcinoma.

116. The adenosine 2A receptor (A2aR) antagonist is CPI-444 (siphoradenant) or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, or a combination thereof, according to any one of claims 88 to 110, for use in the treatment of cancer.

117. The adenosine 2A receptor (A2aR) antagonist is SCH58261 or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, or a combination thereof, according to any one of claims 88 to 110, for use in the treatment of cancer.

118. The adenosine 2A receptor (A2aR) antagonist is SYN115 or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, or a combination thereof, according to any one of claims 88 to 110, a pharmaceutical composition for use in the treatment of cancer.

119. The adenosine 2A receptor (A2aR) antagonist is ZM241365 or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, or a combination thereof, according to any one of claims 88 to 110, for use in the treatment of cancer.

120. The adenosine 2A receptor (A2aR) antagonist is 7MMG or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, or a combination thereof, where X is C and R is para-F, meta-F, or para-CH ３ , 2,4-difluoro, 2,6-difluoro, 3,4-difluoro, 3,4-dimethoxy, meth-(2-methoxyethoxy), meth-(1,3-benzodioxole), para-Cl, para-CF ３ A pharmaceutical composition for use in the treatment of cancer according to any one of claims 88 to 110, selected from the group consisting of para-CN and para-tert-butyl.

121. The adenosine 2A receptor (A2aR) antagonist is 7MMG or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, and combinations thereof, where X is N and R is para-F, meta-F, ortho-F, para-Cl, or meta-CF ３ , 2,4-difluoro, 2,6-difluoro, 3,4-difluoro, meta-(2-methoxyethoxy), meta-(1,3-benzodioxole), para-CH ３ and meta-OCH ３ A pharmaceutical composition for use in the treatment of cancer according to any one of claims 88 to 110, selected from the group consisting of the following.

122. A method of treating cancer with tumor-infiltrating lymphocytes (TILs), (a) To obtain a first TIL population from tumors excised from a patient by processing tumor samples obtained from the patient into multiple tumor fragments; (b) Adding the tumor fragment to the closed system; (c) Performing a first expansion culture by culturing the first TIL population in a cell culture medium containing IL-2 to produce a second TIL population, wherein the first expansion culture is performed in a closed container providing a first gas-permeable surface area, the first expansion culture is performed for about 3 to 14 days to obtain the second TIL population, the second TIL population being at least 50 times larger in number than the first TIL population, the transition from step (b) to step (c) occurring without opening the system, and optionally, the medium containing an adenosine 2A receptor (A2aR) antagonist; (d) Producing a third TIL population by performing a second expansion culture of the cell culture medium of the second TIL population by supplementing it with additional IL-2, OKT-3 and antigen-presenting cells (APCs), wherein the second expansion culture is carried out for about 7 to 14 days to obtain the third TIL population, the third TIL population being a therapeutic TIL population, the second expansion culture is carried out in a closed container providing a second gas-permeable surface area, the transition from step (c) to step (d) occurs without opening the system, and optionally the medium contains an adenosine 2A receptor (A2aR) antagonist; (e) Recovering the therapeutic TIL population obtained from step (d), wherein the transition from step (d) to step (e) occurs without opening the system; and (f) transferring the recovered TIL population from step (e) to an infusion bag, the transfer from step (e) to (f) occurring without opening the system; and (g) administering the therapeutically effective portion of the final TIL population to the patient. A method that includes this.

123. The adenosine 2A receptor (A2aR) antagonist is CPI-444 (Siphora The method according to claim 122, selected from the group consisting of denant, SCH58261, ZM241385, SCH420814, SYN115, 8-CSC, KW-6002, A2A receptor antagonist 1, ADZ4635, vipadenant, ST4206, KF21213, SCH412348, 7MMG-49 or pharmaceutically acceptable salts, solvates, hydrates, cocrystals or prodrugs thereof and combinations thereof.

124. The method according to claim 122, wherein the adenosine 2A receptor (A2aR) antagonist is CPI-444 (siphoradenant) or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal or prodrug thereof, or a combination thereof.

125. The method according to claim 122, wherein the adenosine 2A receptor (A2aR) antagonist is SCH58261 or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal or prodrug thereof, or a combination thereof.

126. The method according to claim 122, wherein the adenosine 2A receptor (A2aR) antagonist is SYN115 or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, or a combination thereof.

127. The method according to claim 122, wherein the adenosine 2A receptor (A2aR) antagonist is ZM241385 or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal or prodrug thereof, or a combination thereof.

128. The adenosine 2A receptor (A2aR) antagonist is 7MMG or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, or a combination thereof, where X is C and R is para-F, meta-F, or para-CH ３ , 2,4-difluoro, 2,6-difluoro, 3,4-difluoro, 3,4-dimethoxy, meth-(2-methoxyethoxy), meth-(1,3-benzodioxole), para-Cl, para-CF ３ The method according to claim 122, selected from the group consisting of para-CN and para-tert-butyl.

129. The adenosine 2A receptor (A2aR) antagonist is 7MMG or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, and combinations thereof, where X is N and R is para-F, meta-F, ortho-F, para-Cl, or meta-CF ３ , 2,4-difluoro, 2,6-difluoro, 3,4-difluoro, meta-(2-methoxyethoxy), meta-(1,3-benzodioxole), para-CH ３ and meta-OCH ３ The method according to claim 122, selected from the group consisting of the following.

130. The method according to any one of claims 122 to 129, wherein the adenosine 2A receptor (A2aR) antagonist is present at a concentration of 0.01 μg / mL to 500 μg / mL at the start of step (d).

131. The method according to claim 130, wherein the adenosine 2A receptor (A2aR) antagonist is present at a concentration of 0.05 μg / mL to 200 μg / mL at the start of step (d).

132. The method according to claim 131, wherein the adenosine 2A receptor (A2aR) antagonist is present at a concentration of about 100 μg / mL at the start of step (d).

133. The method according to any one of claims 122 to 132, wherein the adenosine 2A receptor (A2aR) antagonist is maintained at a concentration of 1 μg / mL to 75 μg / mL throughout step (d).

134. The method according to claim 133, wherein the adenosine 2A receptor (A2aR) antagonist is maintained at a concentration of 5 μg / mL to 50 μg / mL throughout step (d).

135. The method according to claim 134, wherein the adenosine 2A receptor (A2aR) antagonist is maintained at a concentration of about 30 μg / mL throughout step (d).

136. The third TIL group is CD4 in the second TIL group. ＋ CD8 for TIL ＋ Compared to the reference ratio of TIL, CD4 ＋ CD8 for TIL ＋ The method according to any one of claims 122 to 135, showing the increased ratio of TIL.

137. The method according to claim 136, wherein the increased ratio is at least 5% greater than the reference ratio.

138. The method according to claim 137, wherein the increased ratio is at least 10% greater than the reference ratio.

139. The method according to claim 138, wherein the increased ratio is at least 20% greater than the reference ratio.

140. The method according to claim 139, wherein the increased ratio is at least 35% greater than the reference ratio.

141. The method according to claim 140, wherein the increased ratio is at least 50% greater than the reference ratio.

142. The method according to any one of claims 122 to 141, wherein the cancer is selected from the group consisting of melanoma, uveal (intraocular) melanoma, ovarian cancer, cervical cancer, lung cancer, bladder cancer, breast cancer, head and neck cancer (head and neck squamous cell carcinoma), renal cell carcinoma, colorectal cancer, pancreatic cancer, glioblastoma, bile duct cancer, and sarcoma.

143. The method according to any one of claims 122 to 142, wherein the cancer is selected from the group consisting of cutaneous melanoma, uveal (intraocular) melanoma, platinum-resistant ovarian cancer, pancreatic ductal adenocarcinoma, osteosarcoma, triple-negative breast cancer, non-small cell lung cancer (NSCLC), triple-negative breast cancer, melanoma, head and neck cancer, bladder cancer, gastric cancer, microsatellite high instability (MSI-H) colorectal cancer, mismatch repair deficiency (dMMR) colorectal cancer, Hodgkin lymphoma, urothelial carcinoma, and hepatocellular carcinoma.

144. The method according to any one of claims 122 to 144, wherein the adenosine 2a receptor antagonist is present in both the first culture medium and the second culture medium.

145. The process according to any one of claims 54 to 86, wherein the adenosine 2α receptor antagonist is present in both the first culture medium and the second culture medium.

146. The method according to any one of claims 1 to 22, wherein the adenosine 2a receptor antagonist is present in both the first culture medium and the second culture medium.

147. The method according to any one of claims 1 to 22, wherein the tumor is excised and placed in a culture medium containing an anti-CD3 antibody and an adenosine 2a receptor antagonist.

148. The tumor was excised and treated with an anti-CD3 antibody and an adenosine 2a receptor antagonist. The process according to any one of claims 54 to 86, wherein the culture medium is placed in the culture medium containing the process.

149. The method according to any one of claims 122 to 144, wherein the tumor is excised and placed in a culture medium containing an anti-CD3 antibody and an adenosine 2a receptor antagonist.

150. The method according to claim 122, wherein the additional step of treating the patient with an adenosine 2A receptor antagonist is added at the beginning of step (a).

151. The method according to claim 150, wherein the adenosine 2a receptor antagonist is selected from the group consisting of CPI-444 (siforadenanth), SCH58261, ZM241385, SCH420814, SYN115, 8-CSC, KW-6002, A2A receptor antagonist 1, ADZ4635, vipadenant, ST4206, KF21213, SCH412348, 7MMG-49 or pharmaceutically acceptable salts, solvates, hydrates, cocrystals or prodrugs thereof and combinations thereof.

152. The method according to claim 150, wherein the adenosine 2α receptor antagonist is CPI-444 (siforadenanthene) or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal or prodrug thereof, or a combination thereof.

153. The method according to claim 152, wherein the CPI-444 (siforadenanth) is administered orally at a total daily dose of 1 mg / kg to about 100 mg / kg.

154. The method according to claim 153, wherein the CPI-444 (sifoladenant) is administered twice daily at a total daily dose of 200 mg.

155. The method according to claim 154, wherein the CPI-444 (siforadenanth) is administered twice daily at a total daily dose of approximately 100 mg.

156. The method according to any one of claims 152 to 155, wherein the adenosine 2a receptor antagonist is administered daily in a 14-day cycle.

157. The method according to claim 156, wherein the patient is treated with one or more cycles of the adenosine 2a receptor antagonist.

158. The method according to claim 122, wherein the additional step of treating the patient with an adenosine 2A receptor antagonist is added at the beginning of step (f).

159. The method according to claim 158, wherein the adenosine 2a receptor antagonist is selected from the group consisting of CPI-444 (siforadenanth), SCH58261, ZM241385, SCH420814, SYN115, 8-CSC, KW-6002, A2A receptor antagonist 1, ADZ4635, vipadenant, ST4206, KF21213, SCH412348, 7MMG-49 or pharmaceutically acceptable salts, solvates, hydrates, cocrystals or prodrugs thereof and combinations thereof.

160. The method according to claim 158, wherein the adenosine 2α receptor antagonist is CPI-444 (siforadenanthene) or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal or prodrug thereof, or a combination thereof.

161. The method according to claim 160, wherein the CPI-444 (siphoradenanth) is administered orally at a total daily dose of approximately 1 mg / kg to approximately 100 mg / kg.

162. The method according to claim 161, wherein the CPI-444 (siforadenanth) is administered twice daily at a total daily dose of approximately 200 mg.

163. The method according to claim 162, wherein the CPI-444 (siforadenanth) is administered twice daily at a total daily dose of approximately 100 mg.

164. The method according to any one of claims 160 to 163, wherein the adenosine 2a receptor antagonist is administered daily in a 14-day cycle.

165. The method according to claim 164, wherein the patient is treated with one or more cycles of the adenosine 2a receptor antagonist.

166. The method according to any one of claims 122 to 149, wherein the additional step of treating the patient with an adenosine 2A receptor antagonist is added at the beginning of step (a).

167. The method according to any one of claims 122 to 149, wherein the additional step of treating the patient with an adenosine 2A receptor antagonist is added at the end of step (a).

168. The method according to any one of claims 122 to 149, wherein the additional step of treating the patient with an adenosine 2A receptor antagonist is added at the beginning of step (f).

169. The method according to any one of claims 122 to 149, wherein the additional step of treating the patient with an adenosine 2A receptor antagonist is added at the end of step (f).

170. The method according to claim 168 or 169, wherein the adenosine 2A receptor antagonist is initially administered intravenously, and subsequent doses are administered orally.

171. The method according to any one of claims 166 to 170, wherein the adenosine 2A receptor antagonist is selected from the group consisting of CPI-444 (siforadenanth), SCH58261, ZM241385, SCH420814, SYN115, 8-CSC, KW-6002, A2A receptor antagonist 1, ADZ4635, vipardenant, ST4206, KF21213, SCH412348, and 7MMG-49.

172. The method according to any one of claims 122 to 171, wherein a first adenosine 2a receptor antagonist is used in the first and second TIL culture media, and a second adenosine 2a receptor antagonist is administered to the patient.

173. The method according to claim 172, wherein the first and second adenosine 2a receptor antagonists are the same.

174. The first and second adenosine 2a receptor antagonists are different, according to the method of claim 172.

175. The method according to claim 172, wherein the first adenosine 2a receptor antagonist is a member of the xanthine family.

176. The second adenosine 2a receptor antagonists mentioned above are CPI-444 (siphoradenanth), SCH58261, ZM241385, SCH420814, SYN115, 8-CSC, KW-6002, A2A receptor antagonist 1, ADZ4635, and bipadenan. The method according to claim 172, selected from the group consisting of T, ST4206, KF21213, SCH412348, and 7MMG-49.

177. Therapeutic doses of: (1) cisplatin and concurrent radiotherapy; (2) cetuximab followed by radiotherapy; (3) carboplatin, 5-fluorouracil and concurrent radiotherapy; (4) hydroxyurea, 5-fluorouracil and concurrent radiotherapy; (5) cisplatin, paclitaxel and concurrent radiotherapy; (6) cisplatin, infused 5-fluorouracil and concurrent radiotherapy; (7) intermittently administered cisplatin and radiotherapy; (8) docetaxel, cisplatin, 5-fluorouracil and concurrent radiotherapy; (9) paclitaxel, cisplatin, infused 5-fluorouracil and concurrent radiotherapy; (10) cisplatin and radiotherapy followed by cisplatin, 5-fluorouracil and radiotherapy; (11) docetaxel and cisplatin followed by cisplatin and radiotherapy; (12) cisplatin, 5-fluorouracil and docetaxel (13) Cisplatin and docetaxel; (14) Cisplatin and paclitaxel; (15) Carboplatin and paclitaxel; (16) Cisplatin and cetuximab; (17) Cisplatin and 5-fluorouracil; (18) Cisplatin, docetaxel and cetuximab; (19) Carboplatin, docetaxel and cetuximab; (20) Cisplatin and gemcitabine; (21) Gemcitabine and vinol The method according to claim 1, further comprising the step of administering a chemotherapy regimen selected from the group consisting of (22) relbin; (23) cisplatin; (24) carboplatin; (25) paclitaxel; (26) 5-fluorouracil; (27) methotrexate; (28) gemcitabine; (29) capecitabine; (30) cetuximab; (31) afatinib; (32) lapatinib; and (33) neratinib.

178. Therapeutic doses of: (1) cisplatin and concurrent radiotherapy; (2) cetuximab followed by radiotherapy; (3) carboplatin, 5-fluorouracil and concurrent radiotherapy; (4) hydroxyurea, 5-fluorouracil and concurrent radiotherapy; (5) cisplatin, paclitaxel and concurrent radiotherapy; (6) cisplatin, infused 5-fluorouracil and concurrent radiotherapy; (7) intermittently administered cisplatin and radiotherapy; (8) docetaxel, cisplatin, 5-fluorouracil and concurrent radiotherapy; (9) paclitaxel, cisplatin, infused 5-fluorouracil and concurrent radiotherapy; (10) cisplatin and radiotherapy followed by cisplatin, 5-fluorouracil and radiotherapy; (11) docetaxel and cisplatin followed by cisplatin and radiotherapy; (12) cisplatin, 5-fluorouracil and docetaxel; (13) (14) Cisplatin and docetaxel; (15) Cisplatin and paclitaxel; (16) Carboplatin and cetuximab; (17) Cisplatin and 5-fluorouracil; (18) Cisplatin, docetaxel and cetuximab; (19) Carboplatin, docetaxel and cetuximab; (20) Cisplatin and gemcitabine; (21) Gemcitabine and vinorelbine; (22) Ci The method according to any one of claims 122 to 170, further comprising the step of administering a chemotherapy regimen selected from the group consisting of (23) suplatin; (24) carboplatin; (25) paclitaxel; (26) docetaxel; (27) 5-fluorouracil; (28) methotrexate; (29) gemcitabine; (30) capecitabine; (30) cetuximab; (31) afatinib; (32) lapatinib; and (33) neratinib.

179. The method according to any one of claims 122 to 170, further comprising the step of administering a therapeutically effective dose of a PD-1 inhibitor or a PD-L1 inhibitor.

180. The PD-1 inhibitor or PD-L1 inhibitor is nivolumab, pembrolizumab, durvalumab, atezolizumab, avelumab, and their fragments, derivatives, variants, and biosimilars. The method according to claim 179, selected from the group consisting of - and combinations thereof.

181. The method according to claim 179 or 180, further comprising the step of administering an A2aR antagonist.

182. The method according to claim 181, wherein the A2aR antagonist is selected from the group consisting of CPI-444 (siphoradenant), SCH58261, ZM241385, SCH420814, SYN115, 8-CSC, KW-6002, A2A receptor antagonist 1, ADZ4635, vipardenant, ST4206, KF21213, SCH412348, 7MMG-49 or pharmaceutically acceptable salts, solvates, hydrates, cocrystals or prodrugs thereof and combinations thereof.

183. The method according to claim 182, wherein the A2aR antagonist is CPI-444 (siphoradenant) or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal or prodrug thereof, or a combination thereof.

184. CPI-444 (siphoradenant) or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, or prodrugs and combinations thereof are available in 25 mg BID, 50 mg BID, 75 mg BID, 100 mg BID, 125 mg BID, and 150 mg The method according to claim 183, wherein the drug is administered orally in a dose selected from the group consisting of BID, 175 mg BID, 200 mg BID, and 225 mg BID.

185. The method according to claim 183, wherein CPI-444 is administered orally twice daily at a total daily dose of approximately 200 mg over the first 14 days of a 28-day cycle.

186. The method according to claim 183, wherein CPI-444 (sifoladenant) is administered orally twice daily at a total daily dose of approximately 200 mg over each day of a 28-day cycle.

187. The method according to any one of claims 122 to 170, further comprising the step of administering a therapeutically effective dose of a PD-1 inhibitor or a PD-L1 inhibitor and an A2aR antagonist.

188. The method according to claim 187, wherein the PD-1 inhibitor is atezolizumab, and the A2aR antagonist is CPI-444 or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal or prodrug thereof, or a combination thereof.

189. The method according to claim 187, wherein the PD-1 inhibitor or PD-L1 inhibitor is selected from the group consisting of nivolumab, pembrolizumab, durvalumab, atezolizumab, avelumab, and fragments, derivatives, variants, biosimilars, and combinations thereof.

190. The method according to claim 189, wherein the A2aR antagonist is CPI-444 or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, or a combination thereof.

191. The method according to claim 190, wherein the A2aR antagonist is administered orally twice daily at a total daily dose of approximately 200 mg.

192. The method according to claim 191, wherein the A2aR administration is continued for at least 28 days.

193. The administration of A2aR is continued for at least 14 days, as described in claim 191. The method.

194. The method according to claim 191, wherein the administration of A2aR is continued for at least 7 days.

195. The method according to any one of claims 1 to 53, wherein the A2aR antagonist is administered in an order initiated before tumor resection and continued thereafter.

196. The method according to claim 195, wherein the A2aR antagonist is CPI-444 (siphoradenant) or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal or prodrug thereof, or a combination thereof.

197. The method according to any one of claims 1 to 53, wherein the A2aR antagonist is administered continuously, starting two months prior to tumor resection.

198. The method according to any one of claims 1 to 53, wherein the A2aR antagonist is administered continuously, starting at least one month before tumor resection.

199. The method according to any one of claims 1 to 53, wherein the A2aR antagonist is administered continuously, starting at least two weeks before tumor resection.

200. The method according to any one of claims 1 to 53, wherein the A2aR antagonist is administered continuously, starting at least one week before tumor resection.

201. The method according to any one of claims 1 to 53, wherein the A2aR antagonist is administered continuously, starting at least one week before tumor resection.

202. The method according to any one of claims 1 to 53, wherein the A2aR antagonist is administered continuously, starting at least two days before tumor resection.

203. The method according to any one of claims 190 to 203, wherein A2aR is CPI-444 (siphoradenant) or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal or prodrug thereof, or a combination thereof.

204. CPI-444 (siphoradenant) or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, or prodrugs and combinations thereof are available in 25 mg BID, 50 mg BID, 75 mg BID, 100 mg BID, 125 mg BID, and 150 mg The method according to claim 203, wherein the drug is administered orally in a dose selected from the group consisting of BID, 175 mg BID, 200 mg BID, and 225 mg BID.

205. The method according to claim 204, wherein the dose is 100 mg BID.

206. The adenosine 2a receptor antagonist is 【Chemistry 1】 A pharmaceutical composition for use in the treatment of cancer according to claim 88, which is a pharmaceutically acceptable salt, solvate, hydrate, cocrystal or prodrug thereof, or a combination thereof.

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