Composition and method for car t-cell therapy

Abstract

To provide a method for treating a patient having cancer by administering a composition including a CAR T-cell and a small molecule connected to a targeting moiety by a linker to a patient, and a composition to be used for the method.SOLUTION: A method for treating cancer includes: i) a step of administering a compound or a pharmaceutically acceptable salt thereof to a patient, in which the compound includes a small molecule ligand connected to a targeting moiety by a linker; ii) a step of administering a CAR T-cell composition including a first CAR T-cell to the patient, in which the CAR T-cell includes CAR oriented toward a targeting moiety; and iii) a step of administering a CAR T-cell composition including a second CAR T-cell to the patient, in which the CAR T-cell includes CAR oriented toward a targeting moiety.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Application No. 62 / 464,792, filed February 28, 2017, U.S. Provisional Application No. 62 / 480,627, filed April 3, 2017, U.S. Provisional Application No. 62 / 554,421, filed September 5, 2017, U.S. Provisional Application No. 62 / 620701, filed January 23, 2018, U.S. Provisional Application No. 62 / 620,384, filed January 22, 2018, U.S. Provisional Application No. 62 / 620,423, filed January 22, 2018, and U.S. Provisional Application No. 62 / 634,595, filed February 23, 2018, all of which are incorporated herein by reference in their entireties.

[0002] Technical Field The present invention relates to methods of treating a patient with cancer by administering to the patient a composition comprising CAR T cells and administering to the patient a small molecule linked to a targeting moiety by a linker. The present invention also relates to compositions for use in such methods. [Background technology]

[0003] background Immunotherapy based on the adoptive transfer of lymphocytes (e.g., T cells) into patients is a valuable treatment for the treatment of cancer and other diseases. Significant progress has been made in the development of immunotherapy based on the adoptive transfer of lymphocytes. Among many different types of immunotherapeutic agents, one of the most promising immunotherapeutic agents under development is T cells expressing chimeric antigen receptors (CAR T cells). Chimeric antigen receptors (CARs) are genetically engineered receptors designed to target specific antigens, such as tumor antigens. This targeting can result in cytotoxicity against tumors, for example, so that CAR-expressing CAR T cells can target and kill tumors via specific tumor antigens.

[0004] First-generation CARs consist of antibody-derived recognition regions, such as single-chain fragment variable (scFv) regions, and activation signaling domains for recognizing and binding to antigens expressed by tumors. For example, the CD3ζ chain of T cells can serve as a T cell activation signal in CARs. CAR T cells have shown positive results in vitro, but have only limited success in eliminating diseases (e.g., cancer) in clinical trials. One problem is the inability to long-term activate and expand CAR T cell populations in vivo.

[0005] To address this issue and achieve long-term activation of T cells in vivo, second-generation CARs have included costimulatory domains (e.g., CD137, CD28, or CD134). The addition of a costimulatory domain enhances the in vivo proliferation and survival of CAR-containing T cells, and early clinical data indicate that such constructs are promising therapeutic agents for the treatment of diseases such as cancer. Summary of the Invention [Problem to be solved by the invention]

[0006] Despite improvements in CAR T cell therapy, several problems remain. First, 'off-target' toxicity can occur against normal cells expressing the antigen targeted by the CAR T cells (e.g., tumor-associated antigens). Second, uncontrolled CAR T cell activation can cause rapid and uncontrollable elimination of diseased cells (e.g., cancer cells) by the CAR T cells, inducing a series of metabolic disorders called tumor lysis syndrome or cytokine release syndrome (CRS), which can be fatal to the patient. Tumor lysis syndrome and CRS can result from administered CAR T cells that are not easily controlled and are activated uncontrollably. Thus, although CAR T cells hold great promise as a tool in the treatment of diseases such as cancer, there is a need for additional CAR T cell therapies that offer reduced off-target toxicity and more tightly controlled CAR T cell activation. [Means for solving the problem]

[0007] Summary of the Invention The present inventors have discovered a method to reduce off-target toxicity and more tightly control CAR T cell activation, providing an important advancement in CAR T cell therapy. In various embodiments described herein, a small molecule ligand linked to a targeting moiety by a linker is used as a bridge between the cancer and the CAR T cell, directing the CAR T cell to the cancer for cancer remission. In certain embodiments, the "small molecule ligand" can be, for example, folate, DUPA, an NK-1R ligand, a CAIX ligand, a gamma glutamyl transpeptidase ligand, an NKG2D ligand, or a CCK2R ligand, each of which is a small molecule ligand that specifically binds to cancer cells (i.e., the receptors for these ligands are overexpressed in cancer compared to normal tissue).

[0008] In certain embodiments, the "small molecule ligand" is linked to a "targeting moiety" that binds to the CAR expressed by the CAR T cell. In various embodiments, the "targeting moiety" can be selected from, for example, 2,4-dinitrophenol (DNP), 2,4,6-trinitrophenol (TNP), biotin, digoxigenin, fluorescein, fluorescein isothiocyanate (FITC), NHS-fluorescein, pentafluorophenyl ester (PFP), tetrafluorophenyl ester (TFP), knottin, centyrin, and DARPin.

[0009] The "targeting moiety" binds to the recognition region of the genetically modified CAR expressed by the CAR T cell. Thus, the recognition region of the CAR (e.g., a single-chain fragment variable region (scFv), Fab, Fv, Fc, (Fab')2 fragment, etc. of an antibody) is directed to the "targeting moiety." Therefore, the small molecule ligand linked to the targeting moiety by a linker acts as a bridge between the cancer and the CAR T cell, directing the CAR T cell to the cancer for cancer amelioration.

[0010] In certain embodiments, a method of treating cancer is provided, comprising the steps of: i) administering to a patient a compound or a pharmaceutically acceptable salt thereof, wherein the compound comprises a small molecule ligand linked to a targeting moiety by a linker, ii) administering to the patient a first CAR T-cell composition, wherein the CAR T-cell composition comprises CAR T cells and the CAR T cells comprise a CAR directed to a targeting moiety, and iii) administering to the patient a second CAR T-cell composition, wherein the CAR T-cell composition comprises CAR T cells and the CAR T cells comprise a CAR directed to a targeting moiety.

[0011] In other embodiments, a method of treating cancer is provided, comprising the steps of: i) administering to a patient a compound or a pharmaceutically acceptable salt thereof, wherein the compound comprises a small molecule ligand linked to a targeting moiety by a linker, and ii) administering to the patient a CAR T cell composition comprising CAR T cells, wherein the CAR T cells in the composition comprise a CAR directed to a targeting moiety, and the CAR T cell composition comprises a mixture of the CAR T cells and non-transformed T cells.

[0012] In yet another embodiment, a method of treating cancer is provided, comprising the steps of: i) administering to a patient a compound or a pharmaceutically acceptable salt thereof, wherein the compound comprises a small molecule ligand linked to a targeting moiety by a linker, ii) administering to the patient a CAR T cell composition, wherein the CAR T cell composition comprises CAR T cells and the CAR T cells comprise a CAR directed to a targeting moiety, and iii) administering to the patient folic acid, a conjugate comprising folic acid (wherein the conjugate comprising folic acid does not comprise a targeting moiety), or an agent that inhibits CAR T cell activation.

[0013] In other embodiments, a method of treating cancer is provided, comprising the steps of: i) administering to a patient a compound or a pharmaceutically acceptable salt thereof, wherein the compound comprises a small molecule ligand linked to a targeting moiety by a linker, and the compound or a pharmaceutically acceptable salt thereof is at a dosage of about 10 nmole / kg to about 2500 nmole / kg of patient body weight, and ii) administering to the patient a CAR T cell composition comprising CAR T cells, wherein the CAR T cells comprise a CAR directed to a targeting moiety, and the CAR T cells are at a dosage of about 1 million to about 15 million CAR T cells.

[0014] In yet another embodiment, a method of treating cancer is provided, comprising the steps of: i) sequentially administering to a patient a compound or a pharmaceutically acceptable salt thereof, wherein the compound comprises a small molecule ligand linked to a targeting moiety by a linker, ii) administering to the patient a CAR T cell composition comprising CAR T cells, wherein the CAR T cells comprise a CAR directed to the targeting moiety, and iii) terminating the administration of the compound or a pharmaceutically acceptable salt thereof to reduce cytokine release syndrome in the patient.

[0015] In another illustrative embodiment, a method of treating cancer is provided, the method comprising: i) administering to a patient a compound or a pharmaceutically acceptable salt thereof, wherein the compound comprises a small molecule ligand linked to a targeting moiety by a linker, and at least first and second doses of the compound or a pharmaceutically acceptable salt thereof are administered to the patient, wherein the first and second doses are different, and the second dose of the compound or a pharmaceutically acceptable salt thereof is about 2-fold to about 15,000-fold greater than the first dose of the compound or a pharmaceutically acceptable salt thereof, and ii) administering to the patient a CAR T cell composition comprising CAR T cells, wherein the CAR T cells comprise a CAR directed to a targeting moiety.

[0016] In other embodiments, a method of treating cancer is provided, comprising the steps of: i) administering to a patient a compound or a pharmaceutically acceptable salt thereof, wherein the compound comprises a small molecule ligand linked to a targeting moiety by a linker, and wherein the compound or a pharmaceutically acceptable salt thereof is administered to the patient once a week, and ii) administering to the patient a CAR T cell composition comprising CAR T cells, wherein the CAR T cells comprise a CAR directed to the targeting moiety.

[0017] In yet another embodiment, a method of treating cancer is provided, comprising the steps of: i) administering to a patient a first dose of a compound or a pharmaceutically acceptable salt thereof, wherein the compound comprises a small molecule ligand linked to a targeting moiety by a linker; ii) administering to the patient at least a second dose of the compound or a pharmaceutically acceptable salt thereof, wherein the second dose of the compound or a pharmaceutically acceptable salt thereof is at least about 50% less than the first dose of the compound or a pharmaceutically acceptable salt thereof; and iii) administering to the patient a single dose of a CAR T cell composition comprising CAR T cells, wherein the CAR T cells comprise a CAR directed to a targeting moiety.

[0018] In yet another embodiment, a method of treating cancer is provided, comprising the steps of: i) administering to a patient a first compound or a pharmaceutically acceptable salt thereof, wherein the compound comprises a small molecule ligand linked to a targeting moiety by a linker, and wherein the compound or a pharmaceutically acceptable salt thereof is administered to the patient at least about 1 hour prior to administration of a CAR T cell composition comprising CAR T cells, the CAR T cells comprising a CAR directed to a targeting moiety, ii) then administering to the patient a dose of the CAR T cell composition, and iii) then administering to the patient a second compound or a pharmaceutically acceptable salt thereof.

[0019] In another embodiment, a method for treating cancer is provided. The method includes the steps of: i) administering to a patient a compound or a pharmaceutically acceptable salt thereof, wherein the compound comprises a small molecule ligand linked to a targeting moiety by a linker; and ii) administering to the patient a CAR T cell composition, wherein the CAR T cell composition comprises CAR T cells, and the CAR T cells comprise a CAR directed to a targeting moiety, and the small molecule ligand is a PSMA ligand, and the targeting moiety is FITC. In this embodiment, the small molecule ligand linked to the targeting moiety by a linker is represented by the formula [ka] may have:

[0020] In yet another embodiment, a method for treating cancer is provided. The method includes the steps of: i) administering to a patient a compound or a pharmaceutically acceptable salt thereof, wherein the compound comprises a small molecule ligand linked to a targeting moiety by a linker; and ii) administering to the patient a CAR T cell composition, wherein the CAR comprises a CAR T cell, and the CAR T cell comprises a CAR directed to a targeting moiety, and the small molecule ligand is a CAIX ligand, and the targeting moiety is FITC. In this embodiment, the small molecule ligand linked to the targeting moiety by a linker is represented by the formula [ka] may have:

[0021] In yet another embodiment, a method for treating cancer is provided. The method comprises the steps of: i) administering to a patient a first compound or a pharmaceutically acceptable salt thereof, wherein the first compound or a pharmaceutically acceptable salt thereof comprises a PSMA ligand linked to FITC by a linker; ii) administering to a patient a second compound or a pharmaceutically acceptable salt thereof, wherein the second compound or a pharmaceutically acceptable salt thereof comprises a CAIX ligand linked to FITC by a linker; and iii) administering to a patient a CAR T cell composition, wherein the CAR T cell composition comprises CAR T cells, and the CAR T cells comprise a CAR directed to a targeting moiety. In this embodiment, the first compound is represented by the formula [ka] and the second compound may have the formula [ka] may have:

[0022] Further embodiments are also described by the following enumerated sections. Any of the following embodiments in combination with any applicable embodiment described in the Summary of the Invention section, Detailed Description of Exemplary Embodiments section, Examples section, or claims of this patent application is also contemplated.

[0023] 1. A method of treating cancer, comprising: i) administering to a patient a compound or a pharmaceutically acceptable salt thereof, wherein the compound comprises a small molecule ligand linked to a targeting moiety by a linker; ii) administering to the patient a CAR T cell composition comprising a first CAR T cell, the CAR T cell comprising a CAR directed to a targeting moiety; and iii) administering to the patient a CAR T cell composition comprising a second CAR T cell, wherein the CAR T cell comprises a CAR directed to a targeting moiety. A method comprising:

[0024] 2. The method of item 1, wherein the ligand is selected from the group consisting of folic acid, DUPA, NK-1R ligands, CAIX ligands, gamma glutamyl transpeptidase ligands, NKG2D ligands, and CCK2R ligands.

[0025] 3. The method according to either item 1 or 2, wherein the ligand is folic acid.

[0026] 4. The method according to either item 1 or 2, wherein the ligand is an NK-1R ligand.

[0027] 5. The method according to either item 1 or 2, wherein the ligand is DUPA.

[0028] 6. The method according to either item 1 or 2, wherein the ligand is a CCK2R ligand.

[0029] 7. The method according to either item 1 or 2, wherein the ligand is a gamma glutamyl transpeptidase ligand.

[0030] 8. The method of any of items 1 to 7, wherein the targeting moiety is selected from the group consisting of 2,4-dinitrophenol (DNP), 2,4,6-trinitrophenol (TNP), biotin, digoxigenin, fluorescein, fluorescein isothiocyanate (FITC), NHS-fluorescein, pentafluorophenyl ester, tetrafluorophenyl ester, knottin, centyrin, and DARPin.

[0031] 9. The method of any of paragraphs 1 to 8, wherein the targeting moiety is FITC.

[0032] 10. The method of any of paragraphs 1 to 8, wherein the targeting moiety is DNP.

[0033] 11. The method of any one of paragraphs 1 to 8, wherein the targeting moiety is TNP.

[0034] 12. The method according to any one of items 1 to 11, wherein the linker comprises polyethylene glycol (PEG), polyproline, a hydrophilic amino acid, a sugar, a non-natural peptidoglycan, polyvinylpyrrolidone, Pluronic F-127, or a combination thereof.

[0035] 13. The method according to any one of items 1 to 12, wherein the linker comprises PEG.

[0036] 14. The compound or a pharmaceutically acceptable salt thereof has the formula [ka] wherein B is a small molecule ligand, L is a linker, and T is a targeting moiety, wherein L is a group of the formula [ka] (wherein n is 0 to 200). 14. The method according to any one of Items 1 to 13, comprising:

[0037] 15. The method according to item 14, wherein n is an integer of 0 to 150.

[0038] 16. The method according to item 14, wherein n is an integer of 0 to 110.

[0039] 17. The method according to item 14, wherein n is an integer of 0 to 20.

[0040] 18. The method according to item 14, wherein n is an integer of 15 to 20.

[0041] 19. The method according to item 14, wherein n is an integer of 15 to 110.

[0042] 20. The method of any of paragraphs 1 to 9 or 12 to 19, wherein the linker comprises PEG and the targeting moiety is FITC or a pharmaceutically acceptable salt thereof.

[0043] 21. The method according to any one of items 1 to 20, wherein the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 10 nmole / kg to about 10,000 nmole / kg of patient body weight.

[0044] 22. The method according to any one of items 1 to 21, wherein the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 10 nmole / kg to about 5000 nmole / kg of patient body weight.

[0045] 23. The method according to any one of items 1 to 22, wherein the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 10 nmole / kg to about 1000 nmole / kg of patient body weight.

[0046] 24. The method according to any one of items 1 to 23, wherein the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 10 nmole / kg to about 600 nmole / kg of patient body weight.

[0047] 25. The method according to any one of items 1 to 24, wherein the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 200 nmole / kg to about 600 nmole / kg of patient body weight.

[0048] 26. The method according to any one of items 1 to 25, wherein the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 250 nmole / kg to about 600 nmole / kg of patient body weight.

[0049] 27. The cancer is lung cancer, bone cancer, pancreatic cancer, skin cancer, head cancer, neck cancer, cutaneous melanoma, intraocular melanoma, uterine cancer, ovarian cancer, endometrial cancer, rectal cancer, stomach cancer, colon cancer, breast cancer, triple-negative breast cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, non-small cell lung cancer, adrenal cancer, soft tissue sarcoma, osteosarcoma, urethral cancer, prostate cancer, chronic leukemia, acute 27. The method according to any one of items 1 to 26, wherein the cancer is selected from the group consisting of leukemia, acute myeloid leukemia, lymphocytic lymphoma, myeloid leukemia, myelomonocytic leukemia, hairy leukemia, pleural mesothelioma, bladder cancer, Burkitt's lymphoma, ureteral cancer, kidney cancer, renal cell carcinoma, renal pelvis cancer, central nervous system (CNS) neoplasms, primary CNS lymphoma, spinal axis tumor, brainstem glioma, pituitary adenoma, and gastroesophageal junction adenocarcinoma.

[0050] 28. The method according to any one of items 1 to 3 or 8 to 27, wherein the cancer is a folate receptor-expressing cancer.

[0051] 29. The method according to paragraph 28, wherein the cancer is endometrial cancer.

[0052] 30. The method according to paragraph 28, wherein the cancer is non-small cell lung cancer.

[0053] 31. The method of claim 28, wherein the cancer is ovarian cancer.

[0054] 32. The method of paragraph 28, wherein the cancer is triple-negative breast cancer.

[0055] 33. The method according to any one of items 1 to 32, wherein the CAR has a recognition region, and the recognition region is a single-chain fragment variable (scFv) region of an antibody.

[0056] 34. The method according to any one of items 1 to 9 or 12 to 33, wherein the CAR has a recognition region, and the recognition region of the CAR is a single-chain fragment variable (scFv) region of an anti-FITC antibody.

[0057] 35. The method of any of items 1 to 34, wherein the CAR has a costimulatory domain, and the costimulatory domain is selected from the group consisting of CD28, CD137 (4-1BB), CD134 (OX40), and CD278 (ICOS).

[0058] 36. The method of any one of items 1 to 35, wherein the CAR has an activation signaling domain, and the activation signaling domain is T cell CD3 zeta chain or Fc receptor γ.

[0059] 37. The method of any one of items 1 to 9 or 12 to 36, wherein the CAR has a recognition region, which is a single-chain fragment variable (scFv) region of an anti-FITC antibody; the CAR has a costimulatory domain, which is CD137 (4-1BB); and the CAR has an activation signaling domain, which is a T cell CD3ζ chain.

[0060] 38. The method of any of paragraphs 1 to 37, wherein multiple doses of the compound or a pharmaceutically acceptable salt thereof and the CAR T cell composition are administered.

[0061] 39. The method of any of paragraphs 1 to 38, wherein the patient is imaged prior to administration of the compound or a pharmaceutically acceptable salt thereof or prior to administration of the CAR T cell composition.

[0062] 40. The method according to any one of items 1 to 39, wherein the compound or a pharmaceutically acceptable salt thereof is not an antibody and does not include an antibody fragment.

[0063] 41. The method of any of paragraphs 1 to 40, wherein the targeting moiety does not comprise a peptide epitope.

[0064] 42. The method of any of items 1 to 41, wherein CAR T cell toxicity against cancer occurs without cytokine release that results in off-target toxicity in patients.

[0065] 43. The method of any of items 1 to 41, wherein off-target tissue toxicity does not occur in the patient and CAR T cell toxicity against the cancer occurs.

[0066] 44. The method of any of paragraphs 1 to 41, wherein the cancer comprises a tumor, the tumor size is reduced in the patient, and no off-target toxicity occurs.

[0067] 45. The method of any of paragraphs 1 to 44, wherein the CAR T cells comprise a nucleic acid comprising SEQ ID NO:1.

[0068] 46. ​​The method of any of paragraphs 1 to 45, wherein the CAR T cells comprise a polypeptide comprising SEQ ID NO:2.

[0069] 47. The method of paragraph 45, wherein the nucleic acid encodes a chimeric antigen receptor.

[0070] 48. The method of any of paragraphs 1 to 47, wherein the CAR comprises a humanized amino acid sequence.

[0071] 49. The method of any one of items 1 to 47, wherein the CAR consists of a humanized amino acid sequence.

[0072] 50. The method of any of paragraphs 1 to 49, wherein the first round of the CAR T cell composition comprises a mixture of the CAR T cells and non-transformed T cells in a ratio selected from about 1:5 CAR T cells to non-transformed T cells, about 1:4 CAR T cells to non-transformed T cells, about 1:3 CAR T cells to non-transformed T cells, about 1:2 CAR T cells to non-transformed T cells, and about 1:1 CAR T cells to non-transformed T cells.

[0073] 51. The method of any of paragraphs 1 to 50, wherein the second round of the CAR T cell composition comprises a mixture of the CAR T cells and non-transformed T cells in a ratio selected from about 1:5 CAR T cells to non-transformed T cells, about 1:4 CAR T cells to non-transformed T cells, about 1:3 CAR T cells to non-transformed T cells, about 1:2 CAR T cells to non-transformed T cells, and about 1:1 CAR T cells to non-transformed T cells.

[0074] 52. The method of any of items 1 to 51, wherein the first round of the CAR T cell composition comprises a mixture of the CAR T cells and non-transformed T cells at a ratio of CAR T cells to non-transformed T cells of about 1:1 to about 1:5.

[0075] 53. The method of any of paragraphs 1 to 52, wherein the second round of the CAR T cell composition comprises a mixture of the CAR T cells and non-transformed T cells at a ratio of CAR T cells to non-transformed T cells of about 1:1 to 1:5.

[0076] 54. The method of any of paragraphs 1 to 53, wherein the first round of the CAR T cell composition comprises a mixture of about 10 million CAR T cells and about 40 million untransformed T cells.

[0077] 55. The method of any of paragraphs 1 to 54, wherein the second round of the CAR T cell composition comprises a mixture of about 10 million CAR T cells and about 40 million untransformed T cells.

[0078] 56. A method of treating cancer, comprising: i) administering to a patient a compound or a pharmaceutically acceptable salt thereof, wherein the compound comprises a small molecule ligand linked to a targeting moiety by a linker; and ii) administering to the patient a CAR T cell composition, wherein the CAR T cell composition comprises CAR T cells, the CAR T cells comprise a CAR directed to a targeting moiety, and the CAR T cell composition comprises a mixture of the CAR T cells and non-transformed T cells. A method comprising:

[0079] 57. The method of paragraph 56, wherein the ligand is selected from the group consisting of folate, DUPA, an NK-1R ligand, a CAIX ligand, a gamma glutamyl transpeptidase ligand, an NKG2D ligand, and a CCK2R ligand.

[0080] 58. The method of either paragraph 56 or 57, wherein the ligand is folic acid.

[0081] 59. The method of either paragraph 56 or 57, wherein the ligand is an NK-1R ligand.

[0082] 60. The method of either paragraph 56 or 57, wherein the ligand is DUPA.

[0083] 61. The method of either paragraph 56 or 57, wherein the ligand is a CCK2R ligand.

[0084] 62. The method of either paragraph 56 or 57, wherein the ligand is a gamma glutamyl transpeptidase ligand.

[0085] 63. The method of any of paragraphs 56 to 62, wherein the targeting moiety is selected from the group consisting of 2,4-dinitrophenol (DNP), 2,4,6-trinitrophenol (TNP), biotin, digoxigenin, fluorescein, fluorescein isothiocyanate (FITC), NHS-fluorescein, pentafluorophenyl ester, tetrafluorophenyl ester, knottin, centyrin, and DARPin.

[0086] 64. The method of any of paragraphs 56 to 63, wherein the targeting moiety is FITC.

[0087] 65. The method of any of paragraphs 56 to 63, wherein the targeting moiety is DNP.

[0088] 66. The method of any of paragraphs 56 to 63, wherein the targeting moiety is TNP.

[0089] 67. The method of any of items 56 to 66, wherein the linker comprises polyethylene glycol (PEG), polyproline, a hydrophilic amino acid, a sugar, a non-natural peptidoglycan, polyvinylpyrrolidone, Pluronic F-127, or a combination thereof.

[0090] 68. The method of any of items 56 to 67, wherein the linker comprises PEG.

[0091] 69. The compound or a pharmaceutically acceptable salt thereof has the formula [ka] wherein B is a small molecule ligand, L is a linker, and T is a targeting moiety, wherein L is a group of the formula [ka] (wherein n is 0 to 200). Item 69. The method according to any one of Items 56 to 68, comprising:

[0092] 70. The method according to item 69, wherein n is an integer of 0 to 150.

[0093] 71. The method according to item 69, wherein n is an integer of 0 to 110.

[0094] 72. The method according to item 69, wherein n is an integer of 0 to 20.

[0095] 73. The method according to item 69, wherein n is an integer of 15 to 20.

[0096] 74. The method according to item 69, wherein n is an integer of 15 to 110.

[0097] 75. The method of any of paragraphs 56-64 or 67-74, wherein the linker comprises PEG and the targeting moiety is FITC or a pharmaceutically acceptable salt thereof.

[0098] 76. The method according to any one of items 56 to 75, wherein the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 10 nmole / kg to about 10,000 nmole / kg of patient body weight.

[0099] 77. The method according to any one of items 56 to 76, wherein the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 10 nmole / kg to about 5000 nmole / kg of patient body weight.

[0100] 78. The method according to any one of items 56 to 77, wherein the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 10 nmole / kg to about 1000 nmole / kg of patient body weight.

[0101] 79. The method according to any one of items 56 to 78, wherein the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 10 nmole / kg to about 600 nmole / kg of patient body weight.

[0102] 80. The method according to any one of items 56 to 79, wherein the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 200 nmole / kg to about 600 nmole / kg of patient body weight.

[0103] 81. The method according to any one of items 56 to 80, wherein the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 250 nmole / kg to about 600 nmole / kg of patient body weight.

[0104] 82. The cancer is lung cancer, bone cancer, pancreatic cancer, skin cancer, head cancer, neck cancer, cutaneous melanoma, intraocular melanoma, uterine cancer, ovarian cancer, endometrial cancer, rectal cancer, stomach cancer, colon cancer, breast cancer, triple-negative breast cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, non-small cell lung cancer, adrenal cancer, soft tissue sarcoma, osteosarcoma, urethral cancer, prostate cancer, chronic leukemia, acute 82. The method of any of items 56 to 81, wherein the cancer is selected from the group consisting of leukemia, acute myeloid leukemia, lymphocytic lymphoma, myeloid leukemia, myelomonocytic leukemia, hairy leukemia, pleural mesothelioma, bladder cancer, Burkitt's lymphoma, ureteral cancer, kidney cancer, renal cell carcinoma, renal pelvis cancer, central nervous system (CNS) neoplasms, primary CNS lymphoma, spinal axis tumor, brainstem glioma, pituitary adenoma, and gastroesophageal junction adenocarcinoma.

[0105] 83. The method of any of items 56 to 58 or 63 to 82, wherein the cancer is a folate receptor-expressing cancer.

[0106] 84. The method of paragraph 83, wherein the cancer is endometrial cancer.

[0107] 85. The method of paragraph 83, wherein the cancer is non-small cell lung cancer.

[0108] 86. The method of paragraph 83, wherein the cancer is ovarian cancer.

[0109] 87. The method of paragraph 83, wherein the cancer is triple-negative breast cancer.

[0110] 88. The method of any of items 56 to 87, wherein the CAR has a recognition region, and the recognition region is a single-chain fragment variable (scFv) region of an antibody.

[0111] 89. The method of any one of items 56 to 64 or 67 to 88, wherein the CAR has a recognition region, and the recognition region of the CAR is a single-chain fragment variable (scFv) region of an anti-FITC antibody.

[0112] 90. The method of any of paragraphs 56 to 89, wherein the CAR has a costimulatory domain, and the costimulatory domain is selected from the group consisting of CD28, CD137 (4-1BB), CD134 (OX40), and CD278 (ICOS).

[0113] 91. The method of any of items 56 to 90, wherein the CAR has an activation signaling domain, and the activation signaling domain is T cell CD3 zeta chain or Fc receptor γ.

[0114] 92. The method of any one of items 56 to 64 or 67 to 91, wherein the CAR has a recognition region, which is a single-chain fragment variable (scFv) region of an anti-FITC antibody; the CAR has a costimulatory domain, which is CD137 (4-1BB); and the CAR has an activation signaling domain, which is a T cell CD3 zeta chain.

[0115] 93. The method of any of paragraphs 56 to 92, wherein multiple doses of the compound or a pharmaceutically acceptable salt thereof are administered.

[0116] 94. The method of any of paragraphs 56 to 93, wherein the patient is imaged prior to administration of the compound or a pharmaceutically acceptable salt thereof or prior to administration of the CAR T cell composition.

[0117] 95. The method according to any one of items 56 to 94, wherein the compound or a pharmaceutically acceptable salt thereof is not an antibody and does not include an antibody fragment.

[0118] 96. The method of any of paragraphs 56 to 95, wherein the targeting moiety does not comprise a peptide epitope.

[0119] 97. The method of any of items 56 to 96, wherein CAR T cell toxicity against cancer occurs without cytokine release resulting in off-target toxicity in the patient.

[0120] 98. The method of any of items 56 to 96, wherein off-target tissue toxicity does not occur in the patient and CAR T cell toxicity against the cancer occurs.

[0121] 99. The method of any of paragraphs 56 to 96, wherein the cancer comprises a tumor, the tumor size is reduced in the patient, and no off-target toxicity occurs.

[0122] 100. The method of any of paragraphs 56 to 99, wherein the CAR T cells comprise a nucleic acid comprising SEQ ID NO:1.

[0123] 101. The method of any of paragraphs 56 to 100, wherein the CAR T cells comprise a polypeptide comprising SEQ ID NO:2.

[0124] 102. The method of paragraph 100, wherein the nucleic acid encodes a chimeric antigen receptor.

[0125] 103. The method of any of paragraphs 56 to 102, wherein the CAR comprises a humanized amino acid sequence.

[0126] 104. The method of any of paragraphs 56 to 102, wherein the CAR consists of a humanized amino acid sequence.

[0127] 105. The method of any of paragraphs 56 to 104, wherein the mixture of CAR T cells and non-transformed T cells is in a ratio selected from about 1:5 CAR T cells to non-transformed T cells, about 1:4 CAR T cells to non-transformed T cells, about 1:3 CAR T cells to non-transformed T cells, about 1:2 CAR T cells to non-transformed T cells, and about 1:1 CAR T cells to non-transformed T cells.

[0128] 106. The method of any of items 56 to 105, wherein the mixture of CAR T cells and non-transformed T cells has a ratio of CAR T cells to non-transformed T cells of about 1:1 to about 1:5.

[0129] 107. The method of any of paragraphs 56 to 106, wherein the mixture of CAR T cells and non-transformed T cells comprises about 10 million CAR T cells and about 40 million non-transformed T cells.

[0130] 108. A method of treating cancer, comprising: i) administering to a patient a compound or a pharmaceutically acceptable salt thereof, wherein the compound comprises a small molecule ligand linked to a targeting moiety by a linker; ii) administering to the patient a CAR T cell composition, wherein the CAR T cell composition comprises CAR T cells, and the CAR T cells comprise a CAR directed to a targeting moiety; and iii) administering to the patient folic acid, a conjugate comprising folic acid (wherein the conjugate comprising folic acid does not comprise a targeting moiety), or an agent that inhibits activation of CAR T cells. A method comprising:

[0131] 109. The method of paragraph 108, wherein step iii includes administering folic acid.

[0132] 110. The method of either paragraph 108 or 109, wherein step iii includes administering folic acid or leucovorin.

[0133] 111. The method of paragraph 108, wherein step iii comprises administering a conjugate comprising folic acid.

[0134] 112. The method of paragraph 111, wherein the folic acid-containing conjugate comprises folic acid linked to one or more amino acids.

[0135] 113. The conjugate containing folic acid has the formula [ka] Item 112. The method of item 111, comprising:

[0136] 114. The folic acid has the formula [ka] [In the formula, X 1 and Y 1 are each independently a halo, R 2 , OR 2 , S.R. 3 and N.R. 4 R 5 selected from the group consisting of: U, V and W are -(R 6a )C=, -N=, -(R 6a )C(R 7a )- and -N(R 4a)—; Q is selected from the group consisting of C and CH; T is selected from the group consisting of S, O, N, and —C═C—; X 2 and X 3 are each independently oxygen, sulfur, -C(Z)-, -C(Z)O-, -OC(Z)-, -N(R 4b )-, -C(Z)N(R 4b )-, -N(R 4b )C(Z)-, -OC(Z)N(R 4b )-, -N(R 4b )C(Z)O-, -N(R 4b )C(Z)N(R 5b )-, -S(O)-, -S(O)2-, -N(R 4a )S(O)2-, -C(R 6b )(R 7b )-, -N(C≡CH)-, -N(CH2C≡CH)-, C1-C 12 Alkylene and C1-C 12 alkyleneoxy, where Z is oxygen or sulfur; R 1 are hydrogen, halo, C1-C 12 Alkyl and C1-C 12 selected from the group consisting of alkoxy; R 2 , R 3 , R 4 , R 4a , R 4b , R 5 , R 5b , R 6b and R 7b are each independently hydrogen, halo, C-C 12 Alkyl, C1-C 12 Alkoxy, C1-C 12 Alkanoyl, C1-C 12 Alkenyl, C1-C 12 Alkynyl, (C1-C 12 alkoxy)carbonyl and (C1-C 12 alkylamino)carbonyl; R 6 and R 7 are each independently hydrogen, halo, C-C12 Alkyl and C1-C 12 alkoxy; or R 6 and R 7 together to form a carbonyl group; R 6a and R 7a are each independently hydrogen, halo, C-C 12 Alkyl and C1-C 12 alkoxy; or R 6a and R 7a together to form a carbonyl group; p, r, s, and t are each independently 0 or 1; and * represents any covalent bond to the remainder of the conjugate if any additional chemical moiety is part of the folic acid. Item 113. The method according to any one of Items 109 to 112,

[0137] 115. The method of any of paragraphs 108 to 114, wherein the targeting moiety is selected from the group consisting of 2,4-dinitrophenol (DNP), 2,4,6-trinitrophenol (TNP), biotin, digoxigenin, fluorescein, fluorescein isothiocyanate (FITC), NHS-fluorescein, pentafluorophenyl ester, tetrafluorophenyl ester, knottin, centyrin, and DARPin.

[0138] 116. The method of any of paragraphs 108 to 115, wherein the targeting moiety is FITC.

[0139] 117. The method of any of paragraphs 108 to 115, wherein the targeting moiety is DNP.

[0140] 118. The method of any of paragraphs 108 to 115, wherein the targeting moiety is TNP.

[0141] 119. The method of any of paragraphs 108 to 118, wherein the linker comprises polyethylene glycol (PEG), polyproline, a hydrophilic amino acid, a sugar, a non-natural peptidoglycan, polyvinylpyrrolidone, Pluronic F-127, or a combination thereof.

[0142] 120. The method of any of items 108 to 119, wherein the linker comprises PEG.

[0143] 121. The compound or a pharmaceutically acceptable salt thereof has the formula [ka] wherein B is a small molecule ligand, L is a linker, and T is a targeting moiety, wherein L is a group of the formula [ka] (wherein n is 0 to 200). Item 121. The method according to any one of Items 108 to 120,

[0144] 122. The method according to item 121, wherein n is an integer from 0 to 12.

[0145] 123. The method according to item 121, wherein n is an integer of 0 to 150.

[0146] 124. The method according to item 121, wherein n is an integer from 0 to 110.

[0147] 125. The method according to item 121, wherein n is an integer of 0 to 20.

[0148] 126. The method according to item 121, wherein n is an integer of 15 to 20.

[0149] 127. The method according to item 121, wherein n is an integer between 15 and 110.

[0150] 128. The method of any of paragraphs 108-116 or 119-127, wherein the linker comprises PEG and the targeting moiety is FITC or a pharmaceutically acceptable salt thereof.

[0151] 129. The method according to any one of items 108 to 128, wherein the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 10 nmole / kg to about 10,000 nmole / kg of patient body weight.

[0152] 130. The method of any of items 108 to 129, wherein the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 10 nmole / kg to about 5000 nmole / kg of patient body weight.

[0153] 131. The method according to any one of items 108 to 130, wherein the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 10 nmole / kg to about 1000 nmole / kg of patient body weight.

[0154] 132. The method of any of items 108 to 131, wherein the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 10 nmole / kg to about 600 nmole / kg of patient body weight.

[0155] 133. The method of any of items 108 to 132, wherein the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 200 nmole / kg to about 600 nmole / kg of patient body weight.

[0156] 134. The method of any of items 108 to 133, wherein the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 250 nmole / kg to about 600 nmole / kg of patient body weight.

[0157] 135. The cancer is lung cancer, bone cancer, pancreatic cancer, skin cancer, head cancer, neck cancer, cutaneous melanoma, intraocular melanoma, uterine cancer, ovarian cancer, endometrial cancer, rectal cancer, stomach cancer, colon cancer, breast cancer, triple-negative breast cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, non-small cell lung cancer, adrenal cancer, soft tissue sarcoma, osteosarcoma, urethral cancer, prostate cancer, chronic leukemia, acute leukemia 135. The method of any of items 108 to 134, wherein the cancer is selected from the group consisting of hematopoietic leukemia, acute myeloid leukemia, lymphocytic lymphoma, myeloid leukemia, myelomonocytic leukemia, hairy leukemia, pleural mesothelioma, bladder cancer, Burkitt's lymphoma, ureteral cancer, kidney cancer, renal cell carcinoma, renal pelvis cancer, central nervous system (CNS) neoplasms, primary CNS lymphoma, spinal axis tumor, brainstem glioma, pituitary adenoma, and gastroesophageal junction adenocarcinoma.

[0158] 136. The method of any of paragraphs 108 to 135, wherein the ligand moiety of the small molecule ligand linked to the targeting moiety by the linker is folate, and the cancer is a folate receptor-expressing cancer.

[0159] 137. The method of paragraph 136, wherein the cancer is endometrial cancer.

[0160] 138. The method of paragraph 136, wherein the cancer is non-small cell lung cancer.

[0161] 139. The method of paragraph 136, wherein the cancer is ovarian cancer.

[0162] 140. The method of paragraph 136, wherein the cancer is triple-negative breast cancer.

[0163] 141. The method of any of items 108 to 140, wherein the CAR has a recognition region, and the recognition region is a single-chain fragment variable (scFv) region of an antibody.

[0164] 142. The method of any of items 108 to 116 or 119 to 141, wherein the CAR has a recognition region, and the recognition region of the CAR is a single-chain fragment variable (scFv) region of an anti-FITC antibody.

[0165] 143. The method of any of paragraphs 108 to 142, wherein the CAR has a costimulatory domain, and the costimulatory domain is selected from the group consisting of CD28, CD137 (4-1BB), CD134 (OX40), and CD278 (ICOS).

[0166] 144. The method of any of paragraphs 108 to 143, wherein the CAR has an activation signaling domain, and the activation signaling domain is T cell CD3 zeta chain or Fc receptor γ.

[0167] 145. The method of any of items 108 to 116 or 119 to 144, wherein the CAR has a recognition region, which is a single-chain fragment variable (scFv) region of an anti-FITC antibody; the CAR has a costimulatory domain, which is CD137 (4-1BB); and the CAR has an activation signaling domain, which is the T cell CD3ζ chain.

[0168] 146. The method of any of paragraphs 108 to 145, wherein multiple doses of the compound or a pharmaceutically acceptable salt thereof and / or the CAR T cell composition are administered.

[0169] 147. The method of any of paragraphs 108 to 146, wherein the patient is imaged prior to administration of the compound or a pharmaceutically acceptable salt thereof or prior to administration of the CAR T cell composition.

[0170] 148. The method of any one of items 108 to 147, wherein the compound or a pharmaceutically acceptable salt thereof is not an antibody and does not include an antibody fragment.

[0171] 149. The method of any of paragraphs 108 to 148, wherein the targeting moiety does not comprise a peptide epitope.

[0172] 150. The method of any of paragraphs 108 to 149, wherein CAR T cell toxicity against cancer occurs without cytokine release resulting in off-target toxicity in the patient.

[0173] 151. The method of any of paragraphs 108 to 149, wherein off-target tissue toxicity does not occur in the patient and CAR T cell toxicity against the cancer occurs.

[0174] 152. The method of any of paragraphs 108 to 149, wherein the cancer comprises a tumor, the tumor size is reduced in the patient, and no off-target toxicity occurs.

[0175] 153. The method of any of paragraphs 108 to 152, wherein the CAR T cells comprise a nucleic acid comprising SEQ ID NO:1.

[0176] 154. The method of any of paragraphs 108 to 153, wherein the CAR T cells comprise a polypeptide comprising SEQ ID NO:2.

[0177] 155. The method of paragraph 153, wherein the nucleic acid encodes a chimeric antigen receptor.

[0178] 156. The method of any of paragraphs 108 to 155, wherein the CAR comprises a humanized amino acid sequence.

[0179] 157. The method of any of paragraphs 108 to 155, wherein the CAR consists of a humanized amino acid sequence.

[0180] 158. The method of any of paragraphs 108 to 157, wherein the CAR T cell composition comprises a mixture of the CAR T cells and non-transformed T cells in a ratio selected from about 1:5 CAR T cells to non-transformed T cells, about 1:4 CAR T cells to non-transformed T cells, about 1:3 CAR T cells to non-transformed T cells, about 1:2 CAR T cells to non-transformed T cells, and about 1:1 CAR T cells to non-transformed T cells.

[0181] 159. The method of any of paragraphs 108 to 158, wherein the CAR T cell composition comprises a mixture of the CAR T cells and non-transformed T cells at a ratio of CAR T cells to non-transformed T cells of about 1:1 to about 1:5.

[0182] 160. The method of any of paragraphs 108 to 159, wherein the CAR T cell composition comprises a mixture comprising about 10 million CAR T cells and about 40 million untransformed T cells.

[0183] 161. The method of any of items 108 to 160, wherein the agent that inhibits the activation of the CAR T cells is selected from the group consisting of lymphocyte-specific protein tyrosine kinase inhibitors, PI3 kinase inhibitors, IL-2-inducible T cell kinase inhibitors, JAK inhibitors, BTK inhibitors, EC2319, and agents that block binding of CAR T cells to the compound or a pharmaceutically acceptable salt thereof but do not bind to the cancer.

[0184] 162. The method of paragraph 161, wherein an agent that inhibits activation of the CAR T cells is administered, and the agent is a lymphocyte-specific protein tyrosine kinase inhibitor.

[0185] 163. The method of paragraph 162, wherein the lymphocyte-specific protein tyrosine kinase inhibitor is dasatinib.

[0186] 164. The method of paragraph 161, wherein an agent that inhibits activation of the CAR T cells is administered, and the agent is a PI3 kinase inhibitor.

[0187] 165. The method of paragraph 164, wherein the PI3 kinase inhibitor is GDC0980.

[0188] 166. The method of paragraph 161, wherein an agent that inhibits activation of the CAR T cells is administered, and the agent is an IL-2-inducible T cell kinase inhibitor.

[0189] 167. The method of paragraph 166, wherein the IL-2-inducible T cell kinase inhibitor is BMS-509744.

[0190] 168. The method of any of paragraphs 1 to 160, wherein the CAR T cell composition is administered by injection into the patient's bloodstream, and the CAR T cells in the patient's bloodstream are at least 10 percent of the patient's total T cells in the patient's bloodstream about four weeks after injection of the CAR T cell composition.

[0191] 169. The method of any of paragraphs 1 to 160, wherein the CAR T cell composition is administered by injection into the patient's bloodstream, and the CAR T cells in the patient's bloodstream are at least 12 percent of the patient's total T cells in the patient's bloodstream about four weeks after injection of the CAR T cell composition.

[0192] 170. The method of any of paragraphs 1 to 160, wherein the CAR T cell composition is administered by injection into the patient's bloodstream, and the CAR T cells in the patient's bloodstream are at least 15 percent of the patient's total T cells in the patient's bloodstream about four weeks after injection of the CAR T cell composition.

[0193] 171. The method of any of paragraphs 1 to 160 or 168 to 170, wherein the CAR T cells in the CAR T cell composition administered to the patient comprise about 1 million to about 15 million CAR T cells.

[0194] 172. The method of any of paragraphs 1 to 160 or 168 to 171, wherein the dose of CAR T cells in the CAR T cell composition administered to the patient is selected from the group consisting of about 1 million, about 2 million, about 3 million, about 4 million, about 5 million, about 6 million, about 7 million, about 8 million, about 9 million, about 10 million, about 11 million, about 12 million, about 12.5 million, about 13 million, about 14 million, and about 15 million CAR T cells.

[0195] 173. The method of any of paragraphs 1 to 160 or 168 to 170, wherein the CAR T cells in the CAR T cell composition administered to the patient comprise at least about 2 million CAR T cells.

[0196] 174. The method of any of paragraphs 1 to 160 or 168 to 170, wherein the CAR T cells in the CAR T cell composition administered to the patient comprise at least about 5 million CAR T cells.

[0197] 175. The method of any of paragraphs 1 to 160 or 168 to 170, wherein the CAR T cells in the CAR T cell composition administered to the patient comprise at least about 10 million CAR T cells.

[0198] 176. The method of any of paragraphs 1 to 175, wherein the CAR T cells comprise a nucleic acid comprising SEQ ID NO:3.

[0199] 177. The method of any of paragraphs 1 to 176, wherein the CAR T cells comprise a vector comprising SEQ ID NO:1.

[0200] 178. The method of any of paragraphs 1 to 177, wherein the CAR T cells comprise a vector comprising SEQ ID NO:3.

[0201] 179. The method of paragraph 176, wherein the nucleic acid encodes a chimeric antigen receptor.

[0202] 180. The method of any of paragraphs 108 to 160, wherein an agent that inhibits activation of the CAR T cells is administered, the agent blocking binding of the CAR T cells to the compound or a pharmaceutically acceptable salt thereof, but not to the cancer.

[0203] 181. The method of paragraph 180, wherein the agent is fluoresceinamine, FITC, or sodium fluorescein.

[0204] 182. The method of paragraph 180, wherein the agent is FITC.

[0205] 183. A method of treating cancer, comprising: i) administering to a patient a compound or a pharmaceutically acceptable salt thereof, wherein the compound comprises a small molecule ligand linked to a targeting moiety by a linker, and the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 10 nmole / kg to about 2500 nmole / kg of patient body weight; and ii) administering to the patient a CAR T cell composition comprising CAR T cells, wherein the CAR T cells comprise a CAR directed to a targeting moiety, and the CAR T cells are at a dose of about 1 million CAR T cells to about 15 million CAR T cells. A method comprising:

[0206] 184. The method of paragraph 183, wherein the ligand is selected from the group consisting of folate, DUPA, an NK-1R ligand, a CAIX ligand, a gamma glutamyl transpeptidase ligand, an NKG2D ligand, and a CCK2R ligand.

[0207] 185. The method of either paragraph 183 or 184, wherein the ligand is folic acid.

[0208] 186. The method of any of paragraphs 183 to 185, wherein the targeting moiety is selected from the group consisting of 2,4-dinitrophenol (DNP), 2,4,6-trinitrophenol (TNP), biotin, digoxigenin, fluorescein, fluorescein isothiocyanate (FITC), NHS-fluorescein, pentafluorophenyl ester, tetrafluorophenyl ester, knottin, centyrin, and DARPin.

[0209] 187. The method of any of paragraphs 183 to 186, wherein the targeting moiety is FITC.

[0210] 188. The method of any of paragraphs 183 to 187, wherein the linker comprises polyethylene glycol (PEG), polyproline, a hydrophilic amino acid, a sugar, a non-natural peptidoglycan, polyvinylpyrrolidone, Pluronic F-127, or a combination thereof.

[0211] 189. The method of any of paragraphs 183 to 188, wherein the linker comprises PEG.

[0212] 190. The compound or a pharmaceutically acceptable salt thereof has the formula [ka] wherein B is a small molecule ligand, L is a linker, and T is a targeting moiety, wherein L is a group of the formula [ka] (wherein n is 0 to 200). Item 189. The method according to any one of Items 183 to 189,

[0213] 191. The method of any of paragraphs 183 to 190, wherein the linker comprises PEG and the targeting moiety is FITC or a pharmaceutically acceptable salt thereof.

[0214] 192. The method of any of paragraphs 183 to 191, wherein the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 10 nmole / kg to about 100 nmole / kg of patient body weight.

[0215] 193. The method of any of paragraphs 183 to 191, wherein the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 10 nmole / kg to about 50 nmole / kg of patient body weight.

[0216] 194. The method of any of paragraphs 183 to 191, wherein the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 10 nmole / kg to about 20 nmole / kg of patient body weight.

[0217] 195. The method of any of paragraphs 183 to 191, wherein the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 10 nmole / kg to about 600 nmole / kg of patient body weight.

[0218] 196. The method of any of paragraphs 183 to 191, wherein the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 200 nmole / kg to about 600 nmole / kg of patient body weight.

[0219] 197. The method of any of paragraphs 183 to 191, wherein the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 400 nmole / kg to about 600 nmole / kg of patient body weight.

[0220] 198. The method of any of paragraphs 183 to 197, wherein the CAR T cells are administered at a dose of about 1 million CAR T cells to about 12.5 million CAR T cells.

[0221] 199. The method of any of paragraphs 183 to 197, wherein the CAR T cells are administered at a dose of about 1 million CAR T cells to about 7 million CAR T cells.

[0222] 200. The method of any of paragraphs 183 to 197, wherein the CAR T cells are administered at a dose of about 1 million CAR T cells to about 5 million CAR T cells.

[0223] 201. The method of any of paragraphs 183 to 197, wherein the CAR T cells are administered at a dose of about 2 million CAR T cells to about 5 million CAR T cells.

[0224] 202. The cancer is lung cancer, bone cancer, pancreatic cancer, skin cancer, head cancer, neck cancer, cutaneous melanoma, intraocular melanoma, uterine cancer, ovarian cancer, endometrial cancer, rectal cancer, stomach cancer, colon cancer, breast cancer, triple-negative breast cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, non-small cell lung cancer, adrenal cancer, soft tissue sarcoma, osteosarcoma, urethral cancer, prostate cancer, chronic leukemia, acute leukemia 202. The method of any of paragraphs 183 to 201, wherein the cancer is selected from the group consisting of hematopoietic leukemia, acute myeloid leukemia, lymphocytic lymphoma, myeloid leukemia, myelomonocytic leukemia, hairy leukemia, pleural mesothelioma, bladder cancer, Burkitt's lymphoma, ureteral cancer, kidney cancer, renal cell carcinoma, renal pelvis cancer, central nervous system (CNS) neoplasms, primary CNS lymphoma, spinal axis tumor, brainstem glioma, pituitary adenoma and esophagogastric junction adenocarcinoma.

[0225] 203. The method of any of items 183 to 202, wherein the cancer is a folate receptor-expressing cancer.

[0226] 204. The method of any of items 183 to 203, wherein the CAR has a recognition region, which is a single-chain fragment variable (scFv) region of an anti-FITC antibody; the CAR has a costimulatory domain, which is CD137 (4-1BB); and the CAR has an activation signaling domain, which is a T cell CD3ζ chain.

[0227] 205. The method of any of items 183 to 204, wherein the compound or a pharmaceutically acceptable salt thereof is not an antibody and does not include an antibody fragment.

[0228] 206. The method of any of paragraphs 183 to 205, wherein the targeting moiety does not comprise a peptide epitope.

[0229] 207. The method of any of paragraphs 183 to 206, wherein CAR T cell toxicity against cancer occurs without cytokine release resulting in off-target toxicity in the patient.

[0230] 208. The method of any of paragraphs 183 to 206, wherein off-target tissue toxicity does not occur in the patient and CAR T cell toxicity against the cancer occurs.

[0231] 209. The method of any of paragraphs 183 to 206, wherein the cancer comprises a tumor, the tumor size is reduced in the patient, and no off-target toxicity occurs.

[0232] 210. The method of any of paragraphs 183 to 209, wherein the CAR T cells comprise a nucleic acid comprising SEQ ID NO:1.

[0233] 211. The method of any of paragraphs 183 to 209, wherein the CAR T cells comprise a polypeptide comprising SEQ ID NO:2.

[0234] 212. The method of any of paragraphs 183 to 211, wherein the CAR comprises a humanized amino acid sequence.

[0235] 213. The method of any of paragraphs 183 to 212, wherein the CAR consists of a humanized amino acid sequence.

[0236] 214. The method of any of paragraphs 183 to 213, wherein the CAR T cell composition further comprises non-transformed T cells.

[0237] 215. A method of treating cancer, comprising: i) continuously administering to a patient a compound or a pharmaceutically acceptable salt thereof, wherein the compound comprises a small molecule ligand linked to a targeting moiety by a linker; ii) administering to the patient a CAR T cell composition comprising CAR T cells, wherein the CAR T cells comprise a CAR directed to a targeting moiety; and iii) terminating the continuous administration of the compound or a pharmaceutically acceptable salt thereof to inhibit or prevent cytokine release syndrome in the patient. A method comprising:

[0238] 216. The method of paragraph 215, wherein the ligand is selected from the group consisting of folate, DUPA, an NK-1R ligand, a CAIX ligand, a gamma glutamyl transpeptidase ligand, an NKG2D ligand, and a CCK2R ligand.

[0239] 217. The method of either paragraph 215 or 216, wherein the ligand is folic acid.

[0240] 218. The method of any of paragraphs 215 to 217, wherein the targeting moiety is selected from the group consisting of 2,4-dinitrophenol (DNP), 2,4,6-trinitrophenol (TNP), biotin, digoxigenin, fluorescein, fluorescein isothiocyanate (FITC), NHS-fluorescein, pentafluorophenyl ester, tetrafluorophenyl ester, knottin, centyrin, and DARPin.

[0241] 219. The method of any of paragraphs 215 to 218, wherein the targeting moiety is FITC.

[0242] 220. The method of any of paragraphs 215 to 219, wherein the linker comprises polyethylene glycol (PEG), polyproline, a hydrophilic amino acid, a sugar, a non-natural peptidoglycan, polyvinylpyrrolidone, Pluronic F-127, or a combination thereof.

[0243] 221. The method of any of paragraphs 215 to 220, wherein the linker comprises PEG.

[0244] 222. The compound or a pharmaceutically acceptable salt thereof has the formula [ka] wherein B is a small molecule ligand, L is a linker, and T is a targeting moiety, wherein L is a group of the formula [ka] (wherein n is 0 to 200). Item 222. The method according to any one of Items 215 to 221,

[0245] 223. The method of any of paragraphs 215 to 222, wherein the linker comprises PEG and the targeting moiety is FITC or a pharmaceutically acceptable salt thereof.

[0246] 224. The method of any of paragraphs 215 to 223, wherein the compound or a pharmaceutically acceptable salt thereof is administered to the patient continuously for at least 1 hour.

[0247] 225. The method of any of paragraphs 215 to 223, wherein the compound or a pharmaceutically acceptable salt thereof is administered to the patient continuously for at least 4 hours.

[0248] 226. The method of any of paragraphs 215 to 223, wherein the compound or a pharmaceutically acceptable salt thereof is administered to the patient continuously for at least 6 hours.

[0249] 227. The method of any of paragraphs 215 to 223, wherein the continuous administration of the compound or a pharmaceutically acceptable salt thereof is an alternate-day administration regimen.

[0250] 228. The method of any of paragraphs 215 to 223, wherein the continuous administration of the compound or a pharmaceutically acceptable salt thereof is a regimen of three administrations per week.

[0251] 229. The method according to any one of paragraphs 215 to 223, wherein the compound or a pharmaceutically acceptable salt thereof is continuously administered until the patient experiences unacceptable weight loss, fever, hypotension, or pulmonary edema.

[0252] 230. The method of any of paragraphs 215 to 229, wherein the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 200 nmole / kg to about 600 nmole / kg of patient body weight.

[0253] 231. The method of any of paragraphs 215 to 229, wherein the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 400 nmole / kg to about 600 nmole / kg of patient body weight.

[0254] 232. The method of any of paragraphs 215 to 231, wherein about 2 million to about 5 million CAR T cells are administered.

[0255] 233. The method of any of paragraphs 215 to 232, wherein the administration is by intravenous administration.

[0256] 234. The cancer is lung cancer, bone cancer, pancreatic cancer, skin cancer, head cancer, neck cancer, cutaneous melanoma, intraocular melanoma, uterine cancer, ovarian cancer, endometrial cancer, rectal cancer, stomach cancer, colon cancer, breast cancer, triple-negative breast cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, non-small cell lung cancer, adrenal cancer, soft tissue sarcoma, osteosarcoma, urethral cancer, prostate cancer, chronic leukemia, acute leukemia 234. The method of any of items 215 to 233, wherein the cancer is selected from the group consisting of hematopoietic leukemia, acute myeloid leukemia, lymphocytic lymphoma, myeloid leukemia, myelomonocytic leukemia, hairy leukemia, pleural mesothelioma, bladder cancer, Burkitt's lymphoma, ureteral cancer, kidney cancer, renal cell carcinoma, renal pelvis cancer, central nervous system (CNS) neoplasms, primary CNS lymphoma, spinal axis tumor, brainstem glioma, pituitary adenoma and esophagogastric junction adenocarcinoma.

[0257] 235. The method of any of paragraphs 215 to 234, wherein the cancer is a folate receptor-expressing cancer.

[0258] 236. The method of any of items 215 to 235, wherein the CAR has a recognition region, which is a single-chain fragment variable (scFv) region of an anti-FITC antibody; the CAR has a costimulatory domain, which is CD137 (4-1BB); and the CAR has an activation signaling domain, which is the T cell CD3ζ chain.

[0259] 237. The method of any of items 215 to 236, wherein the compound or a pharmaceutically acceptable salt thereof is not an antibody and does not include an antibody fragment.

[0260] 238. The method of any of paragraphs 215 to 237, wherein the targeting moiety does not comprise a peptide epitope.

[0261] 239. The method of any of paragraphs 215 to 238, wherein CAR T cell toxicity against cancer occurs without cytokine release resulting in off-target toxicity in the patient.

[0262] 240. The method of any of paragraphs 215 to 238, wherein off-target tissue toxicity does not occur in the patient and CAR T cell toxicity against the cancer occurs.

[0263] 241. The method of any of paragraphs 215 to 238, wherein the cancer comprises a tumor, the tumor size is reduced in the patient, and no off-target toxicity occurs.

[0264] 242. The method of any of paragraphs 215 to 241, wherein the CAR T cells comprise a nucleic acid comprising SEQ ID NO:1.

[0265] 243. The method of any of paragraphs 215 to 242, wherein the CAR T cells comprise a polypeptide comprising SEQ ID NO:2.

[0266] 244. The method of any of paragraphs 215 to 243, wherein the CAR comprises a humanized amino acid sequence.

[0267] 245. The method of any of paragraphs 215 to 243, wherein the CAR consists of a humanized amino acid sequence.

[0268] 246. The method of any of paragraphs 215 to 245, wherein the CAR T cell composition further comprises non-transformed T cells.

[0269] 247. The method of any of paragraphs 215 to 246, wherein the CAR T cell composition further comprises non-transformed T cells in a ratio selected from the group consisting of about 1:5 CAR T cells to non-transformed T cells, about 1:4 CAR T cells to non-transformed T cells, about 1:3 CAR T cells to non-transformed T cells, about 1:2 CAR T cells to non-transformed T cells, and about 1:1 CAR T cells to non-transformed T cells.

[0270] 248. The method of any of paragraphs 215 to 247, wherein the CAR T cell composition further comprises non-transformed T cells at a ratio of CAR T cells to non-transformed T cells of about 1:1 to about 1:5.

[0271] 249. The method of any of paragraphs 215 to 248, wherein the CAR T cell composition is a mixture of about 10 million CAR T cells and about 40 million non-transformed T cells, further comprising non-transformed T cells.

[0272] 250. The method according to any one of items 215 to 249, wherein the cancer is non-small cell lung cancer.

[0273] 251. The method of any of items 215 to 249, wherein the cancer is ovarian cancer.

[0274] 252. A method for treating cancer, comprising: i) administering to a patient a compound or a pharmaceutically acceptable salt thereof, wherein the compound comprises a small molecule ligand linked to a targeting moiety by a linker, and the compound or a pharmaceutically acceptable salt thereof is administered to the patient weekly; and ii) administering to the patient a CAR T cell composition comprising CAR T cells, wherein the CAR T cells comprise a CAR directed to a targeting moiety. A method comprising:

[0275] 253. The method of paragraph 252, wherein the ligand is selected from the group consisting of folate, DUPA, an NK-1R ligand, a CAIX ligand, a gamma glutamyl transpeptidase ligand, an NKG2D ligand, and a CCK2R ligand.

[0276] 254. The method of either paragraph 252 or 253, wherein the ligand is folic acid.

[0277] 255. The method of any of paragraphs 252 to 254, wherein the targeting moiety is selected from the group consisting of 2,4-dinitrophenol (DNP), 2,4,6-trinitrophenol (TNP), biotin, digoxigenin, fluorescein, fluorescein isothiocyanate (FITC), NHS-fluorescein, pentafluorophenyl ester, tetrafluorophenyl ester, knottin, centyrin, and DARPin.

[0278] 256. The method of any of paragraphs 252 to 255, wherein the targeting moiety is FITC.

[0279] 257. The method of any of paragraphs 252 to 256, wherein the linker comprises polyethylene glycol (PEG), polyproline, a hydrophilic amino acid, a sugar, a non-natural peptidoglycan, polyvinylpyrrolidone, Pluronic F-127, or a combination thereof.

[0280] 258. The method of any of paragraphs 252 to 257, wherein the linker comprises PEG.

[0281] 259. The compound or a pharmaceutically acceptable salt thereof has the formula [ka] wherein B is a small molecule ligand, L is a linker, and T is a targeting moiety, wherein L is a group of the formula [ka] (wherein n is 0 to 200). Item 259. The method according to any one of Items 252 to 258,

[0282] 260. The method of any of paragraphs 252 to 259, wherein the linker comprises PEG and the targeting moiety is FITC or a pharmaceutically acceptable salt thereof.

[0283] 261. The method of any of paragraphs 252 to 260, wherein the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 10 nmole / kg to about 100 nmole / kg of patient body weight.

[0284] 262. The method of any of paragraphs 252 to 261, wherein the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 10 nmole / kg to about 50 nmole / kg of patient body weight.

[0285] 263. The method of any of paragraphs 252 to 262, wherein the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 10 nmole / kg to about 20 nmole / kg of patient body weight.

[0286] 264. The method of any of paragraphs 252 to 263, wherein the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 10 nmole / kg to about 600 nmole / kg of patient body weight.

[0287] 265. The method of any of paragraphs 252 to 264, wherein the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 200 nmole / kg to about 600 nmole / kg of patient body weight.

[0288] 266. The method of any of paragraphs 252 to 265, wherein the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 400 nmole / kg to about 600 nmole / kg of patient body weight.

[0289] 267. The method of any of paragraphs 252 to 266, wherein the CAR T cells are administered at a dose of about 1 million CAR T cells to about 15 million CAR T cells.

[0290] 268. The method of any of paragraphs 252 to 267, wherein the CAR T cells are administered at a dose of about 1 million CAR T cells to about 7 million CAR T cells.

[0291] 269. The method of any of paragraphs 252 to 268, wherein the CAR T cells are administered at a dose of about 1 million CAR T cells to about 5 million CAR T cells.

[0292] 270. The method of any of paragraphs 252 to 269, wherein the CAR T cells are administered at a dose of about 2 million CAR T cells to about 5 million CAR T cells.

[0293] 271. The cancer is lung cancer, bone cancer, pancreatic cancer, skin cancer, head cancer, neck cancer, cutaneous melanoma, intraocular melanoma, uterine cancer, ovarian cancer, endometrial cancer, rectal cancer, stomach cancer, colon cancer, breast cancer, triple-negative breast cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, non-small cell lung cancer, adrenal cancer, soft tissue sarcoma, osteosarcoma, urethral cancer, prostate cancer, chronic leukemia, acute leukemia 271. The method of any of paragraphs 252 to 270, wherein the cancer is selected from the group consisting of hematopoietic leukemia, acute myeloid leukemia, lymphocytic lymphoma, myeloid leukemia, myelomonocytic leukemia, hairy leukemia, pleural mesothelioma, bladder cancer, Burkitt's lymphoma, ureteral cancer, kidney cancer, renal cell carcinoma, renal pelvis cancer, central nervous system (CNS) neoplasms, primary CNS lymphoma, spinal axis tumor, brainstem glioma, pituitary adenoma and esophagogastric junction adenocarcinoma.

[0294] 272. The method of any of paragraphs 252 to 271, wherein the cancer is a folate receptor-expressing cancer.

[0295] 273. The method of any of items 252 to 272, wherein the CAR has a recognition region, which is a single-chain fragment variable (scFv) region of an anti-FITC antibody; the CAR has a costimulatory domain, which is CD137 (4-1BB); and the CAR has an activation signaling domain, which is the T cell CD3ζ chain.

[0296] 274. The method of any of paragraphs 252 to 273, wherein the compound or a pharmaceutically acceptable salt thereof is not an antibody and does not include a fragment of an antibody.

[0297] 275. The method of any of paragraphs 252 to 274, wherein the targeting moiety does not comprise a peptide epitope.

[0298] 276. The method of any of paragraphs 252 to 275, wherein CAR T cell toxicity against cancer occurs without cytokine release resulting in off-target toxicity in the patient.

[0299] 277. The method of any of paragraphs 252 to 275, wherein off-target tissue toxicity does not occur in the patient and CAR T cell toxicity against the cancer occurs.

[0300] 278. The method of any of paragraphs 252 to 275, wherein the cancer comprises a tumor, the tumor size is reduced in the patient, and no off-target toxicity occurs.

[0301] 279. The method of any of paragraphs 252 to 278, wherein the CAR T cells comprise a nucleic acid comprising SEQ ID NO:1.

[0302] 280. The method of any of paragraphs 252 to 278, wherein the CAR T cells comprise a polypeptide comprising SEQ ID NO:2.

[0303] 281. The method of any of paragraphs 252 to 280, wherein the CAR comprises a humanized amino acid sequence.

[0304] 282. The method of any of paragraphs 252 to 280, wherein the CAR consists of a humanized amino acid sequence.

[0305] 283. The method of any of paragraphs 252 to 282, wherein the CAR T cell composition further comprises non-transformed T cells.

[0306] 284. A method of treating cancer, comprising: i) administering to a patient a compound or a pharmaceutically acceptable salt thereof, wherein the compound comprises a small molecule ligand linked to a targeting moiety by a linker, and at least a first dose and a second dose of the compound or a pharmaceutically acceptable salt thereof are administered to the patient, wherein the first dose and the second dose are different, and the second dose of the compound or a pharmaceutically acceptable salt thereof is about 2-fold to about 15,000-fold greater than the first dose of the compound or a pharmaceutically acceptable salt thereof; and ii) administering to the patient a CAR T cell composition comprising CAR T cells, wherein the CAR T cells comprise a CAR directed to a targeting moiety. A method comprising:

[0307] 285. The method of paragraph 284, wherein the first dose, second dose, and third dose are different, the second dose of the compound or its pharmaceutically acceptable salt is about 2 to about 750 times greater than the first dose of the compound or its pharmaceutically acceptable salt, and the third dose of the compound or its pharmaceutically acceptable salt is about 800 to about 10,000 times greater than the first dose of the compound or its pharmaceutically acceptable salt, and at least the first dose, second dose, and third dose of the compound or its pharmaceutically acceptable salt are administered to the patient.

[0308] 286. The method of paragraph 285, wherein the first, second, third, and fourth doses are different, the second dose of the compound or its pharmaceutically acceptable salt being about 2 to about 750 times greater than the first dose of the compound or its pharmaceutically acceptable salt, the third dose of the compound or its pharmaceutically acceptable salt being about 800 to about 7,500 times greater than the first dose of the compound or its pharmaceutically acceptable salt, and the fourth dose of the compound or its pharmaceutically acceptable salt being about 8,000 to about 15,000 times greater than the first dose of the compound or its pharmaceutically acceptable salt, and wherein at least the first, second, third, and fourth doses of the compound or its pharmaceutically acceptable salt are administered to the patient.

[0309] 287. The method of paragraph 286, wherein the second dose of the compound or its pharmaceutically acceptable salt is about 100 times greater than the first dose of the compound or its pharmaceutically acceptable salt, the third dose of the compound or its pharmaceutically acceptable salt is about 1000 times greater than the first dose of the compound or its pharmaceutically acceptable salt, and the fourth dose of the compound or its pharmaceutically acceptable salt is about 10000 times greater than the first dose of the compound or its pharmaceutically acceptable salt.

[0310] 288. The method of any of paragraphs 284 to 287, wherein the ligand is selected from the group consisting of folic acid, DUPA, an NK-1R ligand, a CAIX ligand, a gamma glutamyl transpeptidase ligand, an NKG2D ligand, and a CCK2R ligand.

[0311] 289. The method of any of paragraphs 284 to 288, wherein the ligand is folic acid.

[0312] 290. The method of any of paragraphs 284 to 289, wherein the targeting moiety is selected from the group consisting of 2,4-dinitrophenol (DNP), 2,4,6-trinitrophenol (TNP), biotin, digoxigenin, fluorescein, fluorescein isothiocyanate (FITC), NHS-fluorescein, pentafluorophenyl ester, tetrafluorophenyl ester, knottin, centyrin, and DARPin.

[0313] 291. The method of any of paragraphs 284 to 290, wherein the targeting moiety is FITC.

[0314] 292. The method of any of paragraphs 284 to 291, wherein the linker comprises polyethylene glycol (PEG), polyproline, a hydrophilic amino acid, a sugar, a non-natural peptidoglycan, polyvinylpyrrolidone, Pluronic F-127, or a combination thereof.

[0315] 293. The method of any of paragraphs 284 to 292, wherein the linker comprises PEG.

[0316] 294. The compound or a pharmaceutically acceptable salt thereof has the formula [ka] wherein B is a small molecule ligand, L is a linker, and T is a targeting moiety, wherein L is a group of the formula [ka] (wherein n is 0 to 200). Item 294. The method according to any one of Items 284 to 293,

[0317] 295. The method of any of paragraphs 284 to 294, wherein the linker comprises PEG and the targeting moiety is FITC or a pharmaceutically acceptable salt thereof.

[0318] 296. The method of any of paragraphs 284 to 295, wherein the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 10 nmole / kg to about 100 nmole / kg of patient body weight.

[0319] 297. The method of any of paragraphs 284 to 296, wherein the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 10 nmole / kg to about 50 nmole / kg of patient body weight.

[0320] 298. The method of any of paragraphs 284 to 297, wherein the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 10 nmole / kg to about 20 nmole / kg of patient body weight.

[0321] 299. The method of any of paragraphs 284 to 298, wherein the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 10 nmole / kg to about 600 nmole / kg of patient body weight.

[0322] 300. The method of any of paragraphs 284 to 299, wherein the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 200 nmole / kg to about 600 nmole / kg of patient body weight.

[0323] 301. The method of any of paragraphs 284 to 300, wherein the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 400 nmole / kg to about 600 nmole / kg of patient body weight.

[0324] 302. The method of any of paragraphs 284 to 301, wherein the CAR T cells are administered at a dose of about 1 million CAR T cells to about 15 million CAR T cells.

[0325] 303. The method of any of paragraphs 284 to 302, wherein the CAR T cells are administered at a dose of about 1 million CAR T cells to about 7 million CAR T cells.

[0326] 304. The method of any of paragraphs 284 to 303, wherein the CAR T cells are administered at a dose of about 1 million CAR T cells to about 5 million CAR T cells.

[0327] 305. The method of any of paragraphs 284 to 304, wherein the CAR T cells are administered at a dose of about 2 million CAR T cells to about 5 million CAR T cells.

[0328] 306. The cancer is lung cancer, bone cancer, pancreatic cancer, skin cancer, head cancer, neck cancer, cutaneous melanoma, intraocular melanoma, uterine cancer, ovarian cancer, endometrial cancer, rectal cancer, stomach cancer, colon cancer, breast cancer, triple-negative breast cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, non-small cell lung cancer, adrenal cancer, soft tissue sarcoma, osteosarcoma, urethral cancer, prostate cancer, chronic leukemia, acute leukemia 306. The method of any of paragraphs 284 to 305, wherein the cancer is selected from the group consisting of hematopoietic leukemia, acute myeloid leukemia, lymphocytic lymphoma, myeloid leukemia, myelomonocytic leukemia, hairy leukemia, pleural mesothelioma, bladder cancer, Burkitt's lymphoma, ureteral cancer, kidney cancer, renal cell carcinoma, renal pelvis cancer, central nervous system (CNS) neoplasms, primary CNS lymphoma, spinal axis tumor, brainstem glioma, pituitary adenoma and esophagogastric junction adenocarcinoma.

[0329] 307. The method of any of paragraphs 284 to 306, wherein the cancer is a folate receptor-expressing cancer.

[0330] 308. The method of any of paragraphs 284 to 307, wherein the CAR has a recognition region, which is a single-chain fragment variable (scFv) region of an anti-FITC antibody; the CAR has a costimulatory domain, which is CD137 (4-1BB); and the CAR has an activation signaling domain, which is a T cell CD3ζ chain.

[0331] 309. The method of any of paragraphs 284 to 308, wherein the compound or a pharmaceutically acceptable salt thereof is not an antibody and does not include a fragment of an antibody.

[0332] 310. The method of any of paragraphs 284 to 309, wherein the targeting moiety does not comprise a peptide epitope.

[0333] 311. The method of any of paragraphs 284 to 310, wherein CAR T cell toxicity against cancer occurs without cytokine release resulting in off-target toxicity in the patient.

[0334] 312. The method of any of paragraphs 284 to 310, wherein off-target tissue toxicity does not occur in the patient and CAR T cell toxicity against the cancer occurs.

[0335] 313. The method of any of paragraphs 284 to 310, wherein the cancer comprises a tumor, the tumor size is reduced in the patient, and no off-target toxicity occurs.

[0336] 314. The method of any of paragraphs 284 to 313, wherein the CAR T cells comprise a nucleic acid comprising SEQ ID NO:1.

[0337] 315. The method of any of paragraphs 284 to 313, wherein the CAR T cells comprise a polypeptide comprising SEQ ID NO:2.

[0338] 316. The method of any of paragraphs 284 to 315, wherein the CAR comprises a humanized amino acid sequence.

[0339] 317. The method of any of paragraphs 284 to 315, wherein the CAR consists of a humanized amino acid sequence.

[0340] 318. The method of any of paragraphs 284 to 317, wherein the CAR T cell composition further comprises non-transformed T cells.

[0341] 319. The method of any of paragraphs 1 to 214 or 252 to 318, wherein the compound or a pharmaceutically acceptable salt thereof is continuously administered to a patient, and further comprising a step of terminating the continuous administration of the compound or a pharmaceutically acceptable salt thereof to inhibit or prevent cytokine release syndrome in the patient.

[0342] 320. The method of any of paragraphs 1-107 or 183-318, further comprising administering to the patient folic acid, a conjugate comprising folic acid (wherein the conjugate comprising folic acid does not comprise a targeting moiety), or an agent that inhibits CAR T cell activation.

[0343] 321. The method of any of items 1 to 182 or 215 to 318, wherein the compound or a pharmaceutically acceptable salt thereof is administered in an amount of about 10 nmole / kg to about 2500 nmole / kg of patient body weight, and the CAR T cells are administered in an amount of about 1 million to about 15 million CAR T cells.

[0344] 322. The method of any of paragraphs 1-251 or 284-318, wherein the compound or a pharmaceutically acceptable salt thereof is administered to the patient once a week.

[0345] 323. The method of any of items 1 to 283, wherein the patient is administered at least a first dose and a second dose of the compound or a pharmaceutically acceptable salt thereof, the first dose and the second dose being different, and the second dose of the compound or a pharmaceutically acceptable salt thereof being about 2 to about 15,000 times greater than the first dose of the compound or a pharmaceutically acceptable salt thereof.

[0346] 324. The method of any of paragraphs 56 to 318, wherein the CAR T cell composition is administered at least twice.

[0347] 325. A method for treating cancer, comprising: i) administering to a patient a first dose of a compound or a pharmaceutically acceptable salt thereof, wherein the compound comprises a small molecule ligand linked to a targeting moiety by a linker; ii) administering to the patient at least a second dose of the compound or pharmaceutically acceptable salt thereof, wherein the second dose of the compound or pharmaceutically acceptable salt thereof is at least about 50 percent less than the first dose of the compound or pharmaceutically acceptable salt thereof; and iii) administering to the patient a CAR T cell composition comprising a single CAR T cell, the CAR T cell comprising a CAR directed to a targeting moiety. A method comprising:

[0348] 326. The method of paragraph 325, wherein the second dose of the compound or pharmaceutically acceptable salt thereof is at least about 60 percent less than the first dose of the compound or pharmaceutically acceptable salt thereof.

[0349] 327. The method of paragraph 325, wherein the second dose of the compound or pharmaceutically acceptable salt thereof is at least about 70 percent less than the first dose of the compound or pharmaceutically acceptable salt thereof.

[0350] 328. The method of paragraph 325, wherein the second dose of the compound or pharmaceutically acceptable salt thereof is at least about 80 percent less than the first dose of the compound or pharmaceutically acceptable salt thereof.

[0351] 329. The method of paragraph 325, wherein the second dose of the compound or pharmaceutically acceptable salt thereof is at least about 90 percent less than the first dose of the compound or pharmaceutically acceptable salt thereof.

[0352] 330. The method of paragraph 325, wherein the second dose of the compound or pharmaceutically acceptable salt thereof is at least about 95 percent less than the first dose of the compound or pharmaceutically acceptable salt thereof.

[0353] 331. The method of paragraph 325, wherein the second dose of the compound or pharmaceutically acceptable salt thereof is at least about 96 percent less than the first dose of the compound or pharmaceutically acceptable salt thereof.

[0354] 332. The method of paragraph 325, wherein the second dose of the compound or pharmaceutically acceptable salt thereof is at least about 97 percent less than the first dose of the compound or pharmaceutically acceptable salt thereof.

[0355] 333. The method of paragraph 325, wherein the second dose of the compound or pharmaceutically acceptable salt thereof is at least about 98 percent less than the first dose of the compound or pharmaceutically acceptable salt thereof.

[0356] 334. The method of paragraph 325, wherein the second dose of the compound or pharmaceutically acceptable salt thereof is at least about 99 percent less than the first dose of the compound or pharmaceutically acceptable salt thereof.

[0357] 335. The method of paragraph 325, wherein the second dose of the compound or pharmaceutically acceptable salt thereof is at least about 99.5 percent less than the first dose of the compound or pharmaceutically acceptable salt thereof.

[0358] 336. The method according to any one of items 325 to 335, wherein the first dose of the compound or a pharmaceutically acceptable salt thereof is about 100 nmole / kg to about 1000 nmole / kg of patient body weight.

[0359] 337. The method according to any one of items 325 to 335, wherein the first dose of the compound or a pharmaceutically acceptable salt thereof is about 100 nmole / kg to about 900 nmole / kg of patient body weight.

[0360] 338. The method according to any one of items 325 to 335, wherein the first dose of the compound or a pharmaceutically acceptable salt thereof is about 100 nmole / kg to about 800 nmole / kg of patient body weight.

[0361] 339. The method according to any one of items 325 to 335, wherein the first dose of the compound or a pharmaceutically acceptable salt thereof is about 100 nmole / kg to about 700 nmole / kg of patient body weight.

[0362] 340. The method according to any one of items 325 to 335, wherein the first dose of the compound or a pharmaceutically acceptable salt thereof is about 100 nmole / kg to about 600 nmole / kg of patient body weight.

[0363] 341. The method according to any one of items 325 to 335, wherein the first dose of the compound or a pharmaceutically acceptable salt thereof is about 200 nmole / kg to about 600 nmole / kg of patient body weight.

[0364] 342. The method according to any one of items 325 to 335, wherein the first dose of the compound or a pharmaceutically acceptable salt thereof is about 400 nmole / kg to about 600 nmole / kg of patient body weight.

[0365] 343. The method of any of paragraphs 325 to 335, wherein the first dose of the compound or a pharmaceutically acceptable salt thereof is about 500 nmole / kg of patient body weight.

[0366] 344. The method of paragraph 336, wherein the second dose of the compound or a pharmaceutically acceptable salt thereof is about 0.5 nmole / kg to about 500 nmole / kg of patient body weight.

[0367] 345. The method of paragraph 337, wherein the second dose of the compound or a pharmaceutically acceptable salt thereof is about 0.5 nmole / kg to about 450 nmole / kg of patient body weight.

[0368] 346. The method of paragraph 338, wherein the second dose of the compound or a pharmaceutically acceptable salt thereof is about 0.5 nmole / kg to about 400 nmole / kg of patient body weight.

[0369] 347. The method according to paragraph 339, wherein the second dose of the compound or a pharmaceutically acceptable salt thereof is about 0.5 nmole / kg to about 350 nmole / kg of patient body weight.

[0370] 348. The method according to paragraph 340, wherein the second dose of the compound or a pharmaceutically acceptable salt thereof is about 0.5 nmole / kg to about 300 nmole / kg of patient body weight.

[0371] 349. The method according to paragraph 341, wherein the second dose of the compound or a pharmaceutically acceptable salt thereof is about 1 nmole / kg to about 300 nmole / kg of patient body weight.

[0372] 350. The method of paragraph 342, wherein the second dose of the compound or a pharmaceutically acceptable salt thereof is about 2 nmole / kg to about 300 nmole / kg of patient body weight.

[0373] 351. The method according to paragraph 343, wherein the second dose of the compound or a pharmaceutically acceptable salt thereof is about 2 nmole / kg to about 250 nmole / kg of patient body weight.

[0374] 352. The method of any of paragraphs 336 to 343, wherein the second dose of the compound or a pharmaceutically acceptable salt thereof is about 5 nmole / kg to about 40 nmole / kg of patient body weight.

[0375] 353. The method of any of paragraphs 336 to 343, wherein the second dose of the compound or a pharmaceutically acceptable salt thereof is about 40 nmole / kg to about 150 nmole / kg of patient body weight.

[0376] 354. The method of any of items 325 to 353, further comprising administering a third dose of the compound or a pharmaceutically acceptable salt thereof, wherein the third dose of the compound or a pharmaceutically acceptable salt thereof is the same as the second dose of the compound or a pharmaceutically acceptable salt thereof.

[0377] 355. The method of paragraph 354, further comprising administering a fourth dose of the compound or its pharmaceutically acceptable salt, wherein the fourth dose of the compound or its pharmaceutically acceptable salt is the same as the second dose of the compound or its pharmaceutically acceptable salt and the third dose of the compound or its pharmaceutically acceptable salt.

[0378] 356. The method of any of paragraphs 325 to 355, wherein a dose of the compound or a pharmaceutically acceptable salt thereof administered after the first dose of the compound or a pharmaceutically acceptable salt thereof maintains the inhibition of cancer growth compared to the first dose of the compound or a pharmaceutically acceptable salt thereof.

[0379] 357. The method of any of paragraphs 325 to 356, wherein the CAR T cells are administered at a dose of about 1 million CAR T cells to about 40 million CAR T cells.

[0380] 358. The method of any of paragraphs 325 to 357, wherein the dose of the compound or pharmaceutically acceptable salt thereof administered after the first dose of the compound or pharmaceutically acceptable salt thereof is administered once a week.

[0381] 359. The method of any of paragraphs 325 to 357, wherein the dose of the compound or a pharmaceutically acceptable salt thereof is administered twice weekly.

[0382] 360. The method of any of paragraphs 325 to 359, wherein the ligand is selected from the group consisting of folic acid, DUPA, an NK-1R ligand, a CAIX ligand, a gamma glutamyl transpeptidase ligand, an NKG2D ligand, and a CCK2R ligand.

[0383] 361. The method of any of paragraphs 325 to 360, wherein the ligand is folic acid.

[0384] 362. The method of any of paragraphs 325 to 360, wherein the ligand is an NK-1R ligand.

[0385] 363. The method of any of paragraphs 325 to 360, wherein the ligand is DUPA.

[0386] 364. The method of any of paragraphs 325 to 360, wherein the ligand is a CCK2R ligand.

[0387] 365. The method of any of paragraphs 325 to 360, wherein the ligand is a gamma glutamyl transpeptidase ligand.

[0388] 366. The method of any of paragraphs 325 to 365, wherein the targeting moiety is selected from the group consisting of 2,4-dinitrophenol (DNP), 2,4,6-trinitrophenol (TNP), biotin, digoxigenin, fluorescein, fluorescein isothiocyanate (FITC), NHS-fluorescein, pentafluorophenyl ester, tetrafluorophenyl ester, knottin, centyrin, and DARPin.

[0389] 367. The method of any of paragraphs 325-366, wherein the targeting moiety is FITC.

[0390] 368. The method of any of paragraphs 325-366, wherein the targeting moiety is DNP.

[0391] 369. The method of any of paragraphs 325-366, wherein the targeting moiety is TNP.

[0392] 370. The method of any of paragraphs 325 to 369, wherein the linker comprises polyethylene glycol (PEG), polyproline, a hydrophilic amino acid, a sugar, a non-natural peptidoglycan, polyvinylpyrrolidone, Pluronic F-127, or a combination thereof.

[0393] 371. The method of any of paragraphs 325 to 370, wherein the linker comprises PEG.

[0394] 372. The compound or a pharmaceutically acceptable salt thereof has the formula [ka] wherein B is a small molecule ligand, L is a linker, and T is a targeting moiety, wherein L is a group of the formula [ka] (wherein n is 0 to 200). Item 372. The method according to any one of Items 325 to 371,

[0395] 373. The method of claim 372, wherein n is an integer from 0 to 150.

[0396] 374. The method of claim 372, wherein n is an integer from 0 to 110.

[0397] 375. The method of claim 372, wherein n is an integer from 0 to 20.

[0398] 376. The method of claim 372, wherein n is an integer between 15 and 20.

[0399] 377. The method of claim 372, wherein n is an integer between 15 and 110.

[0400] 378. The method of any of paragraphs 325-367 or 370-377, wherein the linker comprises PEG and the targeting moiety is FITC or a pharmaceutically acceptable salt thereof.

[0401] 379. The cancer is lung cancer, bone cancer, pancreatic cancer, skin cancer, head cancer, neck cancer, cutaneous melanoma, intraocular melanoma, uterine cancer, ovarian cancer, endometrial cancer, rectal cancer, stomach cancer, colon cancer, breast cancer, triple-negative breast cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, non-small cell lung cancer, adrenal cancer, soft tissue sarcoma, osteosarcoma, urethral cancer, prostate cancer, chronic leukemia, acute leukemia 379. The method of any of paragraphs 325 to 378, wherein the cancer is selected from the group consisting of hematopoietic leukemia, acute myeloid leukemia, lymphocytic lymphoma, myeloid leukemia, myelomonocytic leukemia, hairy leukemia, pleural mesothelioma, bladder cancer, Burkitt's lymphoma, ureteral cancer, kidney cancer, renal cell carcinoma, renal pelvis cancer, central nervous system (CNS) neoplasms, primary CNS lymphoma, spinal axis tumor, brainstem glioma, pituitary adenoma and gastroesophageal junction adenocarcinoma.

[0402] 380. The method of any of paragraphs 325 to 361 or 366 to 379, wherein the cancer is a folate receptor-expressing cancer.

[0403] 381. The method of paragraph 380, wherein the cancer is endometrial cancer.

[0404] 382. The method of paragraph 380, wherein the cancer is non-small cell lung cancer.

[0405] 383. The method of paragraph 380, wherein the cancer is ovarian cancer.

[0406] 384. The method of paragraph 380, wherein the cancer is triple-negative breast cancer.

[0407] 385. The method of any of paragraphs 325 to 384, wherein the CAR has a recognition region, and the recognition region is a single-chain fragment variable (scFv) region of an antibody.

[0408] 386. The method of any of paragraphs 325 to 367 or 370 to 385, wherein the CAR has a recognition region, and the recognition region of the CAR is a single-chain fragment variable (scFv) region of an anti-FITC antibody.

[0409] 387. The method of any of paragraphs 325-386, wherein the CAR has a costimulatory domain, and the costimulatory domain is selected from the group consisting of CD28, CD137 (4-1BB), CD134 (OX40), and CD278 (ICOS).

[0410] 388. The method of any of paragraphs 325 to 387, wherein the CAR has an activation signaling domain, and the activation signaling domain is T cell CD3 zeta chain or Fc receptor γ.

[0411] 389. The method of any of paragraphs 325 to 367 or 370 to 388, wherein the CAR has a recognition region, which is a single-chain fragment variable (scFv) region of an anti-FITC antibody; the CAR has a costimulatory domain, which is CD137 (4-1BB); and the CAR has an activation signaling domain, which is a T cell CD3 zeta chain.

[0412] 390. The method of any of paragraphs 325 to 389, wherein multiple doses of the CAR T cell composition are administered.

[0413] 391. The method of any of paragraphs 325 to 390, wherein the patient is imaged prior to administration of the compound or a pharmaceutically acceptable salt thereof or prior to administration of the CAR T cell composition.

[0414] 392. The method of any of paragraphs 325 to 391, wherein the compound or a pharmaceutically acceptable salt thereof is not an antibody and does not include a fragment of an antibody.

[0415] 393. The method of any of paragraphs 325 to 392, wherein the targeting moiety does not comprise a peptide epitope.

[0416] 394. The method of any of paragraphs 325 to 393, wherein CAR T cell toxicity against cancer occurs without cytokine release resulting in off-target toxicity in the patient.

[0417] 395. The method of any of paragraphs 325 to 393, wherein off-target tissue toxicity does not occur in the patient and CAR T cell toxicity against the cancer occurs.

[0418] 396. The method of any of paragraphs 325 to 393, wherein the cancer comprises a tumor, the tumor size is reduced in the patient, and no off-target toxicity occurs.

[0419] 397. The method of any of paragraphs 325 to 398, wherein the CAR T cells comprise a nucleic acid comprising SEQ ID NO:1.

[0420] 398. The method of any of paragraphs 325 to 397, wherein the CAR T cells comprise a polypeptide comprising SEQ ID NO:2.

[0421] 399. The method of paragraph 397, wherein the nucleic acid encodes a chimeric antigen receptor.

[0422] 400. The method of any of paragraphs 325 to 399, wherein the CAR comprises a humanized amino acid sequence.

[0423] 401. The method of any of paragraphs 325 to 399, wherein the CAR consists of a humanized amino acid sequence.

[0424] 402. The method of any of paragraphs 325 to 401, further comprising administering to the patient folic acid, a conjugate comprising folic acid (wherein the conjugate comprising folic acid does not comprise a targeting moiety), or an agent that inhibits CAR T cell activation.

[0425] 403. The method of paragraph 402, wherein an agent that inhibits activation of the CAR T cells is administered to the patient, the agent being an agent that blocks binding of the CAR T cells to the compound or a pharmaceutically acceptable salt thereof but does not bind to the cancer.

[0426] 404. The method of paragraph 403, wherein the agent is fluoresceinamine, sodium fluorescein, or fluorescein.

[0427] 405. The method of paragraph 404, wherein the agent is sodium fluorescein.

[0428] 406. A method for treating cancer, comprising: i) administering to the patient a first compound or a pharmaceutically acceptable salt thereof, wherein the compound comprises a small molecule ligand linked to a targeting moiety by a linker, and the compound or a pharmaceutically acceptable salt thereof is administered to the patient at least about 1 hour prior to administration of a CAR T cell composition comprising CAR T cells, the CAR T cells comprising a CAR directed to the targeting moiety; ii) then administering to the patient a dose of the CAR T cell composition; and iii) then administering to the patient a second dose of the compound or a pharmaceutically acceptable salt thereof. A method comprising:

[0429] 407. The method of paragraph 406, wherein a first dose of the compound or a pharmaceutically acceptable salt thereof is administered to the patient at least about 2 hours before administration of the CAR T cell composition.

[0430] 408. The method of paragraph 406, wherein a first dose of the compound or a pharmaceutically acceptable salt thereof is administered to the patient at least about 4 hours before administration of the CAR T cell composition.

[0431] 409. The method of paragraph 406, wherein a first dose of the compound or a pharmaceutically acceptable salt thereof is administered to the patient at least about 8 hours before administration of the CAR T cell composition.

[0432] 410. The method of paragraph 406, wherein a first dose of the compound or a pharmaceutically acceptable salt thereof is administered to the patient at least about 12 hours before administration of the CAR T cell composition.

[0433] 411. The method of paragraph 406, wherein a first dose of the compound or a pharmaceutically acceptable salt thereof is administered to the patient at least about 16 hours before administration of the CAR T cell composition.

[0434] 412. The method of paragraph 406, wherein a first dose of the compound or a pharmaceutically acceptable salt thereof is administered to the patient at least about 20 hours prior to administration of the CAR T cell composition.

[0435] 413. The method of paragraph 406, wherein a first dose of the compound or a pharmaceutically acceptable salt thereof is administered to the patient at least about 24 hours before administration of the CAR T cell composition.

[0436] 414. The method of any of paragraphs 406 to 413, wherein a second dose of the compound or a pharmaceutically acceptable salt thereof is administered to the patient at least about 24 hours after administration of the CAR T cell composition.

[0437] 415. The method of any of paragraphs 406 to 413, wherein a second dose of the compound or a pharmaceutically acceptable salt thereof is administered to the patient at least about 16 hours after administration of the CAR T cell composition.

[0438] 416. The method of any of paragraphs 406 to 413, wherein a second dose of the compound or a pharmaceutically acceptable salt thereof is administered to the patient at least about 12 hours after administration of the CAR T cell composition.

[0439] 417. The method of any of paragraphs 406 to 413, wherein a second dose of the compound or a pharmaceutically acceptable salt thereof is administered to the patient no later than about 8 hours after administration of the CAR T cell composition.

[0440] 418. The method of any of paragraphs 406 to 413, wherein a second dose of the compound or a pharmaceutically acceptable salt thereof is administered to the patient at least about 4 hours after administration of the CAR T cell composition.

[0441] 419. The method of any of paragraphs 406 to 418, wherein CAR T cell toxicity against cancer occurs without cytokine release resulting in off-target toxicity in the patient.

[0442] 420. The method of any of paragraphs 406 to 418, wherein off-target tissue toxicity does not occur in the patient and CAR T cell toxicity against the cancer occurs.

[0443] 421. The method of any of paragraphs 406 to 418, wherein the cancer comprises a tumor, the tumor size is reduced in the patient, and no off-target toxicity occurs.

[0444] 422. The method of any of paragraphs 406 to 418, wherein the cancer comprises a tumor and the reduction in tumor size in the patient is greater than in a patient who has not been pretreated with the compound or a pharmaceutically acceptable salt thereof prior to administration of the CAR T cell composition.

[0445] 423. The method of any of paragraphs 406 to 422, wherein the ligand is selected from the group consisting of folic acid, DUPA, NK-1R ligands, CAIX ligands, gamma glutamyl transpeptidase ligands, NKG2D ligands, and CCK2R ligands.

[0446] 424. The method of any of paragraphs 406 to 423, wherein the ligand is folic acid.

[0447] 425. The method of any of paragraphs 406 to 423, wherein the ligand is an NK-1R ligand.

[0448] 426. The method of any of paragraphs 406 to 423, wherein the ligand is DUPA.

[0449] 427. The method of any of paragraphs 406 to 423, wherein the ligand is a CCK2R ligand.

[0450] 428. The method of any of paragraphs 406 to 423, wherein the ligand is a gamma glutamyl transpeptidase ligand.

[0451] 429. The method of any of paragraphs 406 to 428, wherein the targeting moiety is selected from the group consisting of 2,4-dinitrophenol (DNP), 2,4,6-trinitrophenol (TNP), biotin, digoxigenin, fluorescein, fluorescein isothiocyanate (FITC), NHS-fluorescein, pentafluorophenyl ester, tetrafluorophenyl ester, knottin, centyrin, and DARPin.

[0452] 430. The method of any of paragraphs 406 to 429, wherein the targeting moiety is FITC.

[0453] 431. The method of any of paragraphs 406-429, wherein the targeting moiety is DNP.

[0454] 432. The method of any of paragraphs 406-429, wherein the targeting moiety is TNP.

[0455] 433. The method of any of paragraphs 406 to 432, wherein the linker comprises polyethylene glycol (PEG), polyproline, a hydrophilic amino acid, a sugar, a non-natural peptidoglycan, polyvinylpyrrolidone, Pluronic F-127, or a combination thereof.

[0456] 434. The method of any of paragraphs 406 to 433, wherein the linker comprises PEG.

[0457] 435. The compound or a pharmaceutically acceptable salt thereof has the formula [ka] wherein B is a small molecule ligand, L is a linker, and T is a targeting moiety, wherein L is a group of the formula [ka] (wherein n is 0 to 200). Item 406 to 434, the method of any one of Items 406 to 434.

[0458] 436. The method of claim 435, wherein n is an integer from 0 to 150.

[0459] 437. The method of claim 435, wherein n is an integer from 0 to 110.

[0460] 438. The method of claim 435, wherein n is an integer from 0 to 20.

[0461] 439. The method of claim 435, wherein n is an integer between 15 and 20.

[0462] 440. The method of claim 435, wherein n is an integer between 15 and 110.

[0463] 441. The method of any of paragraphs 406-430 or 433-440, wherein the linker comprises PEG and the targeting moiety is FITC or a pharmaceutically acceptable salt thereof.

[0464] 442. The method of any of paragraphs 406 to 441, wherein the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 10 nmole / kg to about 10,000 nmole / kg of patient body weight.

[0465] 443. The method of any of paragraphs 406 to 441, wherein the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 10 nmole / kg to about 5000 nmole / kg of patient body weight.

[0466] 444. The method of any of paragraphs 406 to 441, wherein the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 10 nmole / kg to about 1000 nmole / kg of patient body weight.

[0467] 445. The method of any of paragraphs 406 to 441, wherein the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 10 nmole / kg to about 600 nmole / kg of patient body weight.

[0468] 446. The method of any of paragraphs 406 to 441, wherein the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 200 nmole / kg to about 600 nmole / kg of patient body weight.

[0469] 447. The method of any of paragraphs 406 to 441, wherein the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 250 nmole / kg to about 600 nmole / kg of patient body weight.

[0470] 448. The cancer is lung cancer, bone cancer, pancreatic cancer, skin cancer, head cancer, neck cancer, cutaneous melanoma, intraocular melanoma, uterine cancer, ovarian cancer, endometrial cancer, rectal cancer, stomach cancer, colon cancer, breast cancer, triple-negative breast cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, non-small cell lung cancer, adrenal cancer, soft tissue sarcoma, osteosarcoma, urethral cancer, prostate cancer, chronic leukemia, acute leukemia 448. The method of any of paragraphs 406 to 447, wherein the cancer is selected from the group consisting of hematopoietic leukemia, acute myeloid leukemia, lymphocytic lymphoma, myeloid leukemia, myelomonocytic leukemia, hairy leukemia, pleural mesothelioma, bladder cancer, Burkitt's lymphoma, ureteral cancer, kidney cancer, renal cell carcinoma, renal pelvis cancer, central nervous system (CNS) neoplasms, primary CNS lymphoma, spinal axis tumor, brainstem glioma, pituitary adenoma and esophagogastric junction adenocarcinoma.

[0471] 449. The method of any of paragraphs 406 to 424 or 429 to 448, wherein the cancer is a β-expressing cancer.

[0472] 450. The method of paragraph 448, wherein the cancer is endometrial cancer.

[0473] 451. The method of paragraph 448, wherein the cancer is non-small cell lung cancer.

[0474] 452. The method of paragraph 448, wherein the cancer is ovarian cancer.

[0475] 453. The method of paragraph 448, wherein the cancer is triple-negative breast cancer.

[0476] 454. The method of any of paragraphs 406 to 453, wherein the CAR has a recognition region, and the recognition region is a single-chain fragment variable (scFv) region of an antibody.

[0477] 455. The method of any of paragraphs 406 to 430 or 433 to 454, wherein the CAR has a recognition region, and the recognition region of the CAR is a single-chain fragment variable (scFv) region of an anti-FITC antibody.

[0478] 456. The method of any of paragraphs 406 to 455, wherein the CAR has a costimulatory domain, and the costimulatory domain is selected from the group consisting of CD28, CD137 (4-1BB), CD134 (OX40), and CD278 (ICOS).

[0479] 457. The method of any of paragraphs 406 to 456, wherein the CAR has an activation signaling domain, and the activation signaling domain is T cell CD3 zeta chain or Fc receptor γ.

[0480] 458. The method of any of paragraphs 406 to 430 or 433 to 457, wherein the CAR has a recognition region, which is a single-chain fragment variable (scFv) region of an anti-FITC antibody; the CAR has a costimulatory domain, which is CD137 (4-1BB); and the CAR has an activation signaling domain, which is a T cell CD3 zeta chain.

[0481] 459. The method of any of paragraphs 406 to 458, wherein multiple doses of the CAR T cell composition are administered.

[0482] 460. The method of any of paragraphs 406 to 459, wherein the patient is imaged prior to administration of the compound or a pharmaceutically acceptable salt thereof.

[0483] 461. The method of any of paragraphs 406 to 460, wherein the compound or a pharmaceutically acceptable salt thereof is not an antibody and does not include a fragment of an antibody.

[0484] 462. The method of any of paragraphs 406 to 461, wherein the targeting moiety does not comprise a peptide epitope.

[0485] 463. The method of any of paragraphs 406 to 462, wherein the CAR T cells comprise a nucleic acid comprising SEQ ID NO:1.

[0486] 464. The method of any of paragraphs 406 to 463, wherein the CAR T cells comprise a polypeptide comprising SEQ ID NO:2.

[0487] 465. The method of paragraph 463, wherein the nucleic acid encodes a chimeric antigen receptor.

[0488] 466. The method of any of paragraphs 406 to 465, wherein the CAR comprises a humanized amino acid sequence.

[0489] 467. The method of any of paragraphs 406 to 465, wherein the CAR consists of a humanized amino acid sequence.

[0490] 468. The method of any of paragraphs 108 to 182, wherein the patient is administered one or more doses of folic acid, a conjugate comprising folic acid (wherein the conjugate comprising folic acid does not comprise a targeting moiety), or an agent that inhibits CAR T cell activation.

[0491] 469. The method of any of paragraphs 108 to 182, wherein the folic acid, a conjugate comprising folic acid (wherein the conjugate comprising folic acid does not comprise a targeting moiety), or an agent that inhibits CAR T cell activation is administered to the patient before and / or after the compound or a pharmaceutically acceptable salt thereof.

[0492] 470. The method of any of paragraphs 108 to 182, wherein administration of the folic acid, a conjugate comprising folic acid (wherein the conjugate comprising folic acid does not comprise a targeting moiety), or an agent that inhibits CAR T cell activation reduces cytokine levels in the patient.

[0493] 471. The method of paragraph 470, wherein the reduction in cytokine levels occurs about 3 hours after administering to the patient folic acid, a conjugate comprising folic acid (wherein the conjugate comprising folic acid does not comprise a targeting moiety), or an agent that inhibits CAR T cell activation.

[0494] 472. The method of paragraph 470, wherein the reduction in cytokine levels occurs about 6 hours after administering to the patient folic acid, a conjugate comprising folic acid (wherein the conjugate comprising folic acid does not comprise a targeting moiety), or an agent that inhibits CAR T cell activation.

[0495] 473. The method of paragraph 470, wherein the reduction in cytokine levels is relative to the cytokine levels in an untreated patient.

[0496] 474. The method of any of paragraphs 108 to 182, wherein the compound or a pharmaceutically acceptable salt thereof is administered before and after administration of the folic acid, a conjugate comprising folic acid (wherein the conjugate comprising folic acid does not comprise a targeting moiety), or an agent that inhibits CAR T cell activation.

[0497] 475. The method of any of paragraphs 108 to 182, wherein after administration of the folic acid, a conjugate comprising folic acid (wherein the conjugate comprising folic acid does not comprise a targeting moiety), or an agent that inhibits CAR T cell activation, the number of CAR T cells in the patient's blood increases, even if cytokine levels in the patient decrease.

[0498] 476. The method of any of paragraphs 108 to 182, wherein CAR T cell activation is enhanced or maintained relative to a patient not treated with a rescue agent after administration of the folic acid, a conjugate comprising folic acid (wherein the conjugate comprising folic acid does not comprise a targeting moiety), or an agent that inhibits CAR T cell activation, even though cytokine levels in the treated patient are reduced.

[0499] 477. The method of any of paragraphs 108 to 182, wherein the cancer comprises a tumor and the tumor size in the patient does not increase upon administration of the folic acid, a conjugate comprising folic acid (wherein the conjugate comprising folic acid does not comprise a targeting moiety), or an agent that inhibits activation of CAR T cells to the patient.

[0500] 478. The method of paragraph 477, wherein a complete response to the tumor is obtained.

[0501] 479. The method of any of paragraphs 108, 115 to 160, 168 to 182 and 468 to 478, wherein when CRS grade reaches 1, 2, 3 or 4, the patient is administered a drug that inhibits the activation of the CAR T cells.

[0502] 480. The method of any of items 108, 115 to 160, 168 to 182 and 468 to 478, wherein when CRS grade reaches 3 or 4, the patient is administered a drug that inhibits the activation of the CAR T cells.

[0503] 481. A method according to any one of paragraphs 108 to 182 and 468 to 480, in which pulmonary edema is reduced.

[0504] 482. The method of any of paragraphs 108, 115-160, 168-182, and 468-481, wherein the agent that inhibits CAR T cell activation is administered at a dose of about 0.01 to about 300 μmole / kg of patient body weight.

[0505] 483. The method of any of paragraphs 108, 115-160, 168-182, and 468-481, wherein the agent that inhibits CAR T cell activation is administered at a dose of about 0.06 to about 100 μmole / kg of patient body weight.

[0506] 484. The method of any of paragraphs 108, 115-160, 168-182, and 468-481, wherein the agent that inhibits activation of the CAR T cells is administered at a dose of about 0.06 to about 90 μmole / kg of patient body weight.

[0507] 485. The method of any of paragraphs 108, 115-160, 168-182, and 468-481, wherein the agent that inhibits activation of the CAR T cells is administered at a dose of about 0.06 to about 80 μmole / kg of patient body weight.

[0508] 486. The method of any of paragraphs 108, 115-160, 168-182, and 468-481, wherein the agent that inhibits CAR T cell activation is administered at a dose of about 0.06 to about 70 μmole / kg of patient body weight.

[0509] 487. The method of any of paragraphs 108, 115-160, 168-182, and 468-481, wherein the agent that inhibits activation of the CAR T cells is administered at a dose of about 0.06 to about 60 μmole / kg of patient body weight.

[0510] 488. The method of any of paragraphs 108, 115-160, 168-182, and 468-481, wherein the agent that inhibits activation of the CAR T cells is administered at a dose of about 0.06 to about 50 μmole / kg of patient body weight.

[0511] 489. The method of any of paragraphs 108, 115-160, 168-182, and 468-481, wherein the agent that inhibits CAR T cell activation is administered at a dose of about 0.06 to about 40 μmole / kg of patient body weight.

[0512] 490. The method of any of paragraphs 108, 115-160, 168-182, and 468-481, wherein the agent that inhibits activation of the CAR T cells is administered at a dose of about 0.06 to about 30 μmole / kg of patient body weight.

[0513] 491. The method of any of paragraphs 108, 115-160, 168-182, and 468-481, wherein the agent that inhibits CAR T cell activation is administered at a dose of about 0.06 to about 20 μmole / kg of patient body weight.

[0514] 492. The method of any of paragraphs 108, 115-160, 168-182, and 468-481, wherein the agent that inhibits activation of the CAR T cells is administered at a dose of about 0.06 to about 10 μmole / kg of patient body weight.

[0515] 493. The method of any of paragraphs 108, 115-160, 168-182, and 468-481, wherein the agent that inhibits CAR T cell activation is administered at a dose of about 0.06 to about 8 μmole / kg of patient body weight.

[0516] 494. The method of any of paragraphs 108, 115-160, 168-182, and 468-481, wherein the agent that inhibits activation of the CAR T cells is administered at a dose of about 0.06 to about 6 μmole / kg of patient body weight.

[0517] 495. The method of any of paragraphs 108, 115-160, 168-181 and 468-494, wherein an agent that inhibits activation of the CAR T cells is administered to the patient, and the agent is sodium fluorescein.

[0518] 496. A method according to any of paragraphs 1 to 495, wherein CRS is reduced or prevented, resulting in a reduction in tumor volume in the patient.

[0519] 497. A method according to any one of paragraphs 1 to 496, in which weight loss due to CRS is reduced or prevented.

[0520] 498. The method according to any one of items 1 to 3, 8 to 28, 33 to 58, 63 to 83, 88 to 136, 141 to 249, 252 to 361, 366 to 380, 385 to 424, 429 to 449, and 454 to 497, wherein the cancer is acute myeloid leukemia.

[0521] 499. The method of paragraph 498, wherein the cancer expresses folate receptor-β.

[0522] 500. The method of paragraph 498 or 499, wherein the CAR-T cells have a central memory / effector memory phenotype.

[0523] 501. The method of any of paragraphs 1 to 500, wherein the CD8:CD4 ratio of the CAR T cells is about 1:1.

[0524] 502. The method of any of paragraphs 215 to 251, further comprising step iv) of readministering the compound or a pharmaceutically acceptable salt thereof to the patient.

[0525] 503. The method of paragraph 474, wherein subsequent administration of the compound or a pharmaceutically acceptable salt thereof results in CAR T cell activation and cytokine levels in the patient.

[0526] 504. The method of any of paragraphs 1-107, 183-476, or 479-503, wherein the cancer comprises a tumor and a complete response to the tumor is obtained.

[0527] 505. A method for treating cancer, comprising: i) administering to a patient a compound or a pharmaceutically acceptable salt thereof, wherein the compound comprises a small molecule ligand linked to a targeting moiety by a linker; and ii) administering to the patient a CAR T cell composition, wherein the CAR T cell composition comprises CAR T cells, and the CAR T cells comprise a CAR directed to a targeting moiety; and wherein the small molecule ligand is a PSMA ligand and the targeting moiety is FITC. A method comprising:

[0528] 506. A small molecule ligand linked to a targeting moiety by said linker having the formula [ka] Item 505. The method of claim 505, comprising:

[0529] 507. A method for treating cancer, comprising: i) administering to a patient a compound or a pharmaceutically acceptable salt thereof, wherein the compound comprises a small molecule ligand linked to a targeting moiety by a linker; and ii) administering to the patient a CAR T cell composition, wherein the CAR T cell composition comprises CAR T cells, and wherein the CAR T cells comprise a CAR directed to a targeting moiety; and wherein the small molecule ligand is a CAIX ligand and the targeting moiety is FITC. A method comprising:

[0530] 508. A small molecule ligand linked to a targeting moiety by said linker having the formula [ka] Item 507, the method of claim 507, comprising:

[0531] 509. A method for treating cancer, comprising: i) administering to a patient a first compound or a pharmaceutically acceptable salt thereof, wherein the first compound or a pharmaceutically acceptable salt thereof comprises a PSMA ligand linked to FITC by a linker; ii) administering to the patient a second compound or a pharmaceutically acceptable salt thereof, wherein the second compound or a pharmaceutically acceptable salt thereof comprises a CAIX ligand linked to FITC by a linker; and iii) administering to the patient a CAR T cell composition, wherein the CAR T cell composition comprises CAR T cells, and the CAR T cells comprise a CAR directed to a targeting moiety. A method comprising:

[0532] 510. The first compound has the formula [ka] and said second compound has the formula [ka] 509. The method of claim 509, comprising: [Brief explanation of the drawings]

[0533] [Figure 1] Figures 1A-B show anti-FITC CAR T cell-mediated toxicity. Figure 1A shows the weight change for mice in the various treatment groups. Figure 1B shows the detected concentration of IFN-gamma for the various treatment groups. Figure 1C shows the first week survival (%) of mice in the various treatment groups.

[0534] [Figure 2] Figures 2A-B show the effect of anti-FITC CAR T cell control on tumor response. Figure 2A shows tumor growth for mice treated with CAR T cells and PBS or CAR T cells and FITC-folate. Figure 2B shows a summary of tumor response results for the mice used in the study.

[0535] [Figure 3] Figures 3A-D show the effect of FITC-folate concentration on tumor response. Figure 3A shows the detected concentration of IFN-gamma at various FITC-folate concentrations. Figure 3B shows tumor growth after CAR T cell injection in the presence of various FITC-folate concentrations. Figure 3C shows the first week survival (%) of mice. Figure 3D shows a summary of tumor response results for the mice used in the study.

[0536] [Figure 4] Figures 4A-B show the suppression of FITC CAR T cell activation with agents that inhibit mediators of T cell activation signals. Figure 4A shows the change in IFN-gamma concentration as a function of agent. Figure 4B shows the change in CD69 expression as a function of agent.

[0537] [Figure 5] Figure 5 shows a schematic diagram of the constructs used for CAR T transduction.

[0538] [Figure 6]Figures 6A-D show antitumor efficacy and toxicity at various EC17 doses and CAR cell numbers. Figure 6A shows tumor volume over time. Figure 6B shows body weight change over time. Figure 6C shows the maximum percentage weight loss at each EC17 dose. Figure 6D shows the percentage of mice showing sCRS (cytokine release syndrome) at each EC17 dose. (1) No CAR-T + EC17 500 nmole / kg; (2) 12.5 million CAR-T + EC17 10,000 nmole / kg; (3) 12.5 million CAR-T + EC17 1,500 nmole / kg; (4) 12.5 million CAR-T + EC17 500 nmole / kg; (5) 10 million CAR-T + EC17 100 nmole / kg; (6) 10 million CAR-T + EC17 20 nmole / kg.

[0539] [Figure 7] FIG. 7 shows the rescue of mice with sCRS with EC0923 and the observed responses of mice treated or not with EC0923 and organs harvested from mice treated or not with EC0923.

[0540] [Figure 8] Figures 8A-D show the antitumor efficacy and toxicity of various CAR T doses. Figure 8A shows tumor volume over time. Figure 8B shows body weight change over time. Figure 8C shows the maximum percentage of weight loss for each CAR T dose. Figure 8D shows the percentage of mice showing sCRS for each CAR T dose.

[0541] [Figure 9] Figures 9A-B show antitumor efficacy and body weight change at various EC17 doses. Figure 9A shows tumor volume over time. Figure 9B shows body weight change over time.

[0542] [Figure 10]

[0013] Figures 10A-C show the anti-tumor efficacy of various CAR T cells and non-transformed T cell mixtures. Figure 10A shows tumor volume over time; (●) no CAR-T, (○) CAR-T at day 0, (■) CAR-T at day 0, unmodified T at day 52, (▼) CAR-T at days 0, 46, and 52. Figure 10B shows body weight change over time; (●) no CAR-T, (○) CAR-T at day 0, (■) CAR-T at day 0, unmodified T at day 52, (▼) CAR-T at days 0, 46, and 52. Figure 10C shows the amount of CAR T cells in the blood and tumor volume for various CAR T cells and non-transformed T cell mixtures.

[0543] [Figure 11] Figures 11A-B show the antitumor efficacy and toxicity of 5 million CAR T cells and various EC17 administration schedules. Figure 11A shows tumor volume over time. Figure 11B shows body weight change over time.

[0544] [Figure 12] Figure 12 shows the control of CAR T cell-mediated toxicity through the use of competitors to inhibit CAR T cell activation and the control of CAR T cell activation by terminating cross-linking.

[0545] [Figure 13] Figures 13A-C show the results of a FITC-folate dose escalation study. Figure 13A shows the percent body weight change over time after administration of crosslinks and CAR T cells. Figure 13B shows the tumor volume change over time after CAR T cell and crosslink injection. Figure 13C shows the percent survival after the first week of treatment with crosslinks and CAR T cells.

[0546] [Figure 14] Figures 14A-B show the effect of FITC-ligand cross-linking molecules on CAR T cell proliferation and cytokine production. Figure 14A shows the number of CAR T cells 6 days after introduction of CAR T cells into mice. Figure 14B shows the concentrations of serum cytokines IL-2, IFN-γ, and TNF-α 6 days after introduction of CAR T cells into mice.

[0547] [Figure 15] FIG. 15 shows the concentration of IFN-γ as a function of the concentration of FITC-folate in an in vitro assay.

[0548] [Figure 16] FIG. 16 shows rescue (based on measurement of cytokine production) with EC0923 or fluorescein or mice with cytokine release syndrome.

[0549] [Figure 17] Figure 17 shows that CAR-T cell activity (based on measurements of cytokine production) depends on the presence of tumor and EC17 dose level.

[0550] [Figure 18] Figures 18A-C show that CAR-T cells do not proliferate in tumor-free naive mice. Figure 18 shows the weight change in mice (tumor-free) injected with CAR-T cells but not EC17 or with 500 nmole / kg EC17 three times a week. Figures 18B and C show the CAR-T cell counts and spleen size of these mice versus mice bearing HEK (folate-receptor-positive) tumors. For Figures 18B and C, for each group of three bars, the left bar represents tumor-free mice injected with CAR-T cells but not EC17, the middle bar represents tumor-free mice injected with CAR-T cells and EC17, and the right bar represents tumor-bearing mice injected with CAR-T cells and EC17. In Figure 18B, ND was not determined, and the y-axis is logarithmic relative to Figure 18.

[0551] [Figure 19] Figures 19A-B show the effect of CAR-T cells and EC17 injected into mice using the MDA-MB-231 model (high folate receptor expression level - Figure 19A) or the OV90 tumor model (low folate receptor expression level - Figure 19B) on tumor size.

[0552] [Figure 20] Figures 20A-B show the effect of CAR-T cells and various doses of EC17 injected into mice using the MDA-MB-231 model on tumor size (Figure 20A) and weight loss (Figure 20B).

[0553] [Figure 21] Figures 21A and 21B show FITC-CAR-T anti-tumor activity in the MDA-MB-231 model.

[0554] [Figure 22] Figures 22A and 22B show FITC-CAR-T anti-tumor activity in the OV-90 model.

[0555] [Figure 23] Figures 23A and 23B show FITC-CAR-T antitumor activity in the KB model. For the EC17 group, 2 / 3 had sCRS on day 23 and 1 / 3 had sCRS on day 37.

[0556] [Figure 24] Figures 24A and 24B show FITC-CAR-T antitumor activity in the HEK-FRa model.

[0557] [Figure 25] Figures 25A and 25B show FITC-CAR-T anti-tumor activity in the SKOV-3 model.

[0558] [Figure 26] Figure 26, panels C and E, show toxicity studies in EC17 prepainted mice. Panels A and B show the treatment protocol. Panel D shows the effect of EC17 prepainting on tumor size.

[0559] [Figure 27]Figure 27, Panel A shows the treatment protocol. Panel B shows the toxicity study. Panel C shows the effect of EC17 prepainting on tumor toxicity. Line 1: No EC17. Line 2: EC17 4 hours before administration. Line 3: EC17 4 hours before administration, then 24 hours after CAR-T. Line 4: EC17 48 hours after CAR-T.

[0560] [Figure 28] Figure 28, panels A to D, show the number of CAR-T cells in the blood. The number of CAR-T cells in mice without rescue was considered to be 1.

[0561] [Figure 29] Figure 29, panels A-E, shows a comparative study of three rescue agents: folic acid, sodium fluorescein (NAFL), and leucovorin.

[0562] [Figure 30] Figures 30A and 30B show rescue assays. Fluorescein-rescued mice experienced minimal weight loss. All rescued mice achieved a complete response except for 2 / 9 in the fluorescein rescue group. Line 1: no EC17. Line 2: no EC17 but with fluorescein. Line 3: fluorescein rescue. Line 4: leucovorin rescue. Line 5: folic acid rescue. Line 6: no rescue.

[0563] [Figure 31] FIG. 31 shows the sodium fluorescein (60 μmol / kg) rescue test schema.

[0564] [Figure 32] Figures 32A and 32B show NaFL rescue-associated organ weight changes: (1) CAR-T; (2) CAR-T+EC17; (3) CAR-T+EC17+NaFL rescue.

[0565] [Figure 33]Figure 33, panels A to G show cytokine production in mouse blood 7 hours after NaFL rescue.

[0566] [Figure 34] FIG. 34, panels AG show cytokine production in mice (27 hours after NaFL rescue).

[0567] [Figure 35] Figure 35, panels A-E show decreased cytokine production in mouse blood (<7 hours after NaFL rescue).

[0568] [Figure 36] Figures 36A and 36B show the effect of NaFL rescue on FITC CAR-T antitumor activity and body weight change. (1) CAR-T alone; (2) CAR-T + EC17; (3) CAR-T + EC17 + NaFL.

[0569] [Figure 37] Figures 37A and 37B show the effect of rescue on cytokine levels.

[0570] [Figure 38] Figure 38A shows the CAR-T administration schedule, and Figure 38B shows the weight change.

[0571] [Figure 39] Figure 39, panels AD, shows that blood cytokine production is CAR-T dose dependent.

[0572] [Figure 40] Figure 40A shows the dosing schedule, and Figure 40B shows that blood CAR-T counts are EC17 dose-dependent (in vivo on day 3).

[0573] [Figure 41] Figure 41A shows the dosing schedule, and Figure 41B shows that blood CAR-T counts are EC17 dose-dependent, although the differences are small (day 6 in vivo).

[0574] [Figure 42] Figure 42 shows the change in mouse weight after CAR-T and EC17 injection.

[0575] [Figure 43] Figures 43A and 43B show CAR-T cell numbers and spleen sizes in mice after injection of CAR-T cells and EC17. (1) Tumor-bearing mice: CAR-T 5 million + EC17 SIW; (2) Naive mice: CAR-T 8 million without EC17; (3) Naive mice: CAR-T 8 million + EC17 TIW; (4) Naive mice: CAR-T 5 million without EC17; (5) Naive mice: CAR-T 5 million + EC17 TIW.

[0576] [Figure 44] Figure 44 shows cytokine production after injection of EC17 and CAR-T cells in the presence and absence of tumor.

[0577] [Figure 45] Figure 45 shows the universality of anti-FITC CAR T cell therapy: binding of different adapters to CAR T cells. (1) Unstained CAR T cells; (2) CAR T cells labeled with FITC-Alexa 647 + FITC-folate (competition); (3) CAR T cells labeled with FITC-Alexa 647; (4) CAR T cells labeled with FITC-Alexa 647 + FITC-DUPA (competition); (5) CAR T cells labeled with FITX-Alexa 647 + FITC-CA9 (competition).

[0578] [Figure 46] Figure 46 shows that universal Car T cells can eliminate various cancer cells expressing orthogonal antigens after the addition of antigen-matching crosslinks in vitro.

[0579] [Figure 47] Figure 47 shows the correlation between cross-linking concentration and anti-tumor activity of universal CAR T cells in vitro.

[0580] [Figure 48] Figure 48 shows that universal CAR T cells can eliminate a variety of cancer cells expressing orthogonal antigens after addition of an antigen-matched bridge in vivo.

[0581] [Figure 49] Figure 49 shows that universal CAR T cells can eliminate two tumors with a cross-linking cocktail in vivo.

[0582] [Figure 50] FIG. 50 shows the sodium fluorescein (0.06, 0.6, 6 μmol / kg) rescue test schema.

[0583] [Figure 51] Figure 51A shows antitumor activity (6 μmol / kg NaFL rescue), and Figure 51B shows the corresponding body weight changes.

[0584] [Figure 52] Figure 52, panels A-E show cytokine levels in mouse blood after sodium fluorescein rescue.

[0585] [Figure 53] Figure 53, panel A shows the rescue scheme. Panels B and C show the enumeration of blood FITC CAR T cells after rescue.

[0586] [Figure 54] Figure 54 shows the characterization of circulating CAR T cells in mouse blood after rescue.

[0587] [Figure 55] Figure 55A shows the rescue scheme. Panels B and C show the enumeration of CAR T cells in the blood after rescue. (1) Control [no NaFL]; (2) 0.06 μmol / kg NaFL; (3) 0.6 μmol / kg NAFL; (4) 6 μmol.kg NaFL.

[0588] [Figure 56] Figure 56 shows the tumor burden in EC17 treated and untreated animals.

[0589] [Figure 57] Figure 57 summarizes the estimated tumor mass numbers and total tumor weights in all groups tested.

[0590] [Figure 58] Figures 58A and 58B show the characterization of circulating tumor cells.

[0591] [Figure 59] Figures 59A and 59B show the characterization of circulating tumor cells.

[0592] [Figure 60] Figures 60A and 60B show the percent of whole blood that are CAR T cells after EC17 injection.

[0593] [Figure 61] Figures 61A and 61B show the persistence of blood-derived CAR T cells after EC17 infusion with and without rescue and the phenotype after EC17 infusion.

[0594] [Figure 62] Figures 62A and 62B show that upon injection of EC17, CAR T cells localized to metastatic tumor lesions and were absent from adjacent healthy tissue.

[0595] [Figure 63]Figure 63 shows the design and characterization of anti-fluorescein CAR T cells and fluorescein-folate crosslinks. (A) Structure of fluorescein-folate (FITC-folate). (B) Diagram showing the construction of the anti-fluorescein CAR, where SP = signal peptide, scFv = single-chain variable fragment that recognizes fluorescein with a KD = 270 fM, TM = transmembrane domain, 4-1BB = cytoplasmic activation domain from CD137, and CD3ζ = cytoplasmic activation domain of CD3 zeta. (C) Transduction efficiency of CAR T cells assessed by flow cytometry. Open histogram: untransduced T cells; filled histogram: T cells transduced with lentivirus expressing GFP and the CAR construct shown in (B). (D) Demonstration of FITC-folate binding to anti-fluorescein CAR T cells. Colored histograms (gray): CAR T cells without anti-fluorescein staining; open histograms: anti-fluorescein CAR T cells labeled with FITC-Alexa647 (10 nM); colored histograms (black): anti-fluorescein CAR T cells labeled with FITC-Alexa647 (10 nM) in the presence of competitor 100-fold excess FITC-folate (1 μM).

[0596] [Figure 64]Figure 64 shows evidence that FITC-folate cross-linking mediates anti-fluorescein CAR T cell binding to folate receptor-expressing cancer cells (KB cells). (A) Evidence that the FR is expressed in KB cells. Gray histogram: unstained KB cells; black histogram: KB cells labeled with 100 nM FITC-folate in the presence of excess (10 μM) free folate as a competitor; open histogram: KB cells labeled with 100 nM FITC-folate. (B) After addition of correct FITC-folate (100 nM), but not mismatched FITC-DUPA (100 nM) or no (PBS) cross-linking, CAR T cell cytotoxicity is directed toward KB cells. (C) Effect of effector:target cell ratio on CAR T cell lysis of KB cells in the presence of FITC-folate, FITC-DUPA, or no cross-linking. (D) IFNγ production is induced by the addition of FITC-folate (100 nM), but not by FITC-DUPA (100 nM). (E) Proliferation of anti-fluorescein CAR T cells is induced by FITC-folate, but not by FITC-DUPA. (F) Expression of an activation marker (CD69) on anti-fluorescein CAR T cells occurs only after the addition of the correct crosslinker. For panels B, D, E, and F, the ratio of anti-fluorescein CAR T cells to KB cells was 10:1. Bar graphs represent the mean ± sd. n = 3. One-way ANOVA was performed for all comparisons (****P < 0.0001, **P < 0.005, *P < 0.01, ns (not significant)).

[0597] [Figure 65]Figure 65 shows the dependence of CRS in vivo on the presence of anti-fluorescein CAR T cells, folate receptor-positive cancer cells (MDA-MB-231 cells), and FITC-folate. (A) Body weight change (%) determined 4 days after injection of anti-fluorescein CAR T cells (5 x 106) into tumor-free or tumor-bearing mice in the presence or absence of FITC-folate (500 nmole / kg on days 1 and 2). **P<0.01 by one-way ANOVA. (B) Effect of CAR T cell number on body weight change (%) in tumor-bearing mice 4 days after administration of PBS or 500 nmole / kg FITC-folate on days 1 and 2. **P<0.05, ****P<0.0001 by one-way ANOVA. (C) Effect of CAR T cell number in tumor-bearing mice on plasma IFNγ concentrations on day 4. One-way ANOVA: ***P<0.001, ****P<0.0001, ns (not significant). n=5 mice / group. Bars represent mean±sem.

[0598] [Figure 66] Figure 66 shows the control of CRS intensity by crosslinking administration interruption. (A) Analysis of body weight change (%) as an indicator of CRS intensity after administration of a high dose of anti-fluorescein CAR T cells (15x106) in the absence (PBS) or presence of FITC-folate (500 nmole / kg on days 1 and 2 and every other day thereafter). In the interrupted administration regimen, a continuous administration schedule was followed, except that FITC-folate injections were not given on days 4 and 6. (B) Analysis of IFNγ levels in mouse plasma on day 6 using the administration regimen described in part A. (C) Measurement of tumor volume in mice treated as described in part A. n=5 mice / group. Data represent mean±sem. ****P<0.0001 by one-way ANOVA test.

[0599] [Figure 67]Figure 67 shows the effect of blocking cross-linking by competition with free folate or free fluorescein on CAR T cell-mediated cytotoxicity. (A) Measurement of body weight change (%) after administration of anti-fluorescein CAR T cells (15x106) in the absence (PBS) or presence of FITC-folate (administered at 500 nmole / kg on days 1 and 2 and every other day thereafter). For competition studies, 100-fold excess folate was co-injected on days 4 and 6. ****P<0.0001. (B) Analysis of IFNγ levels in the plasma of the treatment groups on day 6. **P<0.005. (C) Measurement of tumor volume in the same treatment groups. n=5 mice / group. Error bars represent the mean±sem. (D) Analysis of the time dependence of cytokine levels in the plasma of CAR T cells after administration of 12-fold excess free fluorescein to suppress CRS. CRS was induced in all mice by injection of 10x106 anti-fluorescein CAR T cells + FITC-folate (500 nmole / kg on day 3). On day 4, 6 μmole / kg free fluorescein was injected to suppress potent CRS, and the indicated cytokines were measured in plasma 3 and 6 hours after fluorescein administration. n = 3 mice per group. Data represent mean ± sem. **P < 0.01, ***P < 0.001, ****P < 0.0001 by two-way ANOVA.

[0600] [Figure 68]Figure 68 shows the effect of cross-linking concentration on the suppression of anti-fluorescein CAR T cell cytokine release and anti-tumor activity in vitro and in vivo. (A) Lysis of MDA-MB-231 cells in culture by anti-fluorescein CAR T cells (5:1 effector:tumor cell ratio) in the presence of various concentrations of FITC-folate (0.001 nM to 100,000 nM). (B) IFNγ release from the cells described in part A. (C) IFNγ levels in the plasma of MDA-MB-231 tumor-bearing mice 6 days after the start of treatment with injection of 15 × 10 CAR T cells. Mice were treated with 5 nmole / kg, 50 nmole / kg, 500 nmole / kg, or 2500 nmole / kg FITC-folate on days 1, 2, 8, 10, and every other day thereafter (treatments on days 4 and 6 were omitted to avoid CRS). (D) Analysis of tumor growth in the treatment groups in panel C. n=5 mice / group. Bars represent mean±sem. *CAR-T cell counts. ***P<0.0001 by one-way ANOVA.

[0601] [Figure 69] Figure 69 shows prevention of CRS by escalating crosslinking dose or decreasing crosslinking dose frequency. Measurement of body weight change (A) and tumor volume (B) in MDA-MB-231 tumor-bearing mice treated with 15x106 CAR T cells + PBS or escalating doses of FITC-folate (0.5 nmole / kg on days 1 and 2, 5 nmole / kg on days 4 and 6, 50 nmole / kg on days 8 and 10, and 500 nmole / kg from day 12 onwards) or a flat dose of 500 nmole / kg every other day. ****P<0.0001 by two-way ANOVA test. Measurement of body weight change (C) and tumor volume (D) in MDA-MB-231 tumor-bearing mice treated with 5x106 CAR T cells + PBS or FITC-folate (500 nmole / kg) at various dosing frequencies: 1) 1 dose / week (days 1, 8, 15, etc.), 2) 2 doses / week (days 1, 4, 8, 11, 15, etc.), or 3 doses / week (days 1, 3, 5, 8, 10, 12, 15, etc.). n=5 mice / group. All data represent the mean ± sem.

[0602] [Figure 70] Figure 70, Panel A shows the dose escalation schema. Panels B-C show the effect of EC17 dose escalation on anti-tumor activity and toxicity (body weight change) of CAR-T therapy.

[0603] [Figure 71] Figure 71, panel A shows a scheme to test whether tumor size correlates with body weight change and IL-6 release during CAR-T / EC17 treatment. Panels B-C show the results for body weight change and IL-6 levels, respectively.

[0604] [Figure 72] Figure 72, panel A shows a scheme for testing whether CAR-T / EC17 treatment is effective in an osteosarcoma model. Panel B shows tumor size results.

[0605] [Figure 73] FIG. 73 shows the weight change for the study described in FIG.

[0606] [Figure 74] Figure 74, panels AF show that HOS cancer cells express FR-α.

[0607] [Figure 75] Figure 75 shows a scheme for testing whether cytokines are produced in response to CAR-T / EC17 treatment and whether NaFL rescues mice from CRS.

[0608] [Figure 76] Figure 76, panels A-E show the reduction of mouse cytokine production by 60 μmol / kg NaFL 7 hours after NaFL rescue.

[0609] [Figure 77]Figure 77, panels A-c show the reduction of mouse cytokine production by 60 μmol / kg NaFL 27 hours after NaFL rescue.

[0610] [Figure 78] Figure 78 shows a scheme for testing the reduction of mouse cytokine production in response to CAR-T / EC17 treatment with various concentrations of NaFL.

[0611] [Figure 79] Figure 79 shows the reduction of MCP-1 in response to CAR-T / EC17 treatment with NaFL rescue.

[0612] [Figure 80] Figure 80 shows the reduction of IL-6 in response to CAR-T / EC17 treatment with NaFL rescue.

[0613] [Figure 81] Figure 81 shows the reduction of IL-10 in response to CAR-T / EC17 treatment with NaFL rescue.

[0614] [Figure 82] Figure 82, panel A shows a scheme for testing whether MCP-1 production in response to CAR-T / EC17 treatment correlates with CAR-T cell number. Panel B shows that MCP-1 production in response to CAR-T / EC17 treatment correlates with CAR-T cell number. DETAILED DESCRIPTION OF THE INVENTION

[0615] definition As used herein, the term "a," "an," or "an" can mean 1 or more. For example, as used herein with respect to numerical values, including integers, fractions, and percentages, "about" generally refers to a range of numbers (e.g., ±5% to 10% of the recited value) that one of ordinary skill in the art would consider equivalent to the recited value (e.g., having the same function or result).

[0616] As used herein, the term "treatment" or "treating" refers to both therapeutic treatment and prophylactic or preventative treatment.

[0617] The term "amelioration" or "ameliorating," as used herein with respect to cancer, can mean a decrease in the symptoms of cancer, a decrease in tumor size, complete or partial removal of a tumor (e.g., a complete or partial response), induction of disease stability, prevention of cancer progression (e.g., progression-free survival), or any other effect on cancer that is considered by a physician to be a therapeutic, preventative, or preventative treatment of cancer.

[0618] As used herein, the term "administer" or "administration" refers to any means of introducing a compound or a pharmaceutically acceptable salt thereof or a CAR T cell composition described herein into a patient, including, but not limited to, oral, intravenous, intramuscular, subcutaneous, and transdermal.

[0619] As used herein, the term "off-target toxicity" means organ damage or weight loss in a patient that is not tolerated by the physician treating the patient, or any other effect on a patient that is not tolerated by the physician treating the patient, such as B-cell aplasia, fever, decreased blood pressure, or pulmonary edema.

[0620] As used herein, the terms "transduction" and "transfection" are used interchangeably and refer to the introduction of nucleic acid into a cell by any artificial method, including viral and non-viral methods.

[0621] Detailed Description of Illustrative Embodiments In various embodiments described herein, a small molecule ligand linked to a targeting moiety by a linker is used as a bridge between the cancer and the CAR T cell (i.e., a T cell expressing a chimeric antigen receptor). The bridge directs the CAR T cell to the cancer for cancer remission. In certain embodiments, the "small molecule ligand" can be folate, a CAIX ligand, DUPA, an NK-1R ligand, a gamma glutamyl transpeptidase ligand, an NKG2D ligand, or a CCK2R ligand, each of which is a small molecule ligand that specifically binds to a cancer cell type (i.e., the receptor for each of these ligands is overexpressed in cancer compared to normal tissue).

[0622] The "targeting moiety" linked to the small molecule ligand binds to the recognition region of the genetically modified CAR expressed by the CAR T cell. Thus, the recognition region of the CAR (e.g., a single-chain fragment variable region (scFv), Fab, Fv, Fc, or (Fab')2 fragment of an antibody, etc.) is directed to the "targeting moiety." Therefore, the small molecule ligand linked to the targeting moiety by a linker serves as a bridge between the cancer and the CAR T cell, directing the CAR T cell to the cancer for cancer remission. In various embodiments, the bridge between the cancer and the CAR T cell can be any of the conjugates shown in the examples.

[0623] The bridge is a small organic molecule, and thus clearance from the bloodstream can be achieved rapidly (e.g., within about 20 minutes). In some embodiments, the CAR T cell response can be directed only to cancer cells that express receptors for the small molecule ligand portion of the 'bridge,' thereby reducing off-target toxicity to normal tissues. Furthermore, this system can be 'universal', since one type of CAR T cell construct can be used to target a wide range of cancers using different 'bridges.' Illustratively, the targeting moiety recognized by the CAR T cell can remain constant so that one type of CAR T cell construct can be used, while the small molecule ligand that binds to the cancer can be modified to allow targeting of a wide range of cancers.

[0624] In the sections below and in the claims, as well as in various embodiments described throughout the specification, a small molecule ligand linked to a targeting moiety by a linker is referred to as a "compound."

[0625] The following enumerated paragraphs describe several embodiments. Any of the following embodiments in combination with any applicable embodiment described in the Summary of the Invention section, Detailed Description of Exemplary Embodiments section, Examples section, or claims of this patent application is also contemplated.

[0626] 1. A method of treating cancer, comprising: i) administering to a patient a compound or a pharmaceutically acceptable salt thereof, wherein the compound comprises a small molecule ligand linked to a targeting moiety by a linker; ii) administering to the patient a CAR T cell composition comprising a first CAR T cell, the CAR T cell comprising a CAR directed to a targeting moiety; and iii) administering to the patient a CAR T cell composition comprising a second CAR T cell, wherein the CAR T cell comprises a CAR directed to a targeting moiety. A method comprising:

[0627] 2. The method of item 1, wherein the ligand is selected from the group consisting of folic acid, DUPA, NK-1R ligands, CAIX ligands, gamma glutamyl transpeptidase ligands, NKG2D ligands, and CCK2R ligands.

[0628] 3. The method according to either item 1 or 2, wherein the ligand is folic acid.

[0629] 4. The method according to either item 1 or 2, wherein the ligand is an NK-1R ligand.

[0630] 5. The method according to either item 1 or 2, wherein the ligand is DUPA.

[0631] 6. The method according to either item 1 or 2, wherein the ligand is a CCK2R ligand.

[0632] 7. The method according to either item 1 or 2, wherein the ligand is a gamma glutamyl transpeptidase ligand.

[0633] 8. The method of any of items 1 to 7, wherein the targeting moiety is selected from the group consisting of 2,4-dinitrophenol (DNP), 2,4,6-trinitrophenol (TNP), biotin, digoxigenin, fluorescein, fluorescein isothiocyanate (FITC), NHS-fluorescein, pentafluorophenyl ester, tetrafluorophenyl ester, knottin, centyrin, and DARPin.

[0634] 9. The method of any of paragraphs 1 to 8, wherein the targeting moiety is FITC.

[0635] 10. The method of any of paragraphs 1 to 8, wherein the targeting moiety is DNP.

[0636] 11. The method of any one of paragraphs 1 to 8, wherein the targeting moiety is TNP.

[0637] 12. The method according to any one of items 1 to 11, wherein the linker comprises polyethylene glycol (PEG), polyproline, a hydrophilic amino acid, a sugar, a non-natural peptidoglycan, polyvinylpyrrolidone, Pluronic F-127, or a combination thereof.

[0638] 13. The method according to any one of items 1 to 12, wherein the linker comprises PEG.

[0639] 14. The compound or a pharmaceutically acceptable salt thereof has the formula [ka] wherein B is a small molecule ligand, L is a linker, and T is a targeting moiety, wherein L is a group of the formula [ka] (wherein n is 0 to 200). 14. The method according to any one of Items 1 to 13, comprising:

[0640] 15. The method according to item 14, wherein n is an integer of 0 to 150.

[0641] 16. The method according to item 14, wherein n is an integer of 0 to 110.

[0642] 17. The method according to item 14, wherein n is an integer of 0 to 20.

[0643] 18. The method according to item 14, wherein n is an integer of 15 to 20.

[0644] 19. The method according to item 14, wherein n is an integer of 15 to 110.

[0645] 20. The method of any of paragraphs 1 to 9 or 12 to 19, wherein the linker comprises PEG and the targeting moiety is FITC or a pharmaceutically acceptable salt thereof.

[0646] 21. The method according to any one of items 1 to 20, wherein the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 10 nmole / kg to about 10,000 nmole / kg of patient body weight.

[0647] 22. The method according to any one of items 1 to 21, wherein the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 10 nmole / kg to about 5000 nmole / kg of patient body weight.

[0648] 23. The method according to any one of items 1 to 22, wherein the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 10 nmole / kg to about 1000 nmole / kg of patient body weight.

[0649] 24. The method according to any one of items 1 to 23, wherein the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 10 nmole / kg to about 600 nmole / kg of patient body weight.

[0650] 25. The method according to any one of items 1 to 24, wherein the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 200 nmole / kg to about 600 nmole / kg of patient body weight.

[0651] 26. The method according to any one of items 1 to 25, wherein the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 250 nmole / kg to about 600 nmole / kg of patient body weight.

[0652] 27. The cancer is lung cancer, bone cancer, pancreatic cancer, skin cancer, head cancer, neck cancer, cutaneous melanoma, intraocular melanoma, uterine cancer, ovarian cancer, endometrial cancer, rectal cancer, stomach cancer, colon cancer, breast cancer, triple-negative breast cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, non-small cell lung cancer, adrenal cancer, soft tissue sarcoma, osteosarcoma, urethral cancer, prostate cancer, chronic leukemia, acute 27. The method according to any one of items 1 to 26, wherein the cancer is selected from the group consisting of leukemia, acute myeloid leukemia, lymphocytic lymphoma, myeloid leukemia, myelomonocytic leukemia, hairy leukemia, pleural mesothelioma, bladder cancer, Burkitt's lymphoma, ureteral cancer, kidney cancer, renal cell carcinoma, renal pelvis cancer, central nervous system (CNS) neoplasms, primary CNS lymphoma, spinal axis tumor, brainstem glioma, pituitary adenoma, and gastroesophageal junction adenocarcinoma.

[0653] 28. The method according to any one of items 1 to 3 or 8 to 27, wherein the cancer is a folate receptor-expressing cancer.

[0654] 29. The method according to paragraph 28, wherein the cancer is endometrial cancer.

[0655] 30. The method according to paragraph 28, wherein the cancer is non-small cell lung cancer.

[0656] 31. The method of claim 28, wherein the cancer is ovarian cancer.

[0657] 32. The method of paragraph 28, wherein the cancer is triple-negative breast cancer.

[0658] 33. The method according to any one of items 1 to 32, wherein the CAR has a recognition region, and the recognition region is a single-chain fragment variable (scFv) region of an antibody.

[0659] 34. The method according to any one of items 1 to 9 or 12 to 33, wherein the CAR has a recognition region, and the recognition region of the CAR is a single-chain fragment variable (scFv) region of an anti-FITC antibody.

[0660] 35. The method of any of items 1 to 34, wherein the CAR has a costimulatory domain, and the costimulatory domain is selected from the group consisting of CD28, CD137 (4-1BB), CD134 (OX40), and CD278 (ICOS).

[0661] 36. The method of any one of items 1 to 35, wherein the CAR has an activation signaling domain, and the activation signaling domain is T cell CD3 zeta chain or Fc receptor γ.

[0662] 37. The method of any one of items 1 to 9 or 12 to 36, wherein the CAR has a recognition region, which is a single-chain fragment variable (scFv) region of an anti-FITC antibody; the CAR has a costimulatory domain, which is CD137 (4-1BB); and the CAR has an activation signaling domain, which is a T cell CD3ζ chain.

[0663] 38. The method of any of paragraphs 1 to 37, wherein multiple doses of the compound or a pharmaceutically acceptable salt thereof and the CAR T cell composition are administered.

[0664] 39. The method of any of paragraphs 1 to 38, wherein the patient is imaged prior to administration of the compound or a pharmaceutically acceptable salt thereof or prior to administration of the CAR T cell composition.

[0665] 40. The method according to any one of items 1 to 39, wherein the compound or a pharmaceutically acceptable salt thereof is not an antibody and does not include an antibody fragment.

[0666] 41. The method of any of paragraphs 1 to 40, wherein the targeting moiety does not comprise a peptide epitope.

[0667] 42. The method of any of items 1 to 41, wherein CAR T cell toxicity against cancer occurs without cytokine release that results in off-target toxicity in patients.

[0668] 43. The method of any of items 1 to 41, wherein off-target tissue toxicity does not occur in the patient and CAR T cell toxicity against the cancer occurs.

[0669] 44. The method of any of paragraphs 1 to 41, wherein the cancer comprises a tumor, the tumor size is reduced in the patient, and no off-target toxicity occurs.

[0670] 45. The method of any of paragraphs 1 to 44, wherein the CAR T cells comprise a nucleic acid comprising SEQ ID NO:1.

[0671] 46. ​​The method of any of paragraphs 1 to 45, wherein the CAR T cells comprise a polypeptide comprising SEQ ID NO:2.

[0672] 47. The method of paragraph 45, wherein the nucleic acid encodes a chimeric antigen receptor.

[0673] 48. The method of any of paragraphs 1 to 47, wherein the CAR comprises a humanized amino acid sequence.

[0674] 49. The method of any one of items 1 to 47, wherein the CAR consists of a humanized amino acid sequence.

[0675] 50. The method of any of paragraphs 1 to 49, wherein the first round of the CAR T cell composition comprises a mixture of the CAR T cells and non-transformed T cells in a ratio selected from about 1:5 CAR T cells to non-transformed T cells, about 1:4 CAR T cells to non-transformed T cells, about 1:3 CAR T cells to non-transformed T cells, about 1:2 CAR T cells to non-transformed T cells, and about 1:1 CAR T cells to non-transformed T cells.

[0676] 51. The method of any of paragraphs 1 to 50, wherein the second round of the CAR T cell composition comprises a mixture of the CAR T cells and non-transformed T cells in a ratio selected from about 1:5 CAR T cells to non-transformed T cells, about 1:4 CAR T cells to non-transformed T cells, about 1:3 CAR T cells to non-transformed T cells, about 1:2 CAR T cells to non-transformed T cells, and about 1:1 CAR T cells to non-transformed T cells.

[0677] 52. The method of any of items 1 to 51, wherein the first round of the CAR T cell composition comprises a mixture of the CAR T cells and non-transformed T cells at a ratio of CAR T cells to non-transformed T cells of about 1:1 to about 1:5.

[0678] 53. The method of any of paragraphs 1 to 52, wherein the second round of the CAR T cell composition comprises a mixture of the CAR T cells and non-transformed T cells at a ratio of CAR T cells to non-transformed T cells of about 1:1 to 1:5.

[0679] 54. The method of any of paragraphs 1 to 53, wherein the first round of the CAR T cell composition comprises a mixture of about 10 million CAR T cells and about 40 million untransformed T cells.

[0680] 55. The method of any of paragraphs 1 to 54, wherein the second round of the CAR T cell composition comprises a mixture of about 10 million CAR T cells and about 40 million untransformed T cells.

[0681] 56. A method of treating cancer, comprising: i) administering to a patient a compound or a pharmaceutically acceptable salt thereof, wherein the compound comprises a small molecule ligand linked to a targeting moiety by a linker; and ii) administering to the patient a CAR T cell composition, wherein the CAR T cell composition comprises CAR T cells, the CAR T cells comprise a CAR directed to a targeting moiety, and the CAR T cell composition comprises a mixture of the CAR T cells and non-transformed T cells. A method comprising:

[0682] 57. The method of paragraph 56, wherein the ligand is selected from the group consisting of folate, DUPA, an NK-1R ligand, a CAIX ligand, a gamma glutamyl transpeptidase ligand, an NKG2D ligand, and a CCK2R ligand.

[0683] 58. The method of either paragraph 56 or 57, wherein the ligand is folic acid.

[0684] 59. The method of either paragraph 56 or 57, wherein the ligand is an NK-1R ligand.

[0685] 60. The method of either paragraph 56 or 57, wherein the ligand is DUPA.

[0686] 61. The method of either paragraph 56 or 57, wherein the ligand is a CCK2R ligand.

[0687] 62. The method of either paragraph 56 or 57, wherein the ligand is a gamma glutamyl transpeptidase ligand.

[0688] 63. The method of any of paragraphs 56 to 62, wherein the targeting moiety is selected from the group consisting of 2,4-dinitrophenol (DNP), 2,4,6-trinitrophenol (TNP), biotin, digoxigenin, fluorescein, fluorescein isothiocyanate (FITC), NHS-fluorescein, pentafluorophenyl ester, tetrafluorophenyl ester, knottin, centyrin, and DARPin.

[0689] 64. The method of any of paragraphs 56 to 63, wherein the targeting moiety is FITC.

[0690] 65. The method of any of paragraphs 56 to 63, wherein the targeting moiety is DNP.

[0691] 66. The method of any of paragraphs 56 to 63, wherein the targeting moiety is TNP.

[0692] 67. The method of any of items 56 to 66, wherein the linker comprises polyethylene glycol (PEG), polyproline, a hydrophilic amino acid, a sugar, a non-natural peptidoglycan, polyvinylpyrrolidone, Pluronic F-127, or a combination thereof.

[0693] 68. The method of any of items 56 to 67, wherein the linker comprises PEG.

[0694] 69. The compound or a pharmaceutically acceptable salt thereof has the formula [ka] wherein B is a small molecule ligand, L is a linker, and T is a targeting moiety, wherein L is a group of the formula [ka] (wherein n is 0 to 200). Item 69. The method according to any one of Items 56 to 68, comprising:

[0695] 70. The method according to item 69, wherein n is an integer of 0 to 150.

[0696] 71. The method according to item 69, wherein n is an integer of 0 to 110.

[0697] 72. The method according to item 69, wherein n is an integer of 0 to 20.

[0698] 73. The method according to item 69, wherein n is an integer of 15 to 20.

[0699] 74. The method according to item 69, wherein n is an integer of 15 to 110.

[0700] 75. The method of any of paragraphs 56-64 or 67-74, wherein the linker comprises PEG and the targeting moiety is FITC or a pharmaceutically acceptable salt thereof.

[0701] 76. The method according to any one of items 56 to 75, wherein the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 10 nmole / kg to about 10,000 nmole / kg of patient body weight.

[0702] 77. The method according to any one of items 56 to 76, wherein the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 10 nmole / kg to about 5000 nmole / kg of patient body weight.

[0703] 78. The method according to any one of items 56 to 77, wherein the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 10 nmole / kg to about 1000 nmole / kg of patient body weight.

[0704] 79. The method according to any one of items 56 to 78, wherein the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 10 nmole / kg to about 600 nmole / kg of patient body weight.

[0705] 80. The method according to any one of items 56 to 79, wherein the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 200 nmole / kg to about 600 nmole / kg of patient body weight.

[0706] 81. The method according to any one of items 56 to 80, wherein the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 250 nmole / kg to about 600 nmole / kg of patient body weight.

[0707] 82. The cancer is lung cancer, bone cancer, pancreatic cancer, skin cancer, head cancer, neck cancer, cutaneous melanoma, intraocular melanoma, uterine cancer, ovarian cancer, endometrial cancer, rectal cancer, stomach cancer, colon cancer, breast cancer, triple-negative breast cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, non-small cell lung cancer, adrenal cancer, soft tissue sarcoma, osteosarcoma, urethral cancer, prostate cancer, chronic leukemia, acute 82. The method of any of items 56 to 81, wherein the cancer is selected from the group consisting of leukemia, acute myeloid leukemia, lymphocytic lymphoma, myeloid leukemia, myelomonocytic leukemia, hairy leukemia, pleural mesothelioma, bladder cancer, Burkitt's lymphoma, ureteral cancer, kidney cancer, renal cell carcinoma, renal pelvis cancer, central nervous system (CNS) neoplasms, primary CNS lymphoma, spinal axis tumor, brainstem glioma, pituitary adenoma, and gastroesophageal junction adenocarcinoma.

[0708] 83. The method of any of items 56 to 58 or 63 to 82, wherein the cancer is a folate receptor-expressing cancer.

[0709] 84. The method of paragraph 83, wherein the cancer is endometrial cancer.

[0710] 85. The method of paragraph 83, wherein the cancer is non-small cell lung cancer.

[0711] 86. The method of paragraph 83, wherein the cancer is ovarian cancer.

[0712] 87. The method of paragraph 83, wherein the cancer is triple-negative breast cancer.

[0713] 88. The method of any of items 56 to 87, wherein the CAR has a recognition region, and the recognition region is a single-chain fragment variable (scFv) region of an antibody.

[0714] 89. The method of any one of items 56 to 64 or 67 to 88, wherein the CAR has a recognition region, and the recognition region of the CAR is a single-chain fragment variable (scFv) region of an anti-FITC antibody.

[0715] 90. The method of any of paragraphs 56 to 89, wherein the CAR has a costimulatory domain, and the costimulatory domain is selected from the group consisting of CD28, CD137 (4-1BB), CD134 (OX40), and CD278 (ICOS).

[0716] 91. The method of any of items 56 to 90, wherein the CAR has an activation signaling domain, and the activation signaling domain is T cell CD3 zeta chain or Fc receptor γ.

[0717] 92. The method of any one of items 56 to 64 or 67 to 91, wherein the CAR has a recognition region, which is a single-chain fragment variable (scFv) region of an anti-FITC antibody; the CAR has a costimulatory domain, which is CD137 (4-1BB); and the CAR has an activation signaling domain, which is a T cell CD3 zeta chain.

[0718] 93. The method of any of paragraphs 56 to 92, wherein multiple doses of the compound or a pharmaceutically acceptable salt thereof are administered.

[0719] 94. The method of any of paragraphs 56 to 93, wherein the patient is imaged prior to administration of the compound or a pharmaceutically acceptable salt thereof or prior to administration of the CAR T cell composition.

[0720] 95. The method according to any one of items 56 to 94, wherein the compound or a pharmaceutically acceptable salt thereof is not an antibody and does not include an antibody fragment.

[0721] 96. The method of any of paragraphs 56 to 95, wherein the targeting moiety does not comprise a peptide epitope.

[0722] 97. The method of any of items 56 to 96, wherein CAR T cell toxicity against cancer occurs without cytokine release resulting in off-target toxicity in the patient.

[0723] 98. The method of any of items 56 to 96, wherein off-target tissue toxicity does not occur in the patient and CAR T cell toxicity against the cancer occurs.

[0724] 99. The method of any of paragraphs 56 to 96, wherein the cancer comprises a tumor, the tumor size is reduced in the patient, and no off-target toxicity occurs.

[0725] 100. The method of any of paragraphs 56 to 99, wherein the CAR T cells comprise a nucleic acid comprising SEQ ID NO:1.

[0726] 101. The method of any of paragraphs 56 to 100, wherein the CAR T cells comprise a polypeptide comprising SEQ ID NO:2.

[0727] 102. The method of paragraph 100, wherein the nucleic acid encodes a chimeric antigen receptor.

[0728] 103. The method of any of paragraphs 56 to 102, wherein the CAR comprises a humanized amino acid sequence.

[0729] 104. The method of any of paragraphs 56 to 102, wherein the CAR consists of a humanized amino acid sequence.

[0730] 105. The method of any of paragraphs 56 to 104, wherein the mixture of CAR T cells and non-transformed T cells is in a ratio selected from about 1:5 CAR T cells to non-transformed T cells, about 1:4 CAR T cells to non-transformed T cells, about 1:3 CAR T cells to non-transformed T cells, about 1:2 CAR T cells to non-transformed T cells, and about 1:1 CAR T cells to non-transformed T cells.

[0731] 106. The method of any of items 56 to 105, wherein the mixture of CAR T cells and non-transformed T cells has a ratio of CAR T cells to non-transformed T cells of about 1:1 to about 1:5.

[0732] 107. The method of any of paragraphs 56 to 106, wherein the mixture of CAR T cells and non-transformed T cells comprises about 10 million CAR T cells and about 40 million non-transformed T cells.

[0733] 108. A method of treating cancer, comprising: i) administering to a patient a compound or a pharmaceutically acceptable salt thereof, wherein the compound comprises a small molecule ligand linked to a targeting moiety by a linker; ii) administering to the patient a CAR T cell composition, the CAR T cell composition comprising CAR T cells, and the CAR T cells comprising a CAR directed to a targeting moiety; and iii) administering to the patient folic acid, a conjugate comprising folic acid (wherein the conjugate comprising folic acid does not comprise a targeting moiety), or an agent that inhibits activation of CAR T cells. A method comprising:

[0734] 109. The method of paragraph 108, wherein step iii includes administering folic acid.

[0735] 110. The method of either paragraph 108 or 109, wherein step iii includes administering folic acid or leucovorin.

[0736] 111. The method of paragraph 108, wherein step iii comprises administering a conjugate comprising folic acid.

[0737] 112. The method of paragraph 111, wherein the folic acid-containing conjugate comprises folic acid linked to one or more amino acids.

[0738] 113. The conjugate containing folic acid has the formula [ka] Item 112. The method of item 111, comprising:

[0739] 114. The folic acid has the formula [ka] [In the formula, X 1 and Y 1 are each independently a halo, R 2 , OR 2 , S.R. 3 and N.R. 4 R 5 selected from the group consisting of: U, V and W are -(R 6a )C=, -N=, -(R 6a )C(R 7a )- and -N(R 4a )—; Q is selected from the group consisting of C and CH; T is selected from the group consisting of S, O, N, and —C═C—; X 2 and X 3 are each independently oxygen, sulfur, -C(Z)-, -C(Z)O-, -OC(Z)-, -N(R 4b )-, -C(Z)N(R 4b )-, -N(R 4b )C(Z)-, -OC(Z)N(R 4b )-, -N(R 4b )C(Z)O-, -N(R 4b )C(Z)N(R 5b )-, -S(O)-, -S(O)2-, -N(R 4a )S(O)2-, -C(R 6b )(R 7b )-, -N(C≡CH)-, -N(CH2C≡CH)-, C1-C 12 Alkylene and C1-C 12 alkyleneoxy, where Z is oxygen or sulfur; R 1 are hydrogen, halo, C1-C 12 Alkyl and C1-C 12 selected from the group consisting of alkoxy; R 2 , R 3 , R 4 , R 4a , R 4b , R 5 , R 5b , R 6b and R 7b are each independently hydrogen, halo, C-C 12 Alkyl, C1-C 12 Alkoxy, C1-C 12 Alkanoyl, C1-C 12 Alkenyl, C1-C 12 Alkynyl, (C1-C 12 alkoxy)carbonyl and (C1-C 12 alkylamino)carbonyl; R 6 and R 7 are each independently hydrogen, halo, C-C 12 Alkyl and C1-C 12 alkoxy; or R 6 and R 7 together to form a carbonyl group; R 6a and R 7a are each independently hydrogen, halo, C-C 12 Alkyl and C1-C 12 alkoxy; or R 6a and R 7a together to form a carbonyl group; p, r, s, and t are each independently 0 or 1; and * represents any covalent bond to the remainder of the conjugate if any additional chemical moiety is part of the folic acid. Item 113. The method according to any one of Items 109 to 112,

[0740] 115. The method of any of paragraphs 108 to 114, wherein the targeting moiety is selected from the group consisting of 2,4-dinitrophenol (DNP), 2,4,6-trinitrophenol (TNP), biotin, digoxigenin, fluorescein, fluorescein isothiocyanate (FITC), NHS-fluorescein, pentafluorophenyl ester, tetrafluorophenyl ester, knottin, centyrin, and DARPin.

[0741] 116. The method of any of paragraphs 108 to 115, wherein the targeting moiety is FITC.

[0742] 117. The method of any of paragraphs 108 to 115, wherein the targeting moiety is DNP.

[0743] 118. The method of any of paragraphs 108 to 115, wherein the targeting moiety is TNP.

[0744] 119. The method of any of paragraphs 108 to 118, wherein the linker comprises polyethylene glycol (PEG), polyproline, a hydrophilic amino acid, a sugar, a non-natural peptidoglycan, polyvinylpyrrolidone, Pluronic F-127, or a combination thereof.

[0745] 120. The method of any of items 108 to 119, wherein the linker comprises PEG.

[0746] 121. The compound or a pharmaceutically acceptable salt thereof has the formula [ka] wherein B is a small molecule ligand, L is a linker, and T is a targeting moiety, wherein L is a group of the formula [ka] (wherein n is 0 to 200). Item 121. The method according to any one of Items 108 to 120,

[0747] 122. The method according to item 121, wherein n is an integer from 0 to 12.

[0748] 123. The method according to item 121, wherein n is an integer of 0 to 150.

[0749] 124. The method according to item 121, wherein n is an integer from 0 to 110.

[0750] 125. The method according to item 121, wherein n is an integer of 0 to 20.

[0751] 126. The method according to item 121, wherein n is an integer of 15 to 20.

[0752] 127. The method according to item 121, wherein n is an integer between 15 and 110.

[0753] 128. The method of any of paragraphs 108-116 or 119-127, wherein the linker comprises PEG and the targeting moiety is FITC or a pharmaceutically acceptable salt thereof.

[0754] 129. The method according to any one of items 108 to 128, wherein the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 10 nmole / kg to about 10,000 nmole / kg of patient body weight.

[0755] 130. The method of any of items 108 to 129, wherein the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 10 nmole / kg to about 5000 nmole / kg of patient body weight.

[0756] 131. The method according to any one of items 108 to 130, wherein the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 10 nmole / kg to about 1000 nmole / kg of patient body weight.

[0757] 132. The method of any of items 108 to 131, wherein the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 10 nmole / kg to about 600 nmole / kg of patient body weight.

[0758] 133. The method of any of items 108 to 132, wherein the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 200 nmole / kg to about 600 nmole / kg of patient body weight.

[0759] 134. The method of any of items 108 to 133, wherein the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 250 nmole / kg to about 600 nmole / kg of patient body weight.

[0760] 135. The cancer is lung cancer, bone cancer, pancreatic cancer, skin cancer, head cancer, neck cancer, cutaneous melanoma, intraocular melanoma, uterine cancer, ovarian cancer, endometrial cancer, rectal cancer, stomach cancer, colon cancer, breast cancer, triple-negative breast cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, non-small cell lung cancer, adrenal cancer, soft tissue sarcoma, osteosarcoma, urethral cancer, prostate cancer, chronic leukemia, acute leukemia 135. The method of any of items 108 to 134, wherein the cancer is selected from the group consisting of hematopoietic leukemia, acute myeloid leukemia, lymphocytic lymphoma, myeloid leukemia, myelomonocytic leukemia, hairy leukemia, pleural mesothelioma, bladder cancer, Burkitt's lymphoma, ureteral cancer, kidney cancer, renal cell carcinoma, renal pelvis cancer, central nervous system (CNS) neoplasms, primary CNS lymphoma, spinal axis tumor, brainstem glioma, pituitary adenoma, and gastroesophageal junction adenocarcinoma.

[0761] 136. The method of any of paragraphs 108 to 135, wherein the ligand moiety of the small molecule ligand linked to the targeting moiety by the linker is folate, and the cancer is a folate receptor-expressing cancer.

[0762] 137. The method of paragraph 136, wherein the cancer is endometrial cancer.

[0763] 138. The method of paragraph 136, wherein the cancer is non-small cell lung cancer.

[0764] 139. The method of paragraph 136, wherein the cancer is ovarian cancer.

[0765] 140. The method of paragraph 136, wherein the cancer is triple-negative breast cancer.

[0766] 141. The method of any of items 108 to 140, wherein the CAR has a recognition region, and the recognition region is a single-chain fragment variable (scFv) region of an antibody.

[0767] 142. The method of any of items 108 to 116 or 119 to 141, wherein the CAR has a recognition region, and the recognition region of the CAR is a single-chain fragment variable (scFv) region of an anti-FITC antibody.

[0768] 143. The method of any of paragraphs 108 to 142, wherein the CAR has a costimulatory domain, and the costimulatory domain is selected from the group consisting of CD28, CD137 (4-1BB), CD134 (OX40), and CD278 (ICOS).

[0769] 144. The method of any of paragraphs 108 to 143, wherein the CAR has an activation signaling domain, and the activation signaling domain is T cell CD3 zeta chain or Fc receptor γ.

[0770] 145. The method of any of items 108 to 116 or 119 to 144, wherein the CAR has a recognition region, which is a single-chain fragment variable (scFv) region of an anti-FITC antibody; the CAR has a costimulatory domain, which is CD137 (4-1BB); and the CAR has an activation signaling domain, which is the T cell CD3ζ chain.

[0771] 146. The method of any of paragraphs 108 to 145, wherein multiple doses of the compound or a pharmaceutically acceptable salt thereof and / or the CAR T cell composition are administered.

[0772] 147. The method of any of paragraphs 108 to 146, wherein the patient is imaged prior to administration of the compound or a pharmaceutically acceptable salt thereof or prior to administration of the CAR T cell composition.

[0773] 148. The method of any one of items 108 to 147, wherein the compound or a pharmaceutically acceptable salt thereof is not an antibody and does not include an antibody fragment.

[0774] 149. The method of any of paragraphs 108 to 148, wherein the targeting moiety does not comprise a peptide epitope.

[0775] 150. The method of any of paragraphs 108 to 149, wherein CAR T cell toxicity against cancer occurs without cytokine release resulting in off-target toxicity in the patient.

[0776] 151. The method of any of paragraphs 108 to 149, wherein off-target tissue toxicity does not occur in the patient and CAR T cell toxicity against the cancer occurs.

[0777] 152. The method of any of paragraphs 108 to 149, wherein the cancer comprises a tumor, the tumor size is reduced in the patient, and no off-target toxicity occurs.

[0778] 153. The method of any of paragraphs 108 to 152, wherein the CAR T cells comprise a nucleic acid comprising SEQ ID NO:1.

[0779] 154. The method of any of paragraphs 108 to 153, wherein the CAR T cells comprise a polypeptide comprising SEQ ID NO:2.

[0780] 155. The method of paragraph 153, wherein the nucleic acid encodes a chimeric antigen receptor.

[0781] 156. The method of any of paragraphs 108 to 155, wherein the CAR comprises a humanized amino acid sequence.

[0782] 157. The method of any of paragraphs 108 to 155, wherein the CAR consists of a humanized amino acid sequence.

[0783] 158. The method of any of paragraphs 108 to 157, wherein the CAR T cell composition comprises a mixture of the CAR T cells and non-transformed T cells in a ratio selected from about 1:5 CAR T cells to non-transformed T cells, about 1:4 CAR T cells to non-transformed T cells, about 1:3 CAR T cells to non-transformed T cells, about 1:2 CAR T cells to non-transformed T cells, and about 1:1 CAR T cells to non-transformed T cells.

[0784] 159. The method of any of paragraphs 108 to 158, wherein the CAR T cell composition comprises a mixture of the CAR T cells and non-transformed T cells at a ratio of CAR T cells to non-transformed T cells of about 1:1 to about 1:5.

[0785] 160. The method of any of paragraphs 108 to 159, wherein the CAR T cell composition comprises a mixture comprising about 10 million CAR T cells and about 40 million untransformed T cells.

[0786] 161. The method of any of items 108 to 160, wherein the agent that inhibits the activation of the CAR T cells is selected from the group consisting of lymphocyte-specific protein tyrosine kinase inhibitors, PI3 kinase inhibitors, IL-2-inducible T cell kinase inhibitors, JAK inhibitors, BTK inhibitors, EC2319, and agents that block binding of CAR T cells to the compound or a pharmaceutically acceptable salt thereof but do not bind to the cancer.

[0787] 162. The method of paragraph 161, wherein an agent that inhibits activation of the CAR T cells is administered, and the agent is a lymphocyte-specific protein tyrosine kinase inhibitor.

[0788] 163. The method of paragraph 162, wherein the lymphocyte-specific protein tyrosine kinase inhibitor is dasatinib.

[0789] 164. The method of paragraph 161, wherein an agent that inhibits activation of the CAR T cells is administered, and the agent is a PI3 kinase inhibitor.

[0790] 165. The method of paragraph 164, wherein the PI3 kinase inhibitor is GDC0980.

[0791] 166. The method of paragraph 161, wherein an agent that inhibits activation of the CAR T cells is administered, and the agent is an IL-2-inducible T cell kinase inhibitor.

[0792] 167. The method of paragraph 166, wherein the IL-2-inducible T cell kinase inhibitor is BMS-509744.

[0793] 168. The method of any of paragraphs 1 to 160, wherein the CAR T cell composition is administered by injection into the patient's bloodstream, and the CAR T cells in the patient's bloodstream are at least 10 percent of the patient's total T cells in the patient's bloodstream about four weeks after injection of the CAR T cell composition.

[0794] 169. The method of any of paragraphs 1 to 160, wherein the CAR T cell composition is administered by injection into the patient's bloodstream, and the CAR T cells in the patient's bloodstream are at least 12 percent of the patient's total T cells in the patient's bloodstream about four weeks after injection of the CAR T cell composition.

[0795] 170. The method of any of paragraphs 1 to 160, wherein the CAR T cell composition is administered by injection into the patient's bloodstream, and the CAR T cells in the patient's bloodstream are at least 15 percent of the patient's total T cells in the patient's bloodstream about four weeks after injection of the CAR T cell composition.

[0796] 171. The method of any of paragraphs 1 to 160 or 168 to 170, wherein the CAR T cells in the CAR T cell composition administered to the patient comprise about 1 million to about 15 million CAR T cells.

[0797] 172. The method of any of paragraphs 1 to 160 or 168 to 171, wherein the dose of CAR T cells in the CAR T cell composition administered to the patient is selected from the group consisting of about 1 million, about 2 million, about 3 million, about 4 million, about 5 million, about 6 million, about 7 million, about 8 million, about 9 million, about 10 million, about 11 million, about 12 million, about 12.5 million, about 13 million, about 14 million, and about 15 million CAR T cells.

[0798] 173. The method of any of paragraphs 1 to 160 or 168 to 170, wherein the CAR T cells in the CAR T cell composition administered to the patient comprise at least about 2 million CAR T cells.

[0799] 174. The method of any of paragraphs 1 to 160 or 168 to 170, wherein the CAR T cells in the CAR T cell composition administered to the patient comprise at least about 5 million CAR T cells.

[0800] 175. The method of any of paragraphs 1 to 160 or 168 to 170, wherein the CAR T cells in the CAR T cell composition administered to the patient comprise at least about 10 million CAR T cells.

[0801] 176. The method of any of paragraphs 1 to 175, wherein the CAR T cells comprise a nucleic acid comprising SEQ ID NO:3.

[0802] 177. The method of any of paragraphs 1 to 176, wherein the CAR T cells comprise a vector comprising SEQ ID NO:1.

[0803] 178. The method of any of paragraphs 1 to 177, wherein the CAR T cells comprise a vector comprising SEQ ID NO:3.

[0804] 179. The method of paragraph 176, wherein the nucleic acid encodes a chimeric antigen receptor.

[0805] 180. The method of any of paragraphs 108 to 160, wherein an agent that inhibits activation of the CAR T cells is administered, the agent blocking binding of the CAR T cells to the compound or a pharmaceutically acceptable salt thereof, but not to the cancer.

[0806] 181. The method of paragraph 180, wherein the agent is fluoresceinamine, FITC, or sodium fluorescein.

[0807] 182. The method of paragraph 180, wherein the agent is FITC.

[0808] 183. A method of treating cancer, comprising: i) administering to a patient a compound or a pharmaceutically acceptable salt thereof, wherein the compound comprises a small molecule ligand linked to a targeting moiety by a linker, and the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 10 nmole / kg to about 2500 nmole / kg of patient body weight; and ii) administering to the patient a CAR T cell composition comprising CAR T cells, wherein the CAR T cells comprise a CAR directed to a targeting moiety, and the CAR T cells are at a dose of about 1 million CAR T cells to about 15 million CAR T cells. A method comprising:

[0809] 184. The method of paragraph 183, wherein the ligand is selected from the group consisting of folate, DUPA, an NK-1R ligand, a CAIX ligand, a gamma glutamyl transpeptidase ligand, an NKG2D ligand, and a CCK2R ligand.

[0810] 185. The method of either paragraph 183 or 184, wherein the ligand is folic acid.

[0811] 186. The method of any of paragraphs 183 to 185, wherein the targeting moiety is selected from the group consisting of 2,4-dinitrophenol (DNP), 2,4,6-trinitrophenol (TNP), biotin, digoxigenin, fluorescein, fluorescein isothiocyanate (FITC), NHS-fluorescein, pentafluorophenyl ester, tetrafluorophenyl ester, knottin, centyrin, and DARPin.

[0812] 187. The method of any of paragraphs 183 to 186, wherein the targeting moiety is FITC.

[0813] 188. The method of any of paragraphs 183 to 187, wherein the linker comprises polyethylene glycol (PEG), polyproline, a hydrophilic amino acid, a sugar, a non-natural peptidoglycan, polyvinylpyrrolidone, Pluronic F-127, or a combination thereof.

[0814] 189. The method of any of paragraphs 183 to 188, wherein the linker comprises PEG.

[0815] 190. The compound or a pharmaceutically acceptable salt thereof has the formula [ka] wherein B is a small molecule ligand, L is a linker, and T is a targeting moiety, wherein L is a group of the formula [ka] (wherein n is 0 to 200). Item 189. The method according to any one of Items 183 to 189,

[0816] 191. The method of any of paragraphs 183 to 190, wherein the linker comprises PEG and the targeting moiety is FITC or a pharmaceutically acceptable salt thereof.

[0817] 192. The method of any of paragraphs 183 to 191, wherein the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 10 nmole / kg to about 100 nmole / kg of patient body weight.

[0818] 193. The method of any of paragraphs 183 to 191, wherein the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 10 nmole / kg to about 50 nmole / kg of patient body weight.

[0819] 194. The method of any of paragraphs 183 to 191, wherein the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 10 nmole / kg to about 20 nmole / kg of patient body weight.

[0820] 195. The method of any of paragraphs 183 to 191, wherein the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 10 nmole / kg to about 600 nmole / kg of patient body weight.

[0821] 196. The method of any of paragraphs 183 to 191, wherein the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 200 nmole / kg to about 600 nmole / kg of patient body weight.

[0822] 197. The method of any of paragraphs 183 to 191, wherein the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 400 nmole / kg to about 600 nmole / kg of patient body weight.

[0823] 198. The method of any of paragraphs 183 to 197, wherein the CAR T cells are administered at a dose of about 1 million CAR T cells to about 12.5 million CAR T cells.

[0824] 199. The method of any of paragraphs 183 to 197, wherein the CAR T cells are administered at a dose of about 1 million CAR T cells to about 7 million CAR T cells.

[0825] 200. The method of any of paragraphs 183 to 197, wherein the CAR T cells are administered at a dose of about 1 million CAR T cells to about 5 million CAR T cells.

[0826] 201. The method of any of paragraphs 183 to 197, wherein the CAR T cells are administered at a dose of about 2 million CAR T cells to about 5 million CAR T cells.

[0827] 202. The cancer is lung cancer, bone cancer, pancreatic cancer, skin cancer, head cancer, neck cancer, cutaneous melanoma, intraocular melanoma, uterine cancer, ovarian cancer, endometrial cancer, rectal cancer, stomach cancer, colon cancer, breast cancer, triple-negative breast cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, non-small cell lung cancer, adrenal cancer, soft tissue sarcoma, osteosarcoma, urethral cancer, prostate cancer, chronic leukemia, acute leukemia 202. The method of any of paragraphs 183 to 201, wherein the cancer is selected from the group consisting of hematopoietic leukemia, acute myeloid leukemia, lymphocytic lymphoma, myeloid leukemia, myelomonocytic leukemia, hairy leukemia, pleural mesothelioma, bladder cancer, Burkitt's lymphoma, ureteral cancer, kidney cancer, renal cell carcinoma, renal pelvis cancer, central nervous system (CNS) neoplasms, primary CNS lymphoma, spinal axis tumor, brainstem glioma, pituitary adenoma and esophagogastric junction adenocarcinoma.

[0828] 203. The method of any of items 183 to 202, wherein the cancer is a folate receptor-expressing cancer.

[0829] 204. The method of any of items 183 to 203, wherein the CAR has a recognition region, which is a single-chain fragment variable (scFv) region of an anti-FITC antibody; the CAR has a costimulatory domain, which is CD137 (4-1BB); and the CAR has an activation signaling domain, which is a T cell CD3ζ chain.

[0830] 205. The method of any of items 183 to 204, wherein the compound or a pharmaceutically acceptable salt thereof is not an antibody and does not include an antibody fragment.

[0831] 206. The method of any of paragraphs 183 to 205, wherein the targeting moiety does not comprise a peptide epitope.

[0832] 207. The method of any of paragraphs 183 to 206, wherein CAR T cell toxicity against cancer occurs without cytokine release resulting in off-target toxicity in the patient.

[0833] 208. The method of any of paragraphs 183 to 206, wherein off-target tissue toxicity does not occur in the patient and CAR T cell toxicity against the cancer occurs.

[0834] 209. The method of any of paragraphs 183 to 206, wherein the cancer comprises a tumor, the tumor size is reduced in the patient, and no off-target toxicity occurs.

[0835] 210. The method of any of paragraphs 183 to 209, wherein the CAR T cells comprise a nucleic acid comprising SEQ ID NO:1.

[0836] 211. The method of any of paragraphs 183 to 209, wherein the CAR T cells comprise a polypeptide comprising SEQ ID NO:2.

[0837] 212. The method of any of paragraphs 183 to 211, wherein the CAR comprises a humanized amino acid sequence.

[0838] 213. The method of any of paragraphs 183 to 212, wherein the CAR consists of a humanized amino acid sequence.

[0839] 214. The method of any of paragraphs 183 to 213, wherein the CAR T cell composition further comprises non-transformed T cells.

[0840] 215. A method of treating cancer, comprising: i) continuously administering to a patient a compound or a pharmaceutically acceptable salt thereof, wherein the compound comprises a small molecule ligand linked to a targeting moiety by a linker; ii) administering to the patient a CAR T cell composition comprising CAR T cells, wherein the CAR T cells comprise a CAR directed to a targeting moiety; and iii) terminating the continuous administration of the compound or a pharmaceutically acceptable salt thereof to inhibit or prevent cytokine release syndrome in the patient. A method comprising:

[0841] 216. The method of paragraph 215, wherein the ligand is selected from the group consisting of folate, DUPA, an NK-1R ligand, a CAIX ligand, a gamma glutamyl transpeptidase ligand, an NKG2D ligand, and a CCK2R ligand.

[0842] 217. The method of either paragraph 215 or 216, wherein the ligand is folic acid.

[0843] 218. The method of any of paragraphs 215 to 217, wherein the targeting moiety is selected from the group consisting of 2,4-dinitrophenol (DNP), 2,4,6-trinitrophenol (TNP), biotin, digoxigenin, fluorescein, fluorescein isothiocyanate (FITC), NHS-fluorescein, pentafluorophenyl ester, tetrafluorophenyl ester, knottin, centyrin, and DARPin.

[0844] 219. The method of any of paragraphs 215 to 218, wherein the targeting moiety is FITC.

[0845] 220. The method of any of paragraphs 215 to 219, wherein the linker comprises polyethylene glycol (PEG), polyproline, a hydrophilic amino acid, a sugar, a non-natural peptidoglycan, polyvinylpyrrolidone, Pluronic F-127, or a combination thereof.

[0846] 221. The method of any of paragraphs 215 to 220, wherein the linker comprises PEG.

[0847] 222. The compound or a pharmaceutically acceptable salt thereof has the formula [ka] wherein B is a small molecule ligand, L is a linker, and T is a targeting moiety, wherein L is a group of the formula [ka] (wherein n is 0 to 200). Item 222. The method according to any one of Items 215 to 221,

[0848] 223. The method of any of paragraphs 215 to 222, wherein the linker comprises PEG and the targeting moiety is FITC or a pharmaceutically acceptable salt thereof.

[0849] 224. The method of any of paragraphs 215 to 223, wherein the compound or a pharmaceutically acceptable salt thereof is administered to the patient continuously for at least 1 hour.

[0850] 225. The method of any of paragraphs 215 to 223, wherein the compound or a pharmaceutically acceptable salt thereof is administered to the patient continuously for at least 4 hours.

[0851] 226. The method of any of paragraphs 215 to 223, wherein the compound or a pharmaceutically acceptable salt thereof is administered to the patient continuously for at least 6 hours.

[0852] 227. The method of any of paragraphs 215 to 223, wherein the continuous administration of the compound or a pharmaceutically acceptable salt thereof is an alternate-day administration regimen.

[0853] 228. The method of any of paragraphs 215 to 223, wherein the continuous administration of the compound or a pharmaceutically acceptable salt thereof is a regimen of three administrations per week.

[0854] 229. The method according to any one of paragraphs 215 to 223, wherein the compound or a pharmaceutically acceptable salt thereof is continuously administered until the patient experiences unacceptable weight loss, fever, hypotension, or pulmonary edema.

[0855] 230. The method of any of paragraphs 215 to 229, wherein the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 200 nmole / kg to about 600 nmole / kg of patient body weight.

[0856] 231. The method of any of paragraphs 215 to 229, wherein the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 400 nmole / kg to about 600 nmole / kg of patient body weight.

[0857] 232. The method of any of paragraphs 215 to 231, wherein about 2 million to about 5 million CAR T cells are administered.

[0858] 233. The method of any of paragraphs 215 to 232, wherein the administration is by intravenous administration.

[0859] 234. The cancer is lung cancer, bone cancer, pancreatic cancer, skin cancer, head cancer, neck cancer, cutaneous melanoma, intraocular melanoma, uterine cancer, ovarian cancer, endometrial cancer, rectal cancer, stomach cancer, colon cancer, breast cancer, triple-negative breast cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, non-small cell lung cancer, adrenal cancer, soft tissue sarcoma, osteosarcoma, urethral cancer, prostate cancer, chronic leukemia, acute leukemia 234. The method of any of items 215 to 233, wherein the cancer is selected from the group consisting of hematopoietic leukemia, acute myeloid leukemia, lymphocytic lymphoma, myeloid leukemia, myelomonocytic leukemia, hairy leukemia, pleural mesothelioma, bladder cancer, Burkitt's lymphoma, ureteral cancer, kidney cancer, renal cell carcinoma, renal pelvis cancer, central nervous system (CNS) neoplasms, primary CNS lymphoma, spinal axis tumor, brainstem glioma, pituitary adenoma and esophagogastric junction adenocarcinoma.

[0860] 235. The method of any of paragraphs 215 to 234, wherein the cancer is a folate receptor-expressing cancer.

[0861] 236. The method of any of items 215 to 235, wherein the CAR has a recognition region, which is a single-chain fragment variable (scFv) region of an anti-FITC antibody; the CAR has a costimulatory domain, which is CD137 (4-1BB); and the CAR has an activation signaling domain, which is the T cell CD3ζ chain.

[0862] 237. The method of any of items 215 to 236, wherein the compound or a pharmaceutically acceptable salt thereof is not an antibody and does not include an antibody fragment.

[0863] 238. The method of any of paragraphs 215 to 237, wherein the targeting moiety does not comprise a peptide epitope.

[0864] 239. The method of any of paragraphs 215 to 238, wherein CAR T cell toxicity against cancer occurs without cytokine release resulting in off-target toxicity in the patient.

[0865] 240. The method of any of paragraphs 215 to 238, wherein off-target tissue toxicity does not occur in the patient and CAR T cell toxicity against the cancer occurs.

[0866] 241. The method of any of paragraphs 215 to 238, wherein the cancer comprises a tumor, the tumor size is reduced in the patient, and no off-target toxicity occurs.

[0867] 242. The method of any of paragraphs 215 to 241, wherein the CAR T cells comprise a nucleic acid comprising SEQ ID NO:1.

[0868] 243. The method of any of paragraphs 215 to 242, wherein the CAR T cells comprise a polypeptide comprising SEQ ID NO:2.

[0869] 244. The method of any of paragraphs 215 to 243, wherein the CAR comprises a humanized amino acid sequence.

[0870] 245. The method of any of paragraphs 215 to 243, wherein the CAR consists of a humanized amino acid sequence.

[0871] 246. The method of any of paragraphs 215 to 245, wherein the CAR T cell composition further comprises non-transformed T cells.

[0872] 247. The method of any of paragraphs 215 to 246, wherein the CAR T cell composition further comprises non-transformed T cells in a ratio selected from the group consisting of about 1:5 CAR T cells to non-transformed T cells, about 1:4 CAR T cells to non-transformed T cells, about 1:3 CAR T cells to non-transformed T cells, about 1:2 CAR T cells to non-transformed T cells, and about 1:1 CAR T cells to non-transformed T cells.

[0873] 248. The method of any of paragraphs 215 to 247, wherein the CAR T cell composition further comprises non-transformed T cells at a ratio of CAR T cells to non-transformed T cells of about 1:1 to about 1:5.

[0874] 249. The method of any of paragraphs 215 to 248, wherein the CAR T cell composition is a mixture of about 10 million CAR T cells and about 40 million non-transformed T cells, further comprising non-transformed T cells.

[0875] 250. The method according to any one of items 215 to 249, wherein the cancer is non-small cell lung cancer.

[0876] 251. The method of any of items 215 to 249, wherein the cancer is ovarian cancer.

[0877] 252. A method for treating cancer, comprising: i) administering to a patient a compound or a pharmaceutically acceptable salt thereof, wherein the compound comprises a small molecule ligand linked to a targeting moiety by a linker, and the compound or a pharmaceutically acceptable salt thereof is administered to the patient weekly; and ii) administering to the patient a CAR T cell composition comprising CAR T cells, wherein the CAR T cells comprise a CAR directed to a targeting moiety. A method comprising:

[0878] 253. The method of paragraph 252, wherein the ligand is selected from the group consisting of folate, DUPA, an NK-1R ligand, a CAIX ligand, a gamma glutamyl transpeptidase ligand, an NKG2D ligand, and a CCK2R ligand.

[0879] 254. The method of either paragraph 252 or 253, wherein the ligand is folic acid.

[0880] 255. The method of any of paragraphs 252 to 254, wherein the targeting moiety is selected from the group consisting of 2,4-dinitrophenol (DNP), 2,4,6-trinitrophenol (TNP), biotin, digoxigenin, fluorescein, fluorescein isothiocyanate (FITC), NHS-fluorescein, pentafluorophenyl ester, tetrafluorophenyl ester, knottin, centyrin, and DARPin.

[0881] 256. The method of any of paragraphs 252 to 255, wherein the targeting moiety is FITC.

[0882] 257. The method of any of paragraphs 252 to 256, wherein the linker comprises polyethylene glycol (PEG), polyproline, a hydrophilic amino acid, a sugar, a non-natural peptidoglycan, polyvinylpyrrolidone, Pluronic F-127, or a combination thereof.

[0883] 258. The method of any of paragraphs 252 to 257, wherein the linker comprises PEG.

[0884] 259. The compound or a pharmaceutically acceptable salt thereof has the formula [ka] wherein B is a small molecule ligand, L is a linker, and T is a targeting moiety, wherein L is a group of the formula [ka] (wherein n is 0 to 200). Item 259. The method according to any one of Items 252 to 258,

[0885] 260. The method of any of paragraphs 252 to 259, wherein the linker comprises PEG and the targeting moiety is FITC or a pharmaceutically acceptable salt thereof.

[0886] 261. The method of any of paragraphs 252 to 260, wherein the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 10 nmole / kg to about 100 nmole / kg of patient body weight.

[0887] 262. The method of any of paragraphs 252 to 261, wherein the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 10 nmole / kg to about 50 nmole / kg of patient body weight.

[0888] 263. The method of any of paragraphs 252 to 262, wherein the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 10 nmole / kg to about 20 nmole / kg of patient body weight.

[0889] 264. The method of any of paragraphs 252 to 263, wherein the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 10 nmole / kg to about 600 nmole / kg of patient body weight.

[0890] 265. The method of any of paragraphs 252 to 264, wherein the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 200 nmole / kg to about 600 nmole / kg of patient body weight.

[0891] 266. The method of any of paragraphs 252 to 265, wherein the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 400 nmole / kg to about 600 nmole / kg of patient body weight.

[0892] 267. The method of any of paragraphs 252 to 266, wherein the CAR T cells are administered at a dose of about 1 million CAR T cells to about 15 million CAR T cells.

[0893] 268. The method of any of paragraphs 252 to 267, wherein the CAR T cells are administered at a dose of about 1 million CAR T cells to about 7 million CAR T cells.

[0894] 269. The method of any of paragraphs 252 to 268, wherein the CAR T cells are administered at a dose of about 1 million CAR T cells to about 5 million CAR T cells.

[0895] 270. The method of any of paragraphs 252 to 269, wherein the CAR T cells are administered at a dose of about 2 million CAR T cells to about 5 million CAR T cells.

[0896] 271. The cancer is lung cancer, bone cancer, pancreatic cancer, skin cancer, head cancer, neck cancer, cutaneous melanoma, intraocular melanoma, uterine cancer, ovarian cancer, endometrial cancer, rectal cancer, stomach cancer, colon cancer, breast cancer, triple-negative breast cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, non-small cell lung cancer, adrenal cancer, soft tissue sarcoma, osteosarcoma, urethral cancer, prostate cancer, chronic leukemia, acute leukemia 271. The method of any of paragraphs 252 to 270, wherein the cancer is selected from the group consisting of hematopoietic leukemia, acute myeloid leukemia, lymphocytic lymphoma, myeloid leukemia, myelomonocytic leukemia, hairy leukemia, pleural mesothelioma, bladder cancer, Burkitt's lymphoma, ureteral cancer, kidney cancer, renal cell carcinoma, renal pelvis cancer, central nervous system (CNS) neoplasms, primary CNS lymphoma, spinal axis tumor, brainstem glioma, pituitary adenoma and esophagogastric junction adenocarcinoma.

[0897] 272. The method of any of paragraphs 252 to 271, wherein the cancer is a folate receptor-expressing cancer.

[0898] 273. The method of any of items 252 to 272, wherein the CAR has a recognition region, which is a single-chain fragment variable (scFv) region of an anti-FITC antibody; the CAR has a costimulatory domain, which is CD137 (4-1BB); and the CAR has an activation signaling domain, which is the T cell CD3ζ chain.

[0899] 274. The method of any of paragraphs 252 to 273, wherein the compound or a pharmaceutically acceptable salt thereof is not an antibody and does not include a fragment of an antibody.

[0900] 275. The method of any of paragraphs 252 to 274, wherein the targeting moiety does not comprise a peptide epitope.

[0901] 276. The method of any of paragraphs 252 to 275, wherein CAR T cell toxicity against cancer occurs without cytokine release resulting in off-target toxicity in the patient.

[0902] 277. The method of any of paragraphs 252 to 275, wherein off-target tissue toxicity does not occur in the patient and CAR T cell toxicity against the cancer occurs.

[0903] 278. The method of any of paragraphs 252 to 275, wherein the cancer comprises a tumor, the tumor size is reduced in the patient, and no off-target toxicity occurs.

[0904] 279. The method of any of paragraphs 252 to 278, wherein the CAR T cells comprise a nucleic acid comprising SEQ ID NO:1.

[0905] 280. The method of any of paragraphs 252 to 278, wherein the CAR T cells comprise a polypeptide comprising SEQ ID NO:2.

[0906] 281. The method of any of paragraphs 252 to 280, wherein the CAR comprises a humanized amino acid sequence.

[0907] 282. The method of any of paragraphs 252 to 280, wherein the CAR consists of a humanized amino acid sequence.

[0908] 283. The method of any of paragraphs 252 to 282, wherein the CAR T cell composition further comprises non-transformed T cells.

[0909] 284. A method of treating cancer, comprising: i) administering to a patient a compound or a pharmaceutically acceptable salt thereof, wherein the compound comprises a small molecule ligand linked to a targeting moiety by a linker, and at least a first dose and a second dose of the compound or a pharmaceutically acceptable salt thereof are administered to the patient, wherein the first dose and the second dose are different, and the second dose of the compound or a pharmaceutically acceptable salt thereof is about 2-fold to about 15,000-fold greater than the first dose of the compound or a pharmaceutically acceptable salt thereof; and ii) administering to the patient a CAR T cell composition comprising CAR T cells, wherein the CAR T cells comprise a CAR directed to a targeting moiety. A method comprising:

[0910] 285. The method of paragraph 284, wherein the first, second, and third doses are different, the second dose of the compound or its pharmaceutically acceptable salt being about 2 to about 750 times greater than the first dose of the compound or its pharmaceutically acceptable salt, and the third dose of the compound or its pharmaceutically acceptable salt being about 800 to about 10,000 times greater than the first dose of the compound or its pharmaceutically acceptable salt, and at least the first, second, and third doses of the compound or its pharmaceutically acceptable salt are administered to the patient.

[0911] 286. The method of paragraph 285, wherein the first dose, second dose, third dose, and fourth dose are different, the second dose of the compound or its pharmaceutically acceptable salt is about 2 to about 750 times greater than the first dose of the compound or its pharmaceutically acceptable salt, the third dose of the compound or its pharmaceutically acceptable salt is about 800 to about 7,500 times greater than the first dose of the compound or its pharmaceutically acceptable salt, and the fourth dose of the compound or its pharmaceutically acceptable salt is about 8,000 to about 15,000 times greater than the first dose of the compound or its pharmaceutically acceptable salt, and at least the first dose, second dose, third dose, and fourth dose of the compound or its pharmaceutically acceptable salt are administered to the patient.

[0912] 287. The method of paragraph 286, wherein the second dose of the compound or its pharmaceutically acceptable salt is about 100 times greater than the first dose of the compound or its pharmaceutically acceptable salt, the third dose of the compound or its pharmaceutically acceptable salt is about 1000 times greater than the first dose of the compound or its pharmaceutically acceptable salt, and the fourth dose of the compound or its pharmaceutically acceptable salt is about 10000 times greater than the first dose of the compound or its pharmaceutically acceptable salt.

[0913] 288. The method of any of paragraphs 284 to 287, wherein the ligand is selected from the group consisting of folic acid, DUPA, an NK-1R ligand, a CAIX ligand, a gamma glutamyl transpeptidase ligand, an NKG2D ligand, and a CCK2R ligand.

[0914] 289. The method of any of paragraphs 284 to 288, wherein the ligand is folic acid.

[0915] 290. The method of any of paragraphs 284 to 289, wherein the targeting moiety is selected from the group consisting of 2,4-dinitrophenol (DNP), 2,4,6-trinitrophenol (TNP), biotin, digoxigenin, fluorescein, fluorescein isothiocyanate (FITC), NHS-fluorescein, pentafluorophenyl ester, tetrafluorophenyl ester, knottin, centyrin, and DARPin.

[0916] 291. The method of any of paragraphs 284 to 290, wherein the targeting moiety is FITC.

[0917] 292. The method of any of paragraphs 284 to 291, wherein the linker comprises polyethylene glycol (PEG), polyproline, a hydrophilic amino acid, a sugar, a non-natural peptidoglycan, polyvinylpyrrolidone, Pluronic F-127, or a combination thereof.

[0918] 293. The method of any of paragraphs 284 to 292, wherein the linker comprises PEG.

[0919] 294. The compound or a pharmaceutically acceptable salt thereof has the formula [ka] wherein B is a small molecule ligand, L is a linker, and T is a targeting moiety, wherein L is a group of the formula [ka] (wherein n is 0 to 200). Item 294. The method according to any one of Items 284 to 293,

[0920] 295. The method of any of paragraphs 284 to 294, wherein the linker comprises PEG and the targeting moiety is FITC or a pharmaceutically acceptable salt thereof.

[0921] 296. The method of any of paragraphs 284 to 295, wherein the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 10 nmole / kg to about 100 nmole / kg of patient body weight.

[0922] 297. The method of any of paragraphs 284 to 296, wherein the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 10 nmole / kg to about 50 nmole / kg of patient body weight.

[0923] 298. The method of any of paragraphs 284 to 297, wherein the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 10 nmole / kg to about 20 nmole / kg of patient body weight.

[0924] 299. The method of any of paragraphs 284 to 298, wherein the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 10 nmole / kg to about 600 nmole / kg of patient body weight.

[0925] 300. The method of any of paragraphs 284 to 299, wherein the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 200 nmole / kg to about 600 nmole / kg of patient body weight.

[0926] 301. The method of any of paragraphs 284 to 300, wherein the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 400 nmole / kg to about 600 nmole / kg of patient body weight.

[0927] 302. The method of any of paragraphs 284 to 301, wherein the CAR T cells are administered at a dose of about 1 million CAR T cells to about 15 million CAR T cells.

[0928] 303. The method of any of paragraphs 284 to 302, wherein the CAR T cells are administered at a dose of about 1 million CAR T cells to about 7 million CAR T cells.

[0929] 304. The method of any of paragraphs 284 to 303, wherein the CAR T cells are administered at a dose of about 1 million CAR T cells to about 5 million CAR T cells.

[0930] 305. The method of any of paragraphs 284 to 304, wherein the CAR T cells are administered at a dose of about 2 million CAR T cells to about 5 million CAR T cells.

[0931] 306. The cancer is lung cancer, bone cancer, pancreatic cancer, skin cancer, head cancer, neck cancer, cutaneous melanoma, intraocular melanoma, uterine cancer, ovarian cancer, endometrial cancer, rectal cancer, stomach cancer, colon cancer, breast cancer, triple-negative breast cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, non-small cell lung cancer, adrenal cancer, soft tissue sarcoma, osteosarcoma, urethral cancer, prostate cancer, chronic leukemia, acute leukemia 306. The method of any of paragraphs 284 to 305, wherein the cancer is selected from the group consisting of hematopoietic leukemia, acute myeloid leukemia, lymphocytic lymphoma, myeloid leukemia, myelomonocytic leukemia, hairy leukemia, pleural mesothelioma, bladder cancer, Burkitt's lymphoma, ureteral cancer, kidney cancer, renal cell carcinoma, renal pelvis cancer, central nervous system (CNS) neoplasms, primary CNS lymphoma, spinal axis tumor, brainstem glioma, pituitary adenoma and esophagogastric junction adenocarcinoma.

[0932] 307. The method of any of paragraphs 284 to 306, wherein the cancer is a folate receptor-expressing cancer.

[0933] 308. The method of any of paragraphs 284 to 307, wherein the CAR has a recognition region, which is a single-chain fragment variable (scFv) region of an anti-FITC antibody; the CAR has a costimulatory domain, which is CD137 (4-1BB); and the CAR has an activation signaling domain, which is a T cell CD3ζ chain.

[0934] 309. The method of any of paragraphs 284 to 308, wherein the compound or a pharmaceutically acceptable salt thereof is not an antibody and does not include a fragment of an antibody.

[0935] 310. The method of any of paragraphs 284 to 309, wherein the targeting moiety does not comprise a peptide epitope.

[0936] 311. The method of any of paragraphs 284 to 310, wherein CAR T cell toxicity against cancer occurs without cytokine release resulting in off-target toxicity in the patient.

[0937] 312. The method of any of paragraphs 284 to 310, wherein off-target tissue toxicity does not occur in the patient and CAR T cell toxicity against the cancer occurs.

[0938] 313. The method of any of paragraphs 284 to 310, wherein the cancer comprises a tumor, the tumor size is reduced in the patient, and no off-target toxicity occurs.

[0939] 314. The method of any of paragraphs 284 to 313, wherein the CAR T cells comprise a nucleic acid comprising SEQ ID NO:1.

[0940] 315. The method of any of paragraphs 284 to 313, wherein the CAR T cells comprise a polypeptide comprising SEQ ID NO:2.

[0941] 316. The method of any of paragraphs 284 to 315, wherein the CAR comprises a humanized amino acid sequence.

[0942] 317. The method of any of paragraphs 284 to 315, wherein the CAR consists of a humanized amino acid sequence.

[0943] 318. The method of any of paragraphs 284 to 317, wherein the CAR T cell composition further comprises non-transformed T cells.

[0944] 319. The method of any of paragraphs 1 to 214 or 252 to 318, wherein the compound or a pharmaceutically acceptable salt thereof is continuously administered to a patient, and further comprising a step of terminating the continuous administration of the compound or a pharmaceutically acceptable salt thereof to inhibit or prevent cytokine release syndrome in the patient.

[0945] 320. The method of any of paragraphs 1-107 or 183-318, further comprising administering to the patient folic acid, a conjugate comprising folic acid (wherein the conjugate comprising folic acid does not comprise a targeting moiety), or an agent that inhibits CAR T cell activation.

[0946] 321. The method of any of items 1 to 182 or 215 to 318, wherein the compound or a pharmaceutically acceptable salt thereof is administered in an amount of about 10 nmole / kg to about 2500 nmole / kg of patient body weight, and the CAR T cells are administered in an amount of about 1 million to about 15 million CAR T cells.

[0947] 322. The method of any of paragraphs 1-251 or 284-318, wherein the compound or a pharmaceutically acceptable salt thereof is administered to the patient once a week.

[0948] 323. The method of any of items 1 to 283, wherein at least a first dose and a second dose of a compound or a pharmaceutically acceptable salt thereof are administered to a patient, the first dose and the second dose being different, and the second dose of the compound or a pharmaceutically acceptable salt thereof being about 2 to about 15,000 times greater than the first dose of the compound or a pharmaceutically acceptable salt thereof.

[0949] 324. The method of any of paragraphs 56 to 318, wherein the CAR T cell composition is administered at least twice.

[0950] 325. A method for treating cancer, comprising: i) administering to a patient a first dose of a compound or a pharmaceutically acceptable salt thereof, wherein the compound comprises a small molecule ligand linked to a targeting moiety by a linker; ii) administering to the patient at least a second dose of the compound or pharmaceutically acceptable salt thereof, wherein the second dose of the compound or pharmaceutically acceptable salt thereof is at least about 50 percent less than the first dose of the compound or pharmaceutically acceptable salt thereof; and iii) administering to the patient a CAR T cell composition comprising a single CAR T cell, the CAR T cell comprising a CAR directed to a targeting moiety. A method comprising:

[0951] 326. The method of paragraph 325, wherein the second dose of the compound or pharmaceutically acceptable salt thereof is at least about 60 percent less than the first dose of the compound or pharmaceutically acceptable salt thereof.

[0952] 327. The method of paragraph 325, wherein the second dose of the compound or pharmaceutically acceptable salt thereof is at least about 70 percent less than the first dose of the compound or pharmaceutically acceptable salt thereof.

[0953] 328. The method of paragraph 325, wherein the second dose of the compound or pharmaceutically acceptable salt thereof is at least about 80 percent less than the first dose of the compound or pharmaceutically acceptable salt thereof.

[0954] 329. The method of paragraph 325, wherein the second dose of the compound or pharmaceutically acceptable salt thereof is at least about 90 percent less than the first dose of the compound or pharmaceutically acceptable salt thereof.

[0955] 330. The method of paragraph 325, wherein the second dose of the compound or pharmaceutically acceptable salt thereof is at least about 95 percent less than the first dose of the compound or pharmaceutically acceptable salt thereof.

[0956] 331. The method of paragraph 325, wherein the second dose of the compound or pharmaceutically acceptable salt thereof is at least about 96 percent less than the first dose of the compound or pharmaceutically acceptable salt thereof.

[0957] 332. The method of paragraph 325, wherein the second dose of the compound or pharmaceutically acceptable salt thereof is at least about 97 percent less than the first dose of the compound or pharmaceutically acceptable salt thereof.

[0958] 333. The method of paragraph 325, wherein the second dose of the compound or pharmaceutically acceptable salt thereof is at least about 98 percent less than the first dose of the compound or pharmaceutically acceptable salt thereof.

[0959] 334. The method of paragraph 325, wherein the second dose of the compound or pharmaceutically acceptable salt thereof is at least about 99 percent less than the first dose of the compound or pharmaceutically acceptable salt thereof.

[0960] 335. The method of paragraph 325, wherein the second dose of the compound or pharmaceutically acceptable salt thereof is at least about 99.5 percent less than the first dose of the compound or pharmaceutically acceptable salt thereof.

[0961] 336. The method according to any one of items 325 to 335, wherein the first dose of the compound or a pharmaceutically acceptable salt thereof is about 100 nmole / kg to about 1000 nmole / kg of patient body weight.

[0962] 337. The method according to any one of items 325 to 335, wherein the first dose of the compound or a pharmaceutically acceptable salt thereof is about 100 nmole / kg to about 900 nmole / kg of patient body weight.

[0963] 338. The method according to any one of items 325 to 335, wherein the first dose of the compound or a pharmaceutically acceptable salt thereof is about 100 nmole / kg to about 800 nmole / kg of patient body weight.

[0964] 339. The method according to any one of items 325 to 335, wherein the first dose of the compound or a pharmaceutically acceptable salt thereof is about 100 nmole / kg to about 700 nmole / kg of patient body weight.

[0965] 340. The method according to any one of items 325 to 335, wherein the first dose of the compound or a pharmaceutically acceptable salt thereof is about 100 nmole / kg to about 600 nmole / kg of patient body weight.

[0966] 341. The method according to any one of items 325 to 335, wherein the first dose of the compound or a pharmaceutically acceptable salt thereof is about 200 nmole / kg to about 600 nmole / kg of patient body weight.

[0967] 342. The method according to any one of items 325 to 335, wherein the first dose of the compound or a pharmaceutically acceptable salt thereof is about 400 nmole / kg to about 600 nmole / kg of patient body weight.

[0968] 343. The method of any of paragraphs 325 to 335, wherein the first dose of the compound or a pharmaceutically acceptable salt thereof is about 500 nmole / kg of patient body weight.

[0969] 344. The method of paragraph 336, wherein the second dose of the compound or a pharmaceutically acceptable salt thereof is about 0.5 nmole / kg to about 500 nmole / kg of patient body weight.

[0970] 345. The method of paragraph 337, wherein the second dose of the compound or a pharmaceutically acceptable salt thereof is about 0.5 nmole / kg to about 450 nmole / kg of patient body weight.

[0971] 346. The method of paragraph 338, wherein the second dose of the compound or a pharmaceutically acceptable salt thereof is about 0.5 nmole / kg to about 400 nmole / kg of patient body weight.

[0972] 347. The method according to paragraph 339, wherein the second dose of the compound or a pharmaceutically acceptable salt thereof is about 0.5 nmole / kg to about 350 nmole / kg of patient body weight.

[0973] 348. The method according to paragraph 340, wherein the second dose of the compound or a pharmaceutically acceptable salt thereof is about 0.5 nmole / kg to about 300 nmole / kg of patient body weight.

[0974] 349. The method according to paragraph 341, wherein the second dose of the compound or a pharmaceutically acceptable salt thereof is about 1 nmole / kg to about 300 nmole / kg of patient body weight.

[0975] 350. The method of paragraph 342, wherein the second dose of the compound or a pharmaceutically acceptable salt thereof is about 2 nmole / kg to about 300 nmole / kg of patient body weight.

[0976] 351. The method according to paragraph 343, wherein the second dose of the compound or a pharmaceutically acceptable salt thereof is about 2 nmole / kg to about 250 nmole / kg of patient body weight.

[0977] 352. The method of any of paragraphs 336 to 343, wherein the second dose of the compound or a pharmaceutically acceptable salt thereof is about 5 nmole / kg to about 40 nmole / kg of patient body weight.

[0978] 353. The method of any of paragraphs 336 to 343, wherein the second dose of the compound or a pharmaceutically acceptable salt thereof is about 40 nmole / kg to about 150 nmole / kg of patient body weight.

[0979] 354. The method of any of items 325 to 353, further comprising administering a third dose of the compound or a pharmaceutically acceptable salt thereof, wherein the third dose of the compound or a pharmaceutically acceptable salt thereof is the same as the second dose of the compound or a pharmaceutically acceptable salt thereof.

[0980] 355. The method of paragraph 354, further comprising administering a fourth dose of the compound or its pharmaceutically acceptable salt, wherein the fourth dose of the compound or its pharmaceutically acceptable salt is the same as the second dose of the compound or its pharmaceutically acceptable salt and the third dose of the compound or its pharmaceutically acceptable salt.

[0981] 356. The method of any of items 325 to 355, wherein a dose of the compound or a pharmaceutically acceptable salt thereof administered after the first administration of the compound or a pharmaceutically acceptable salt thereof maintains the inhibition of cancer growth compared to the first administration of the compound or a pharmaceutically acceptable salt thereof.

[0982] 357. The method of any of paragraphs 325 to 356, wherein the CAR T cells are administered at a dose of about 1 million CAR T cells to about 40 million CAR T cells.

[0983] 358. The method of any of paragraphs 325 to 357, wherein the dose of the compound or pharmaceutically acceptable salt thereof administered after the first administration of the compound or pharmaceutically acceptable salt thereof is administered once weekly.

[0984] 359. The method of any of paragraphs 325 to 357, wherein the dose of the compound or a pharmaceutically acceptable salt thereof is administered twice weekly.

[0985] 360. The method of any of paragraphs 325 to 359, wherein the ligand is selected from the group consisting of folic acid, DUPA, an NK-1R ligand, a CAIX ligand, a gamma glutamyl transpeptidase ligand, an NKG2D ligand, and a CCK2R ligand.

[0986] 361. The method of any of paragraphs 325 to 360, wherein the ligand is folic acid.

[0987] 362. The method of any of paragraphs 325 to 360, wherein the ligand is an NK-1R ligand.

[0988] 363. The method of any of paragraphs 325 to 360, wherein the ligand is DUPA.

[0989] 364. The method of any of paragraphs 325 to 360, wherein the ligand is a CCK2R ligand.

[0990] 365. The method of any of paragraphs 325 to 360, wherein the ligand is a gamma glutamyl transpeptidase ligand.

[0991] 366. The method of any of paragraphs 325 to 365, wherein the targeting moiety is selected from the group consisting of 2,4-dinitrophenol (DNP), 2,4,6-trinitrophenol (TNP), biotin, digoxigenin, fluorescein, fluorescein isothiocyanate (FITC), NHS-fluorescein, pentafluorophenyl ester, tetrafluorophenyl ester, knottin, centyrin, and DARPin.

[0992] 367. The method of any of paragraphs 325-366, wherein the targeting moiety is FITC.

[0993] 368. The method of any of paragraphs 325-366, wherein the targeting moiety is DNP.

[0994] 369. The method of any of paragraphs 325-366, wherein the targeting moiety is TNP.

[0995] 370. The method of any of paragraphs 325 to 369, wherein the linker comprises polyethylene glycol (PEG), polyproline, a hydrophilic amino acid, a sugar, a non-natural peptidoglycan, polyvinylpyrrolidone, Pluronic F-127, or a combination thereof.

[0996] 371. The method of any of paragraphs 325 to 370, wherein the linker comprises PEG.

[0997] 372. The compound or a pharmaceutically acceptable salt thereof has the formula [ka] wherein B is a small molecule ligand, L is a linker, and T is a targeting moiety, wherein L is a group of the formula [ka] (wherein n is 0 to 200). Item 372. The method according to any one of Items 325 to 371,

[0998] 373. The method of claim 372, wherein n is an integer from 0 to 150.

[0999] 374. The method of claim 372, wherein n is an integer from 0 to 110.

[1000] 375. The method of claim 372, wherein n is an integer from 0 to 20.

[1001] 376. The method of claim 372, wherein n is an integer between 15 and 20.

[1002] 377. The method of claim 372, wherein n is an integer between 15 and 110.

[1003] 378. The method of any of paragraphs 325-367 or 370-377, wherein the linker comprises PEG and the targeting moiety is FITC or a pharmaceutically acceptable salt thereof.

[1004] 379. The cancer is lung cancer, bone cancer, pancreatic cancer, skin cancer, head cancer, neck cancer, cutaneous melanoma, intraocular melanoma, uterine cancer, ovarian cancer, endometrial cancer, rectal cancer, stomach cancer, colon cancer, breast cancer, triple-negative breast cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, non-small cell lung cancer, adrenal cancer, soft tissue sarcoma, osteosarcoma, urethral cancer, prostate cancer, chronic leukemia, acute leukemia 379. The method of any of paragraphs 325 to 378, wherein the cancer is selected from the group consisting of hematopoietic leukemia, acute myeloid leukemia, lymphocytic lymphoma, myeloid leukemia, myelomonocytic leukemia, hairy leukemia, pleural mesothelioma, bladder cancer, Burkitt's lymphoma, ureteral cancer, kidney cancer, renal cell carcinoma, renal pelvis cancer, central nervous system (CNS) neoplasms, primary CNS lymphoma, spinal axis tumor, brainstem glioma, pituitary adenoma and gastroesophageal junction adenocarcinoma.

[1005] 380. The method of any of paragraphs 325 to 361 or 366 to 379, wherein the cancer is a folate receptor-expressing cancer.

[1006] 381. The method of paragraph 380, wherein the cancer is endometrial cancer.

[1007] 382. The method of paragraph 380, wherein the cancer is non-small cell lung cancer.

[1008] 383. The method of paragraph 380, wherein the cancer is ovarian cancer.

[1009] 384. The method of paragraph 380, wherein the cancer is triple-negative breast cancer.

[1010] 385. The method of any of paragraphs 325 to 384, wherein the CAR has a recognition region, and the recognition region is a single-chain fragment variable (scFv) region of an antibody.

[1011] 386. The method of any of paragraphs 325 to 367 or 370 to 385, wherein the CAR has a recognition region, and the recognition region of the CAR is a single-chain fragment variable (scFv) region of an anti-FITC antibody.

[1012] 387. The method of any of paragraphs 325-386, wherein the CAR has a costimulatory domain, and the costimulatory domain is selected from the group consisting of CD28, CD137 (4-1BB), CD134 (OX40), and CD278 (ICOS).

[1013] 388. The method of any of paragraphs 325 to 387, wherein the CAR has an activation signaling domain, and the activation signaling domain is T cell CD3 zeta chain or Fc receptor γ.

[1014] 389. The method of any of paragraphs 325 to 367 or 370 to 388, wherein the CAR has a recognition region, which is a single-chain fragment variable (scFv) region of an anti-FITC antibody; the CAR has a costimulatory domain, which is CD137 (4-1BB); and the CAR has an activation signaling domain, which is a T cell CD3 zeta chain.

[1015] 390. The method of any of paragraphs 325 to 389, wherein multiple doses of the CAR T cell composition are administered.

[1016] 391. The method of any of paragraphs 325 to 390, wherein the patient is imaged prior to administration of the compound or a pharmaceutically acceptable salt thereof or prior to administration of the CAR T cell composition.

[1017] 392. The method of any of paragraphs 325 to 391, wherein the compound or a pharmaceutically acceptable salt thereof is not an antibody and does not include a fragment of an antibody.

[1018] 393. The method of any of paragraphs 325 to 392, wherein the targeting moiety does not comprise a peptide epitope.

[1019] 394. The method of any of paragraphs 325 to 393, wherein CAR T cell toxicity against cancer occurs without cytokine release resulting in off-target toxicity in the patient.

[1020] 395. The method of any of paragraphs 325 to 393, wherein off-target tissue toxicity does not occur in the patient and CAR T cell toxicity against the cancer occurs.

[1021] 396. The method of any of paragraphs 325 to 393, wherein the cancer comprises a tumor, the tumor size is reduced in the patient, and no off-target toxicity occurs.

[1022] 397. The method of any of paragraphs 325 to 398, wherein the CAR T cells comprise a nucleic acid comprising SEQ ID NO:1.

[1023] 398. The method of any of paragraphs 325 to 397, wherein the CAR T cells comprise a polypeptide comprising SEQ ID NO:2.

[1024] 399. The method of paragraph 397, wherein the nucleic acid encodes a chimeric antigen receptor.

[1025] 400. The method of any of paragraphs 325 to 399, wherein the CAR comprises a humanized amino acid sequence.

[1026] 401. The method of any of paragraphs 325 to 399, wherein the CAR consists of a humanized amino acid sequence.

[1027] 402. The method of any of paragraphs 325 to 401, further comprising administering to the patient folic acid, a conjugate comprising folic acid (wherein the conjugate comprising folic acid does not comprise a targeting moiety), or an agent that inhibits CAR T cell activation.

[1028] 403. The method of paragraph 402, wherein an agent that inhibits activation of the CAR T cells is administered to the patient, the agent being an agent that blocks binding of the CAR T cells to the compound or a pharmaceutically acceptable salt thereof but does not bind to the cancer.

[1029] 404. The method of paragraph 403, wherein the agent is fluoresceinamine, sodium fluorescein, or fluorescein.

[1030] 405. The method of paragraph 404, wherein the agent is sodium fluorescein.

[1031] 406. A method for treating cancer, comprising: i) administering to the patient a first dose of a compound or a pharmaceutically acceptable salt thereof, wherein the compound comprises a small molecule ligand linked to a targeting moiety by a linker, and the compound or the pharmaceutically acceptable salt thereof is administered to the patient at least about 1 hour prior to administration of a CAR T cell composition comprising CAR T cells, the CAR T cells comprising a CAR directed to the targeting moiety; ii) then administering to the patient a dose of the CAR T cell composition; and iii) then administering to the patient a second dose of the compound or a pharmaceutically acceptable salt thereof. A method comprising:

[1032] 407. The method of paragraph 406, wherein the first dose of the compound or a pharmaceutically acceptable salt thereof is administered to the patient at least about 2 hours before administration of the CAR T cell composition.

[1033] 408. The method of paragraph 406, wherein the first dose of the compound or a pharmaceutically acceptable salt thereof is administered to the patient at least about 4 hours before administration of the CAR T cell composition.

[1034] 409. The method of paragraph 406, wherein the first dose of the compound or a pharmaceutically acceptable salt thereof is administered to the patient at least about 8 hours before administration of the CAR T cell composition.

[1035] 410. The method of paragraph 406, wherein the first dose of the compound or a pharmaceutically acceptable salt thereof is administered to the patient at least about 12 hours before administration of the CAR T cell composition.

[1036] 411. The method of paragraph 406, wherein the first dose of the compound or a pharmaceutically acceptable salt thereof is administered to the patient at least about 16 hours before administration of the CAR T cell composition.

[1037] 412. The method of paragraph 406, wherein a first dose of the compound or a pharmaceutically acceptable salt thereof is administered to the patient at least about 20 hours before administration of the CAR T cell composition.

[1038] 413. The method of paragraph 406, wherein a first dose of the compound or a pharmaceutically acceptable salt thereof is administered to the patient at least about 24 hours before administration of the CAR T cell composition.

[1039] 414. The method of any of paragraphs 406 to 413, wherein a second dose of the compound or a pharmaceutically acceptable salt thereof is administered to the patient no later than about 24 hours after administration of the CAR T cell composition.

[1040] 415. The method of any of paragraphs 406 to 413, wherein a second dose of the compound or a pharmaceutically acceptable salt thereof is administered to the patient no later than about 16 hours after administration of the CAR T cell composition.

[1041] 416. The method of any of paragraphs 406 to 413, wherein a second dose of the compound or a pharmaceutically acceptable salt thereof is administered to the patient no later than about 12 hours after administration of the CAR T cell composition.

[1042] 417. The method of any of paragraphs 406 to 413, wherein a second dose of the compound or a pharmaceutically acceptable salt thereof is administered to the patient no later than about 8 hours after administration of the CAR T cell composition.

[1043] 418. The method of any of paragraphs 406 to 413, wherein a second dose of the compound or a pharmaceutically acceptable salt thereof is administered to the patient no later than about 4 hours after administration of the CAR T cell composition.

[1044] 419. The method of any of paragraphs 406 to 418, wherein CAR T cell toxicity against cancer occurs without cytokine release resulting in off-target toxicity in the patient.

[1045] 420. The method of any of paragraphs 406 to 418, wherein off-target tissue toxicity does not occur in the patient and CAR T cell toxicity against the cancer occurs.

[1046] 421. The method of any of paragraphs 406 to 418, wherein the cancer comprises a tumor, the tumor size is reduced in the patient, and no off-target toxicity occurs.

[1047] 422. The method of any of paragraphs 406 to 418, wherein the cancer comprises a tumor and the reduction in tumor size in the patient is greater than in a patient who has not been pretreated with the compound or a pharmaceutically acceptable salt thereof prior to administration of the CAR T cell composition.

[1048] 423. The method of any of paragraphs 406 to 422, wherein the ligand is selected from the group consisting of folic acid, DUPA, NK-1R ligands, CAIX ligands, gamma glutamyl transpeptidase ligands, NKG2D ligands, and CCK2R ligands.

[1049] 424. The method of any of paragraphs 406 to 423, wherein the ligand is folic acid.

[1050] 425. The method of any of paragraphs 406 to 423, wherein the ligand is an NK-1R ligand.

[1051] 426. The method of any of paragraphs 406 to 423, wherein the ligand is DUPA.

[1052] 427. The method of any of paragraphs 406 to 423, wherein the ligand is a CCK2R ligand.

[1053] 428. The method of any of paragraphs 406 to 423, wherein the ligand is a gamma glutamyl transpeptidase ligand.

[1054] 429. The method of any of paragraphs 406 to 428, wherein the targeting moiety is selected from the group consisting of 2,4-dinitrophenol (DNP), 2,4,6-trinitrophenol (TNP), biotin, digoxigenin, fluorescein, fluorescein isothiocyanate (FITC), NHS-fluorescein, pentafluorophenyl ester, tetrafluorophenyl ester, knottin, centyrin, and DARPin.

[1055] 430. The method of any of paragraphs 406 to 429, wherein the targeting moiety is FITC.

[1056] 431. The method of any of paragraphs 406-429, wherein the targeting moiety is DNP.

[1057] 432. The method of any of paragraphs 406-429, wherein the targeting moiety is TNP.

[1058] 433. The method of any of paragraphs 406 to 432, wherein the linker comprises polyethylene glycol (PEG), polyproline, a hydrophilic amino acid, a sugar, a non-natural peptidoglycan, polyvinylpyrrolidone, Pluronic F-127, or a combination thereof.

[1059] 434. The method of any of paragraphs 406 to 433, wherein the linker comprises PEG.

[1060] 435. The compound or a pharmaceutically acceptable salt thereof has the formula [ka] wherein B is a small molecule ligand, L is a linker, and T is a targeting moiety, wherein L is a group of the formula [ka] (wherein n is 0 to 200). Item 406 to 434, the method of any one of Items 406 to 434.

[1061] 436. The method of claim 435, wherein n is an integer from 0 to 150.

[1062] 437. The method of claim 435, wherein n is an integer from 0 to 110.

[1063] 438. The method of claim 435, wherein n is an integer from 0 to 20.

[1064] 439. The method of claim 435, wherein n is an integer between 15 and 20.

[1065] 440. The method of claim 435, wherein n is an integer between 15 and 110.

[1066] 441. The method of any of paragraphs 406-430 or 433-440, wherein the linker comprises PEG and the targeting moiety is FITC or a pharmaceutically acceptable salt thereof.

[1067] 442. The method of any of paragraphs 406 to 441, wherein the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 10 nmole / kg to about 10,000 nmole / kg of patient body weight.

[1068] 443. The method of any of paragraphs 406 to 441, wherein the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 10 nmole / kg to about 5000 nmole / kg of patient body weight.

[1069] 444. The method of any of paragraphs 406 to 441, wherein the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 10 nmole / kg to about 1000 nmole / kg of patient body weight.

[1070] 445. The method of any of paragraphs 406 to 441, wherein the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 10 nmole / kg to about 600 nmole / kg of patient body weight.

[1071] 446. The method of any of paragraphs 406 to 441, wherein the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 200 nmole / kg to about 600 nmole / kg of patient body weight.

[1072] 447. The method of any of paragraphs 406 to 441, wherein the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 250 nmole / kg to about 600 nmole / kg of patient body weight.

[1073] 448. The cancer is lung cancer, bone cancer, pancreatic cancer, skin cancer, head cancer, neck cancer, cutaneous melanoma, intraocular melanoma, uterine cancer, ovarian cancer, endometrial cancer, rectal cancer, stomach cancer, colon cancer, breast cancer, triple-negative breast cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, non-small cell lung cancer, adrenal cancer, soft tissue sarcoma, osteosarcoma, urethral cancer, prostate cancer, chronic leukemia, acute leukemia 448. The method of any of paragraphs 406 to 447, wherein the cancer is selected from the group consisting of hematopoietic leukemia, acute myeloid leukemia, lymphocytic lymphoma, myeloid leukemia, myelomonocytic leukemia, hairy leukemia, pleural mesothelioma, bladder cancer, Burkitt's lymphoma, ureteral cancer, kidney cancer, renal cell carcinoma, renal pelvis cancer, central nervous system (CNS) neoplasms, primary CNS lymphoma, spinal axis tumor, brainstem glioma, pituitary adenoma and esophagogastric junction adenocarcinoma.

[1074] 449. The method of any of paragraphs 406 to 424 or 429 to 448, wherein the cancer is a folate receptor-expressing cancer.

[1075] 450. The method of paragraph 448, wherein the cancer is endometrial cancer.

[1076] 451. The method of paragraph 448, wherein the cancer is non-small cell lung cancer.

[1077] 452. The method of paragraph 448, wherein the cancer is ovarian cancer.

[1078] 453. The method of paragraph 448, wherein the cancer is triple-negative breast cancer.

[1079] 454. The method of any of paragraphs 406 to 453, wherein the CAR has a recognition region, and the recognition region is a single-chain fragment variable (scFv) region of an antibody.

[1080] 455. The method of any of paragraphs 406 to 430 or 433 to 454, wherein the CAR has a recognition region, and the recognition region of the CAR is a single-chain fragment variable (scFv) region of an anti-FITC antibody.

[1081] 456. The method of any of paragraphs 406 to 455, wherein the CAR has a costimulatory domain, and the costimulatory domain is selected from the group consisting of CD28, CD137 (4-1BB), CD134 (OX40), and CD278 (ICOS).

[1082] 457. The method of any of paragraphs 406 to 456, wherein the CAR has an activation signaling domain, and the activation signaling domain is T cell CD3 zeta chain or Fc receptor γ.

[1083] 458. The method of any of paragraphs 406 to 430 or 433 to 457, wherein the CAR has a recognition region, which is a single-chain fragment variable (scFv) region of an anti-FITC antibody; the CAR has a costimulatory domain, which is CD137 (4-1BB); and the CAR has an activation signaling domain, which is a T cell CD3 zeta chain.

[1084] 459. The method of any of paragraphs 406 to 458, wherein multiple doses of the CAR T cell composition are administered.

[1085] 460. The method of any of paragraphs 406 to 459, wherein the patient is imaged prior to administration of the compound or a pharmaceutically acceptable salt thereof.

[1086] 461. The method of any of paragraphs 406 to 460, wherein the compound or a pharmaceutically acceptable salt thereof is not an antibody and does not include an antibody fragment.

[1087] 462. The method of any of paragraphs 406 to 461, wherein the targeting moiety does not comprise a peptide epitope.

[1088] 463. The method of any of paragraphs 406 to 462, wherein the CAR T cells comprise a nucleic acid comprising SEQ ID NO:1.

[1089] 464. The method of any of paragraphs 406 to 463, wherein the CAR T cells comprise a polypeptide comprising SEQ ID NO:2.

[1090] 465. The method of paragraph 463, wherein the nucleic acid encodes a chimeric antigen receptor.

[1091] 466. The method of any of paragraphs 406 to 465, wherein the CAR comprises a humanized amino acid sequence.

[1092] 467. The method of any of paragraphs 406 to 465, wherein the CAR consists of a humanized amino acid sequence.

[1093] 468. The method of any of paragraphs 108 to 182, wherein the patient is administered one or more doses of folic acid, a conjugate comprising folic acid (wherein the conjugate comprising folic acid does not comprise a targeting moiety), or an agent that inhibits CAR T cell activation.

[1094] 469. The method of any of paragraphs 108 to 182, wherein the folic acid, a conjugate comprising folic acid (wherein the conjugate comprising folic acid does not comprise a targeting moiety), or an agent that inhibits CAR T cell activation is administered to the patient before and / or after the compound or a pharmaceutically acceptable salt thereof.

[1095] 470. The method of any of paragraphs 108 to 182, wherein administration of the folic acid, a conjugate comprising folic acid (wherein the conjugate comprising folic acid does not comprise a targeting moiety), or an agent that inhibits CAR T cell activation reduces cytokine levels in the patient.

[1096] 471. The method of paragraph 470, wherein the reduction in cytokine levels occurs about 3 hours after administering to the patient folic acid, a conjugate comprising folic acid (wherein the conjugate comprising folic acid does not comprise a targeting moiety), or an agent that inhibits CAR T cell activation.

[1097] 472. The method of paragraph 470, wherein the reduction in cytokine levels occurs about 6 hours after administering to the patient folic acid, a conjugate comprising folic acid (wherein the conjugate comprising folic acid does not comprise a targeting moiety), or an agent that inhibits CAR T cell activation.

[1098] 473. The method of paragraph 470, wherein the reduction in cytokine levels is relative to the cytokine levels in an untreated patient.

[1099] 474. The method of any of paragraphs 108 to 182, wherein the compound or a pharmaceutically acceptable salt thereof is administered before and after administration of the folic acid, a conjugate comprising folic acid (wherein the conjugate comprising folic acid does not comprise a targeting moiety), or an agent that inhibits CAR T cell activation.

[1100] 475. The method of any of paragraphs 108 to 182, wherein after administration of the folic acid, a conjugate comprising folic acid (wherein the conjugate comprising folic acid does not comprise a targeting moiety), or an agent that inhibits CAR T cell activation, the number of CAR T cells in the patient's blood increases, even if cytokine levels in the patient decrease.

[1101] 476. The method of any of paragraphs 108 to 182, wherein CAR T cell activation is enhanced or maintained relative to a patient not treated with a rescue agent after administration of the folic acid, a conjugate comprising folic acid (wherein the conjugate comprising folic acid does not comprise a targeting moiety), or an agent that inhibits CAR T cell activation, even though cytokine levels in the treated patient are reduced.

[1102] 477. The method of any of paragraphs 108 to 182, wherein the cancer comprises a tumor and the tumor size in the patient does not increase upon administration of the folic acid, a conjugate comprising folic acid (wherein the conjugate comprising folic acid does not comprise a targeting moiety), or an agent that inhibits activation of CAR T cells to the patient.

[1103] 478. The method of paragraph 477, wherein a complete response to the tumor is obtained.

[1104] 479. The method of any of paragraphs 108, 115 to 160, 168 to 182 and 468 to 478, wherein when CRS grade reaches 1, 2, 3 or 4, the patient is administered a drug that inhibits the activation of the CAR T cells.

[1105] 480. The method of any of items 108, 115 to 160, 168 to 182 and 468 to 478, wherein when CRS grade reaches 3 or 4, the patient is administered a drug that inhibits the activation of the CAR T cells.

[1106] 481. A method according to any one of paragraphs 108 to 182 and 468 to 480, in which pulmonary edema is reduced.

[1107] 482. The method of any of paragraphs 108, 115 to 160, 168 to 182, and 468 to 481, wherein the agent that inhibits CAR T cell activation is administered at a dose of about 0.01 to about 300 μmole / kg of patient body weight.

[1108] 483. The method of any of paragraphs 108, 115 to 160, 168 to 182, and 468 to 481, wherein the agent that inhibits CAR T cell activation is administered at a dose of about 0.06 to about 100 μmole / kg of patient body weight.

[1109] 484. The method of any of paragraphs 108, 115 to 160, 168 to 182, and 468 to 481, wherein the agent that inhibits CAR T cell activation is administered at a dose of about 0.06 to about 90 μmole / kg of patient body weight.

[1110] 485. The method of any of paragraphs 108, 115 to 160, 168 to 182, and 468 to 481, wherein the agent that inhibits CAR T cell activation is administered at a dose of about 0.06 to about 80 μmole / kg of patient body weight.

[1111] 486. The method of any of paragraphs 108, 115 to 160, 168 to 182, and 468 to 481, wherein the agent that inhibits CAR T cell activation is administered at a dose of about 0.06 to about 70 μmole / kg of patient body weight.

[1112] 487. The method of any of paragraphs 108, 115 to 160, 168 to 182, and 468 to 481, wherein the agent that inhibits CAR T cell activation is administered at a dose of about 0.06 to about 60 μmole / kg of patient body weight.

[1113] 488. The method of any of paragraphs 108, 115 to 160, 168 to 182, and 468 to 481, wherein the agent that inhibits CAR T cell activation is administered at a dose of about 0.06 to about 50 μmole / kg of patient body weight.

[1114] 489. The method of any of paragraphs 108, 115 to 160, 168 to 182, and 468 to 481, wherein the agent that inhibits CAR T cell activation is administered at a dose of about 0.06 to about 40 μmole / kg of patient body weight.

[1115] 490. The method of any of paragraphs 108, 115 to 160, 168 to 182, and 468 to 481, wherein the agent that inhibits CAR T cell activation is administered at a dose of about 0.06 to about 30 μmole / kg of patient body weight.

[1116] 491. The method of any of paragraphs 108, 115 to 160, 168 to 182, and 468 to 481, wherein the agent that inhibits CAR T cell activation is administered at a dose of about 0.06 to about 20 μmole / kg of patient body weight.

[1117] 492. The method of any of paragraphs 108, 115 to 160, 168 to 182, and 468 to 481, wherein the agent that inhibits CAR T cell activation is administered at a dose of about 0.06 to about 10 μmole / kg of patient body weight.

[1118] 493. The method of any of paragraphs 108, 115 to 160, 168 to 182, and 468 to 481, wherein the agent that inhibits CAR T cell activation is administered at a dose of about 0.06 to about 8 μmole / kg of patient body weight.

[1119] 494. The method of any of paragraphs 108, 115 to 160, 168 to 182, and 468 to 481, wherein the agent that inhibits CAR T cell activation is administered at a dose of about 0.06 to about 6 μmole / kg of patient body weight.

[1120] 495. The method of any of paragraphs 108, 115-160, 168-181 and 468-494, wherein an agent that inhibits activation of the CAR T cells is administered to the patient, and the agent is sodium fluorescein.

[1121] 496. A method according to any of paragraphs 1 to 495, wherein CRS is reduced or prevented, resulting in a reduction in tumor volume in the patient.

[1122] 497. A method according to any one of paragraphs 1 to 496, in which weight loss due to CRS is reduced or prevented.

[1123] 498. The method according to any one of items 1 to 3, 8 to 28, 33 to 58, 63 to 83, 88 to 136, 141 to 249, 252 to 361, 366 to 380, 385 to 424, 429 to 449, and 454 to 497, wherein the cancer is acute myeloid leukemia.

[1124] 499. The method of paragraph 498, wherein the cancer expresses folate receptor-β.

[1125] 500. The method of paragraph 498 or 499, wherein the CAR-T cells have a central memory / effector memory phenotype.

[1126] 501. The method of any of paragraphs 1 to 500, wherein the CD8:CD4 ratio of the CAR T cells is about 1:1.

[1127] 502. The method of any of paragraphs 215 to 251, further comprising step iv) of readministering the compound or a pharmaceutically acceptable salt thereof to the patient.

[1128] 503. The method of paragraph 474, wherein subsequent administration of the compound or a pharmaceutically acceptable salt thereof results in CAR T cell activation and cytokine levels in the patient.

[1129] 504. The method of any of paragraphs 1-107, 183-476, or 479-503, wherein the cancer comprises a tumor and a complete response to the tumor is obtained.

[1130] 505. A method for treating cancer, comprising: i) administering to a patient a compound or a pharmaceutically acceptable salt thereof, wherein the compound comprises a small molecule ligand linked to a targeting moiety by a linker; and ii) administering to the patient a CAR T cell composition, wherein the CAR T cell composition comprises CAR T cells, and the CAR T cells comprise a CAR directed to a targeting moiety; and wherein the small molecule ligand is a PSMA ligand and the targeting moiety is FITC. A method comprising:

[1131] 506. A small molecule ligand linked to a targeting moiety by said linker having the formula [ka] Item 505. The method of claim 505, comprising:

[1132] 507. A method for treating cancer, comprising: i) administering to a patient a compound or a pharmaceutically acceptable salt thereof, wherein the compound comprises a small molecule ligand linked to a targeting moiety by a linker; and ii) administering to the patient a CAR T cell composition, wherein the CAR T cell composition comprises CAR T cells, and wherein the CAR T cells comprise a CAR directed to a targeting moiety; and wherein the small molecule ligand is a CAIX ligand and the targeting moiety is FITC. A method comprising:

[1133] 508. A small molecule ligand linked to a targeting moiety by said linker having the formula [ka] Item 507, the method of claim 507, comprising:

[1134] 509. A method for treating cancer, comprising: i) administering to a patient a first compound or a pharmaceutically acceptable salt thereof, wherein the first compound or a pharmaceutically acceptable salt thereof comprises a PSMA ligand linked to FITC by a linker; ii) administering to the patient a second compound or a pharmaceutically acceptable salt thereof, wherein the second compound or a pharmaceutically acceptable salt thereof comprises a CAIX ligand linked to FITC by a linker; and iii) administering to the patient a CAR T cell composition, wherein the CAR T cell composition comprises CAR T cells, and the CAR T cells comprise a CAR directed to a targeting moiety. A method comprising:

[1135] 510. The first compound has the formula [ka] and said second compound has the formula [ka] 509. The method of claim 509, comprising:

[1136] Thus, in certain embodiments, a method of treating cancer is provided, comprising the steps of: i) administering to a patient a compound or a pharmaceutically acceptable salt thereof, wherein the compound comprises a small molecule ligand linked to a targeting moiety by a linker, ii) administering to the patient a first CAR T-cell composition, wherein the CAR T-cell composition comprises CAR T cells and wherein the CAR T cells comprise a CAR directed to a targeting moiety, and iii) administering to the patient a second CAR T-cell composition, wherein the CAR T-cell composition comprises CAR T cells and wherein the CAR T cells comprise a CAR directed to a targeting moiety.

[1137] In other embodiments, a method of treating cancer is provided, comprising the steps of: i) administering to a patient a compound or a pharmaceutically acceptable salt thereof, wherein the compound comprises a small molecule ligand linked to a targeting moiety by a linker, and ii) administering to the patient a CAR T cell composition comprising CAR T cells, wherein the CAR T cells in the composition comprise a CAR directed to a targeting moiety, and the CAR T cell composition comprises a mixture of the CAR T cells and non-transformed T cells.

[1138] In yet another embodiment, a method of treating cancer is provided, comprising the steps of: i) administering to a patient a compound or a pharmaceutically acceptable salt thereof, wherein the compound comprises a small molecule ligand linked to a targeting moiety by a linker, ii) administering to the patient a CAR T cell composition, wherein the CAR T cell composition comprises CAR T cells and the CAR T cells comprise a CAR directed to a targeting moiety, and iii) administering to the patient folic acid, a conjugate comprising folic acid (wherein the conjugate comprising folic acid does not comprise a targeting moiety), or a drug that inhibits activation of CAR T cells.

[1139] In other embodiments, a method of treating cancer is provided, comprising the steps of: i) administering to a patient a compound or a pharmaceutically acceptable salt thereof, wherein the compound comprises a small molecule ligand linked to a targeting moiety by a linker, and the compound or a pharmaceutically acceptable salt thereof is at a dosage of about 10 nmole / kg to about 2500 nmole / kg of patient body weight, and ii) administering to the patient a CAR T cell composition comprising CAR T cells, wherein the CAR T cells comprise a CAR directed to a targeting moiety, and the CAR T cells are at a dosage of about 1 million to about 15 million CAR T cells.

[1140] In yet another embodiment, a method of treating cancer is provided, comprising the steps of: i) continuously administering to a patient a compound or a pharmaceutically acceptable salt thereof, wherein the compound comprises a small molecule ligand linked to a targeting moiety by a linker, ii) administering to the patient a CAR T cell composition comprising CAR T cells, wherein the CAR T cells comprise a CAR directed to a targeting moiety, and iii) terminating the continuous administration of the compound or a pharmaceutically acceptable salt thereof to block or prevent cytokine release syndrome in the patient.

[1141] In another illustrative embodiment, a method of treating cancer is provided, the method comprising: i) administering to a patient a compound or a pharmaceutically acceptable salt thereof, wherein the compound comprises a small molecule ligand linked to a targeting moiety by a linker, and at least first and second doses of the compound or a pharmaceutically acceptable salt thereof are administered to the patient, wherein the first and second doses are different, and the second dose of the compound or a pharmaceutically acceptable salt thereof is about 2-fold to about 15,000-fold greater than the first dose of the compound or a pharmaceutically acceptable salt thereof, and ii) administering to the patient a CAR T cell composition comprising CAR T cells, wherein the CAR T cells comprise a CAR directed to a targeting moiety.

[1142] In other embodiments, a method of treating cancer is provided, comprising the steps of: i) administering to a patient a compound or a pharmaceutically acceptable salt thereof, wherein the compound comprises a small molecule ligand linked to a targeting moiety by a linker, and wherein the compound or a pharmaceutically acceptable salt thereof is administered to the patient once a week, and ii) administering to the patient a CAR T cell composition comprising CAR T cells, wherein the CAR T cells comprise a CAR directed to the targeting moiety.

[1143] In yet another embodiment, a method of treating cancer is provided, comprising the steps of: i) administering to a patient a first dose of a compound or a pharmaceutically acceptable salt thereof, wherein the compound comprises a small molecule ligand linked to a targeting moiety by a linker; ii) administering to the patient at least a second dose of the compound or a pharmaceutically acceptable salt thereof, wherein the second dose of the compound or a pharmaceutically acceptable salt thereof is at least about 50% less than the first dose of the compound or a pharmaceutically acceptable salt thereof; and iii) administering to the patient a single dose of a CAR T cell composition comprising CAR T cells, wherein the CAR T cells comprise a CAR directed to a targeting moiety.

[1144] In yet another embodiment, a method of treating cancer is provided, comprising the steps of: i) administering to a patient a first compound or a pharmaceutically acceptable salt thereof, wherein the compound comprises a small molecule ligand linked to a targeting moiety by a linker, and wherein the compound or a pharmaceutically acceptable salt thereof is administered to the patient at least about 1 hour prior to administration of a CAR T cell composition comprising CAR T cells, the CAR T cells comprising a CAR directed to a targeting moiety, ii) then administering to the patient an amount of the CAR T cell composition, and iii) then administering to the patient a second compound or a pharmaceutically acceptable salt thereof.

[1145] In another embodiment, a method for treating cancer is provided, comprising the steps of: i) administering to a patient a compound or a pharmaceutically acceptable salt thereof, wherein the compound comprises a small molecule ligand linked to a targeting moiety by a linker; and ii) administering to the patient a CAR T cell composition, wherein the CAR T cell composition comprises CAR T cells, and the CAR T cells comprise a CAR directed to a targeting moiety, and the small molecule ligand is a PSMA ligand, and the targeting moiety is FITC. In this embodiment, the small molecule ligand linked to the targeting moiety by a linker is represented by the formula [ka] may have:

[1146] In yet another embodiment, a method for treating cancer is provided, comprising: i) administering to a patient a compound or a pharmaceutically acceptable salt thereof, wherein the compound comprises a small molecule ligand linked to a targeting moiety by a linker; and ii) administering to the patient a CAR T cell composition, wherein the CAR comprises a CAR T cell, the CAR T cell comprises a CAR directed to a targeting moiety, the small molecule ligand is a CAIX ligand, and the targeting moiety is FITC. In this embodiment, the small molecule ligand linked to the targeting moiety by a linker is represented by the formula [ka] may have:

[1147] In yet another embodiment, a method for treating cancer is provided. The method comprises the steps of: i) administering to a patient a first compound or a pharmaceutically acceptable salt thereof, wherein the first compound or a pharmaceutically acceptable salt thereof comprises a PSMA ligand linked to FITC by a linker; ii) administering to a patient a second compound or a pharmaceutically acceptable salt thereof, wherein the second compound or a pharmaceutically acceptable salt thereof comprises a CAIX ligand linked to FITC by a linker; and iii) administering to a patient a CAR T cell composition, wherein the CAR T cell composition comprises CAR T cells, and the CAR T cells comprise a CAR directed to a targeting moiety. In this embodiment, the first compound is of the formula [ka] and the second compound has the formula [ka] may have:

[1148] Accordingly, various embodiments are provided in the preceding 12 paragraphs and in the above-listed sections, and all applicable embodiments described in this Detailed Description of Illustrative Embodiments, Summary of the Invention, Examples, and Claims apply to these embodiments.

[1149] A "patient" as used herein may be a human, or in the case of veterinary applications, the patient may be a laboratory animal, an agricultural animal, a domestic animal, or a wild animal. In various embodiments, the patient may be a laboratory animal such as a rodent (e.g., a mouse, rat, hamster, etc.), rabbit, monkey, chimpanzee, or other laboratory animal; a domestic animal such as a dog, cat, or rabbit; an agricultural animal such as a cow, horse, pig, sheep, or goat; or a captive wild animal such as a bear, panda, lion, tiger, leopard, elephant, zebra, giraffe, gorilla, dolphin, or whale.

[1150] In various embodiments, the cancer to be treated may be selected from carcinoma, sarcoma, osteosarcoma, lymphoma, melanoma, mesothelioma, nasopharyngeal carcinoma, leukemia, adenocarcinoma, or myeloma. In other embodiments, the cancer is lung cancer, bone cancer, pancreatic cancer, skin cancer, head cancer, neck cancer, cutaneous melanoma, intraocular melanoma, uterine cancer, ovarian cancer, endometrial cancer, rectal cancer, stomach cancer, colon cancer, breast cancer, triple-negative breast cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, non-small cell lung cancer, adrenal cancer, soft tissue sarcoma, osteosarcoma, urinary tract cancer ... The cancer may be urinary tract cancer, prostate cancer, chronic leukemia, acute leukemia including acute myeloid leukemia, lymphocytic lymphoma, myeloid leukemia, myelomonocytic leukemia, hairy leukemia, pleural mesothelioma, bladder cancer, Burkitt's lymphoma, ureter cancer, kidney cancer, renal cell carcinoma, renal pelvis cancer, central nervous system (CNS) neoplasms, primary CNS lymphoma, spinal axis tumors, brainstem glioma, pituitary adenoma, and esophagogastric junction adenocarcinoma.

[1151] In some of these embodiments, the cancer is a folate receptor-expressing cancer. In other embodiments, the cancer is a folate receptor alpha-expressing cancer. In yet other embodiments, the cancer is a folate receptor beta-expressing cancer. In some of these embodiments, the cancer is endometrial cancer, non-small cell lung cancer, ovarian cancer, or triple-negative breast cancer. In other embodiments, the cancer being treated is a tumor. In other embodiments, the cancer is malignant. In other embodiments, the cancer is acute myeloid leukemia. In yet other embodiments, the cancer is acute myeloid leukemia, and the cancer expresses folate receptor beta. In yet other embodiments, the cancer is acute myeloid leukemia, and the CAR-T cells have a central memory / effector memory phenotype. In yet other embodiments, the CD8:CD4 ratio of the CAR T cells is about 1:1. In other embodiments, the CD8:CD4 ratio is about a 1.2 to 1 ratio, about a 1 to 1.2 ratio, about a 1.3 to 1 ratio, about a 1 to 1.3 ratio, about a 1.4 to 1 ratio, about a 1 to 1.4 ratio, about a 1.5 to 1 ratio, or about a 1 to 1.5 ratio. In still other embodiments where the cancer is acute myeloid leukemia and a rescue agent is used, the CAR T cells may be present in the patient for at least about 40 days, at least about 45 days, at least about 50 days, at least about 55 days, at least about 60 days, at least about 70 days, at least about 80 days, at least about 90 days, or at least about 100 days after administration of the CAR T cells, even after use of the rescue agent to block or prevent CRS. In other embodiments where the cancer is acute myeloid leukemia or other cancers, the CAR T cells associated with the tumor may have increased CD25 expression compared to CAR T cells not associated with the tumor.

[1152] In certain embodiments, the "small molecule ligand" is selected from the group consisting of folic acid, DUPA (a ligand bound by PSMA-positive human prostate cancer cells and other cancer cell types), NK-1R ligands (receptors for NK-1R ligands are found, for example, in colon and pancreatic cancer), CAIX ligands (receptors for CAIX ligands are found, for example, in renal, ovarian, vulvar, and breast cancer), gamma glutamyl transpeptidase ligands (transpeptidases are found, for example, in ovarian cancer, colon cancer, liver cancer, astrocytoma, melanoma, and and leukemias), NKG2D ligands (receptors for NKG2D ligands are found, for example, in cancers of the lung, colon, kidney, prostate, and T- and B-cell lymphomas), or CCK2R ligands (receptors for CCK2R ligands are found, among others, in cancers of the thyroid, lung, pancreas, ovary, brain, stomach, gastrointestinal stromal, and colon), each of which is a small molecule ligand that binds specifically to the cancer cell type (i.e., receptors for each of these ligands may be overexpressed in cancer relative to normal tissue).

[1153] In certain embodiments, the small molecule ligand may have a mass of less than about 10,000 daltons, less than about 9000 daltons, less than about 8,000 daltons, less than about 7000 daltons, less than about 6000 daltons, less than about 5000 daltons, less than about 4500 daltons, less than about 4000 daltons, less than about 3500 daltons, less than about 3000 daltons, less than about 2500 daltons, less than about 2000 daltons, less than about 1500 daltons, less than about 1000 daltons, or less than about 500 daltons. In other embodiments, the small molecule ligand can have a mass of about 1 to about 10,000 daltons, about 1 to about 9000 daltons, about 1 to about 8,000 daltons, about 1 to about 7000 daltons, about 1 to about 6000 daltons, about 1 to about 5000 daltons, about 1 to about 4500 daltons, about 1 to about 4000 daltons, about 1 to about 3500 daltons, about 1 to about 3000 daltons, about 1 to about 2500 daltons, about 1 to about 2000 daltons, about 1 to about 1500 daltons, about 1 to about 1000 daltons, or about 1 to about 500 daltons.

[1154] In certain embodiments, the DUPA derivative can be a small molecule ligand linked to a targeting moiety, and the DUPA derivatives are described in WO2015 / 057852, which is incorporated herein by reference.

[1155] In some embodiments, the small molecule ligand in the context of "small molecule ligand linked to a linker" is folic acid. In various embodiments, folic acid can be folic acid, a folic acid analog, or another folate receptor-binding molecule. In various embodiments, folic acid analogs that can be used include folinic acid (e.g., leucovorin), pteropolyglutamic acid, and folate receptor-binding pteridines, such as tetrahydropterin, dihydrofolic acid, tetrahydrofolic acid, and their deaza and dideaza analogs. The terms "deaza" and "dideaza" analogs refer to art-recognized analogs in which one or two nitrogen atoms in the naturally occurring folic acid structure are replaced with carbon atoms. For example, deaza analogs include 1-deaza, 3-deaza, 5-deaza, 8-deaza, and 10-deaza analogs. Dideaza analogs include, for example, 1,5-dideaza, 5,10-dideaza, 8,10-dideaza, and 5,8-dideaza analogs. These folic acid analogs are conventionally referred to as "folic acid" due to their ability to bind to folic acid receptors. Other folic acid receptor binding analogs include aminopterin, amethopterin (methotrexate), N10-methylfolic acid, 2-deamino-hydroxyfolic acid, deaza-analogues such as 1-deazamethopterin or 3-deazamethopterin, and 3',5'-dichloro-4-amino-4-deoxy-N10-methylpteroylglutamic acid (dichloromethotrexate).

[1156] In other embodiments, the small molecule ligand in the context of "a small molecule ligand linked to a linker" is of the formula [ka] [In the formula, X 1 and Y 1 are each independently a halo, R 2 , OR 2 , S.R. 3 and N.R.4 R 5 selected from the group consisting of: U, V and W are -(R 6a )C=, -N=, -(R 6a )C(R 7a )- and -N(R 4a )—; Q is selected from the group consisting of C and CH; T is selected from the group consisting of S, O, N, and —C═C—; X 2 and X 3 are each independently oxygen, sulfur, -C(Z)-, -C(Z)O-, -OC(Z)-, -N(R 4b )-, -C(Z)N(R 4b )-, -N(R 4b )C(Z)-, -OC(Z)N(R 4b )-, -N(R 4b )C(Z)O-, -N(R 4b )C(Z)N(R 5b )-, -S(O)-, -S(O)2-, -N(R 4a )S(O)2-, -C(R 6b )(R 7b )-, -N(C≡CH)-, -N(CH2C≡CH)-, C1-C 12 Alkylene and C1-C 12 alkyleneoxy, where Z is oxygen or sulfur; R 1 are hydrogen, halo, C1-C 12 Alkyl and C1-C 12 selected from the group consisting of alkoxy; R 2 , R 3 , R 4 , R 4a , R 4b , R 5 , R 5b , R 6b and R 7b are each independently hydrogen, halo, C-C 12 Alkyl, C1-C 12 Alkoxy, C1-C 12 Alkanoyl, C1-C 12 Alkenyl, C1-C 12Alkynyl, (C1-C 12 alkoxy)carbonyl and (C1-C 12 alkylamino)carbonyl; R 6 and R 7 are each independently hydrogen, halo, C-C 12 Alkyl and C1-C 12 alkoxy; or R 6 and R 7 together to form a carbonyl group; R 6a and R 7a are each independently hydrogen, halo, C-C 12 Alkyl and C1-C 12 alkoxy; or R 6a and R 7a together to form a carbonyl group; p, r, s, and t are each independently 0 or 1; and * represents any covalent bond to the remainder of the conjugate if any additional chemical moiety is part of the folic acid. may have:

[1157] In some embodiments, the "targeting moiety" that binds to the CAR expressed by the CAR T cells can be selected from, for example, 2,4-dinitrophenol (DNP), 2,4,6-trinitrophenol (TNP), biotin, digoxigenin, fluorescein, fluorescein isothiocyanate (FITC), NHS-fluorescein, pentafluorophenyl ester, tetrafluorophenyl ester, knottin, centyrin, DARPin, affibody, affilin, anticalin, atrimer, avimer, bicyclic peptide, FN3 scaffold, cys-knot, fynomer, Kunitz domain, or Obody. The nature of the targeting moiety must be such that it can be recognized and bound to the CAR, preferably with specificity, and is limited only by its relatively low molecular weight. In various embodiments, typical targeting moieties are haptens, including small organic molecules.

[1158] In one illustrative embodiment, the targeting moiety can have the following illustrative structure: [ka] wherein X is oxygen, nitrogen, or sulfur, where X is attached to a linker, L; and Y is OR a , N.R. a 2 or NR a 3 + and Y' is O, NR a or NR a 2 + wherein each R, at each occurrence, is independently selected from H, fluoro, sulfonic acid, sulfonate, and salts thereof, and the like; and R a is hydrogen or alkyl.

[1159] In certain illustrative embodiments, the linker may comprise polyethylene glycol (PEG), polyproline, a hydrophilic amino acid, a sugar, a non-natural peptidoglycan, polyvinylpyrrolidone, Pluronic F-127, or a combination thereof.

[1160] In other illustrative embodiments, the linker in the compounds described herein, or pharmaceutically acceptable salts thereof, can comprise a direct bond (e.g., a reaction between an isothiocyanate group of FITC and a free amine group of a small molecule ligand), or the bond can be via an intermediate linker. In certain embodiments, the intermediate linker, if present, can be any biocompatible linker known in the art, such as a bivalent linker. In certain illustrative embodiments, the bivalent linker can contain from about 1 to about 30 carbon atoms. In other illustrative embodiments, the bivalent linker can contain from about 2 to about 20 carbon atoms. In other embodiments, lower molecular weight bivalent linkers (i.e., those having an approximate molecular weight of from about 30 to about 300 daltons) are used. In other embodiments, suitable linker lengths include, but are not limited to, linkers having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 or more atoms.

[1161] In various embodiments, the small molecule ligand linked to the targeting moiety has the formula [ka] wherein B is a small molecule ligand, L is a linker, and T is a targeting moiety, wherein L is a group of the formula [ka] (wherein n is 0 to 200). In other embodiments, n can be 0 to 150, 0 to 110, 0 to 100, 0 to 90, 0 to 80, 0 to 70, 0 to 60, 0 to 50, 0 to 40, 0 to 30, 0 to 20, 0 to 15, 0 to 14, 0 to 13, 0 to 12, 0 to 11, 0 to 10, 0 to 9, 0 to 8, 0 to 7, 0 to 6, 0 to 5, 0 to 4, 0 to 3, 0 to 2, 0-1, 15-16, 15-17, 15-18, 15-19, 15-20, 15-21, 15-22, 15-23, 15-24, 15-25, 15-26, 15-27, 15-28, 15-29, 15-30, 15-31, 15-32, 15-33, 15-34, 15-35, 15-36, 15-37 7, 15 to 38, 15 to 39, 15 to 40, 15 to 50, 15 to 60, 15 to 70, 15 to 80, 15 to 90, 15 to 100, 15 to 110, 15 to 120, 15 to 130, 15 to 140, 15 to 150, or n may be an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, It can be 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 50, 60, 70, 80, 90, 100, 108, 110, 120, 130, 140 or 150.

[1162] In other embodiments, the linker can be a bivalent linker that can include one or more spacers. Illustrative spacers are shown in the following table. In the following non-limiting description of illustrative spacers: * indicates the point of attachment to a small molecule ligand or targeting moiety or other bivalent linker moiety. [Table 1]

[1163] In other embodiments, the small molecule ligand (bridge) linked to the targeting moiety can have any of the following structures: [ka] [ka] [ka]

[1164] In other embodiments, the compound or pharmaceutically acceptable salt thereof is not an antibody and does not include a fragment of an antibody, hi yet other embodiments, the targeting moiety does not include a peptide epitope.

[1165] In one illustrative embodiment, the small molecule ligand (bridge) linked to the targeting moiety by a linker comprises fluorescein isothiocyanate (FITC) linked to the small molecule ligand. In some embodiments, the cancer may overexpress a receptor for the small molecule ligand. In other embodiments, for example, cytotoxic T cells or other types of T cells may be transformed to express a CAR comprising an anti-FITC scFv. In this embodiment, the CAR targets FITC, and as a result of the binding of the small molecule ligand to the cancer, the cancer may be decorated with FITC molecules. Therefore, toxicity to normal, non-target cells may be avoided. In this embodiment, when anti-FITC CAR-expressing T cells bind FITC, the CAR T cells are activated and the cancer is alleviated.

[1166] The " pharmaceutically acceptable salt " of the small molecule ligand linked to the targeting moiety by a linker is intended. As used herein, the term " pharmaceutically acceptable salt " refers to the salt whose counterion can be used in medicine. In various embodiments, such salts include, but are not limited to: 1) the acid addition salts that can be obtained by the reaction of free base parent compound with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, sulfuric acid and perchloric acid, or organic acids such as acetic acid, oxalic acid, (D) or (L) malic acid, maleic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, tartaric acid, citric acid, succinic acid or malonic acid; or 2) the salts that form when the acidic protons present in the parent compound are replaced by metal ions, for example, alkali metal ions, alkaline earth ions or aluminum ions; or complexes with organic bases such as ethanolamine, diethanolamine, triethanolamine, trimethamine, N-methylglucamine, etc. Pharmaceutically acceptable salts are well known to those of skill in the art, and all such pharmaceutically acceptable salts are contemplated in conjunction with the embodiments described herein.

[1167] In various embodiments, suitable acid addition salts are those with acids that form non-toxic salts. Illustrative examples include acetate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hybenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfonate, naphthylate, 2-naptylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, saccharate, stearate, succinate, tartrate, tosylate, and trifluoroacetate.

[1168] In various embodiments, suitable base salts are formed from bases that form non-toxic salts. Illustrative examples include arginine salts, benzathine salts, calcium salts, choline salts, diethylamine salts, diolamine salts, glycine salts, lysine salts, magnesium salts, meglumine salts, olamine salts, potassium salts, sodium salts, tromethamine salts, and zinc salts. Hemi-salts of acids and bases can also be formed, such as hemisulfate and hemicalcium salts.

[1169] In certain illustrative embodiments, the compounds described herein, or pharmaceutical salts thereof, may have one or more chiral centers or may otherwise be capable of existing as multiple stereoisomers. Thus, various embodiments may include pure stereoisomers as well as stereoisomeric mixtures, such as enantiomers, diastereomers, and enantiomerically or diastereomerically enriched mixtures. In certain embodiments, the compounds described herein, or pharmaceutically acceptable salts thereof, may be capable of existing as geometric isomers. Thus, various embodiments may include pure geometric isomers or mixtures of geometric isomers.

[1170] In certain embodiments, the compounds described herein or pharmaceutically acceptable salts thereof can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to the unsolvated forms and are encompassed within the scope of the present invention.

[1171] The methods described herein also utilize T lymphocytes (e.g., cytotoxic T lymphocytes) engineered to express a chimeric antigen receptor (CAR) that recognizes and binds to a cross-linked targeting moiety (e.g., FITC, DNP, or TNP). In one embodiment, the CARs described herein comprise three domains: 1) a recognition region (e.g., a single-chain fragment variable (scFv) region of an antibody, a Fab fragment, etc.) that specifically recognizes and binds to the targeting moiety, 2) a costimulatory domain that enhances T lymphocyte proliferation and survival, and 3) an activation signaling domain that generates a T lymphocyte activation signal.

[1172] In various embodiments, as non-limiting examples, the scFv region of an antibody that binds to folic acid, DUPA, a CAIX ligand, an NK-1R ligand, a gamma glutamyl transpeptidase ligand, an NKG2D ligand, or a CCK2R ligand may be used. In illustrative, non-limiting embodiments, the scFv region may be prepared from (i) antibodies known in the art that bind to a targeting moiety, (ii) antibodies prepared de novo using a selected targeting moiety, such as a hapten, and (iii) sequence variants derived from the scFv region of such antibodies, e.g., an scFv region having at least about 80%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 99.5% sequence identity to the amino acid sequence of the scFv region from which it is derived.

[1173] In some embodiments, the costimulatory domain acts to enhance the proliferation and survival of cytotoxic T lymphocytes by binding to the targeting portion of the CAR. Suitable costimulatory domains include, but are not limited to, CD28, CD137 (4-1BB), tumor necrosis factor (TNF) receptor family members, CD134 (OX40), TNFR-superfamily members of receptors, CD27, CD30, CD150, DAP10, NKG2D, and CD278 (ICOS), CD28-superfamily costimulatory molecules expressed on activated T cells, or combinations thereof. Those skilled in the art will understand that sequence variants of these costimulatory domains can be used without adversely affecting the present invention, provided that the variants have the same or similar activity as the domains they are modeled after. In various embodiments, such variants have at least about 80%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 99.5% sequence identity to the amino acid sequence of the domain from which they are derived.

[1174] In illustrative embodiments, the activation signaling domain acts to activate T lymphocytes (e.g., cytotoxic T lymphocytes) upon binding to the targeting portion of the CAR. In various embodiments, suitable activation signaling domains include T cell CD3 zeta chain, CD3 delta receptor protein, mbl receptor protein, B29 receptor protein, and Fc receptor gamma. Those skilled in the art will understand that sequence variants of these activation signaling domains can be used, where the variants have the same or similar activity as the domain from which they are modeled. In various embodiments, variants have at least about 80%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 99.5% sequence identity with the amino acid sequence of the domain from which they are derived.

[1175] In some embodiments, a construct encoding a CAR is produced using genetic engineering techniques, such as those detailed in Sambrook et al., "Molecular Cloning: A Laboratory Manual", 3rd Edition, Cold Spring Harbor Laboratory Press, (2001), incorporated herein by reference, and Green and Sambrook, "Molecular Cloning: A Laboratory Manual", 4th Edition, Cold Spring Harbor Laboratory Press, (2012).

[1176] As an example, a plasmid or viral expression vector (e.g., lentiviral vector, retroviral vector, sleeping beauty, and piggyback (a transposon / transposase system including a non-viral-mediated CAR gene delivery system)) encoding a fusion protein comprising a recognition region, one or more costimulatory domains, and an activation signaling domain linked in-frame in a 5' to 3' direction can be produced. In other embodiments, other arrangements are permissible, including a recognition region, an activation signaling domain, and one or more costimulatory domains. In certain embodiments, the arrangement of the recognition region in the fusion protein is such that presentation of the extracellular surface region is generally achieved. In certain embodiments, the CAR may include additional elements such as a signal peptide (e.g., a CD8α signal peptide) to ensure proper export of the fusion protein to the cell surface, a transmembrane domain (e.g., a CD8α transmembrane domain, a CD28 transmembrane domain, or a CD3ζ transmembrane domain) to ensure that the fusion protein is maintained as an integral membrane protein, and a hinge domain (e.g., a CD8α hinge) that provides flexibility to the recognition region and allows for strong binding to the targeting moiety.

[1177] A diagram of an exemplary CAR is shown in Figure 5, where the fusion protein sequence is incorporated into a lentiviral expression vector, "SP" is the signal peptide, the CAR is an anti-FITC CAR, the CD8α hinge and CD8α transmembrane domains are present, the costimulatory domain is 4-1BB, and the activation signaling domain is CD3ζ. Exemplary nucleic acid sequences ...

Claims

1. 1. A pharmaceutical composition comprising a compound or a pharma- ceutical acceptable salt thereof for use in a method of treating cancer in a patient, comprising: the compound or a pharma- ceutically acceptable salt thereof comprises folic acid linked by a linker to a targeting moiety, the targeting moiety being fluorescein, fluorescein isothiocyanate (FITC) or NHS-fluorescein; the patient's bloodstream comprises a CAR T cell composition comprising a CAR T cell, the CAR T cell comprising a CAR directed to a targeting moiety; the method comprising administering to the patient at least a first dose and a second dose of a compound or a pharma- ceutically acceptable salt thereof, wherein the first and second doses are different and the second dose of the compound or a pharma- ceutically acceptable salt thereof is from 2 to 15,000 times the amount of the compound or a pharma- ceutically acceptable salt thereof in the first dose; Pharmaceutical compositions.

2. administering to a patient at least a first dose, a second dose, and a third dose of the compound or a pharma- ceutically acceptable salt thereof; The first dose, second dose, and third dose are different; the amount of the compound or a pharma- ceutically acceptable salt thereof in the second dose is 2 to 750 times that of the compound or a pharma- ceutically acceptable salt thereof in the first dose, and the amount of the compound or a pharma- ceutically acceptable salt thereof in the third dose is 800 to 10,000 times that of the compound or a pharma- ceutically acceptable salt thereof in the first dose; The pharmaceutical composition of claim 1.

3. administering to a patient at least a first dose, a second dose, a third dose, and a fourth dose of the compound or a pharma- ceutically acceptable salt thereof; The first dose, second dose, third dose, and fourth dose are different; the compound or a pharma- ceutically acceptable salt thereof in the second dose is administered in an amount 2 to 750 times that of the compound or a pharma- ceutically acceptable salt thereof in the first dose, the compound or a pharma- ceutically acceptable salt thereof in the third dose is administered in an amount 800 to 7500 times that of the compound or a pharma- ceutically acceptable salt thereof in the first dose, and the compound or a pharma- ceutically acceptable salt thereof in the fourth dose is administered in an amount 8000 to 15000 times that of the compound or a pharma- ceutically acceptable salt thereof in the first dose; The pharmaceutical composition of claim 1.

4. the amount of the compound or its pharma- ceutically acceptable salt in the second dose is 100 times that of the compound or its pharma- ceutically acceptable salt in the first dose, the amount of the compound or its pharma- ceutically acceptable salt in the third dose is 1000 times that of the compound or its pharma- ceutically acceptable salt in the first dose, and the amount of the compound or its pharma- ceutically acceptable salt in the fourth dose is 10000 times that of the compound or its pharma- ceutically acceptable salt in the first dose; The pharmaceutical composition according to claim 3.

5. The cancer is selected from the group consisting of lung cancer, bone cancer, pancreatic cancer, skin cancer, head cancer, neck cancer, cutaneous melanoma, intraocular melanoma, uterine cancer, ovarian cancer, endometrial cancer, rectal cancer, stomach cancer, colon cancer, breast cancer, triple-negative breast cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, non-small cell lung cancer, adrenal cancer, soft tissue sarcoma, osteosarcoma, selected from the group consisting of urethral cancer, prostate cancer, chronic leukemia, acute leukemia, acute myeloid leukemia, lymphocytic lymphoma, myeloid leukemia, myelomonocytic leukemia, hairy cell leukemia, pleural mesothelioma, bladder cancer, Burkitt's lymphoma, ureteral cancer, kidney cancer, renal cell carcinoma, renal pelvis cancer, central nervous system (CNS) neoplasms, primary CNS lymphoma, spinal axis tumors, brain stem glioma, pituitary adenoma, and gastroesophageal junction adenocarcinoma; The pharmaceutical composition according to any one of claims 1 to 4.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the CAR has a recognition region, which is an anti-fluorescein antibody or a portion thereof, and optionally the recognition region is a single-chain fragment variable (scFv) region of an anti-FITC antibody.

7. the compound or a pharma- ceutically acceptable salt thereof is administered continuously to a patient; The method further comprises terminating the continuous administration of the compound or a pharma- ceutically acceptable salt thereof to inhibit or prevent cytokine release syndrome in the patient. The pharmaceutical composition according to any one of claims 1 to 6.

8. 8. The pharmaceutical composition of any of claims 1-7, further comprising administering to the patient folic acid, a conjugate comprising folic acid without a targeting moiety, or an agent that blocks activation of CAR T cells.

9. The pharmaceutical composition of any one of claims 1 to 8, wherein the compound or a pharma- ceutically acceptable salt thereof is administered to a patient once a week.

10. The pharmaceutical composition of any of claims 1 to 9, wherein the CAR T cell composition is administered to a patient prior to administration of the compound or a pharma- ceutically acceptable salt thereof.

11. 9. The pharmaceutical composition of claim 8, wherein the agent that blocks activation of CAR T cells is sodium fluorescein.

12. The compound has the following formula: The pharmaceutical composition according to any one of claims 1 to 11, comprising:

13. 1. Use of a compound or a pharma- ceutical acceptable salt thereof for the manufacture of a medicament for treating cancer in a patient, comprising: the compound or a pharma- ceutically acceptable salt thereof comprises folic acid linked by a linker to a targeting moiety, the targeting moiety being fluorescein, fluorescein isothiocyanate (FITC) or NHS-fluorescein; the patient's bloodstream comprises a CAR T cell composition comprising a CAR T cell, the CAR T cell comprising a CAR directed to a targeting moiety; The use of treating cancer by a method comprising administering to the patient at least a first dose and a second dose of a compound or a pharma- ceutically acceptable salt thereof, wherein the first dose and the second dose are different, and the amount of the compound or a pharma- ceutically acceptable salt thereof in the second dose is 2 to 15,000 times the amount of the compound or a pharma- ceutically acceptable salt thereof in the first dose.

14. administering to a patient at least a first dose, a second dose, and a third dose of the compound or a pharma- ceutically acceptable salt thereof; The first dose, second dose, and third dose are different; the amount of the compound or a pharma- ceutically acceptable salt thereof in the second dose is 2 to 750 times that of the compound or a pharma- ceutically acceptable salt thereof in the first dose, and the amount of the compound or a pharma- ceutically acceptable salt thereof in the third dose is 800 to 10,000 times that of the compound or a pharma- ceutically acceptable salt thereof in the first dose; 14. The use according to claim 13.

15. administering to a patient at least a first dose, a second dose, a third dose, and a fourth dose of the compound or a pharma- ceutically acceptable salt thereof; The first dose, second dose, third dose, and fourth dose are different; the compound or a pharma- ceutically acceptable salt thereof in the second dose is administered in an amount 2 to 750 times that of the compound or a pharma- ceutically acceptable salt thereof in the first dose, the compound or a pharma- ceutically acceptable salt thereof in the third dose is administered in an amount 800 to 7500 times that of the compound or a pharma- ceutically acceptable salt thereof in the first dose, and the compound or a pharma- ceutically acceptable salt thereof in the fourth dose is administered in an amount 8000 to 15000 times that of the compound or a pharma- ceutically acceptable salt thereof in the first dose; 15. The use according to claim 14.

16. the amount of the compound or its pharma- ceutically acceptable salt in the second dose is 100 times that of the compound or its pharma- ceutically acceptable salt in the first dose, the amount of the compound or its pharma- ceutically acceptable salt in the third dose is 1000 times that of the compound or its pharma- ceutically acceptable salt in the first dose, and the amount of the compound or its pharma- ceutically acceptable salt in the fourth dose is 10000 times that of the compound or its pharma- ceutically acceptable salt in the first dose; 16. The use according to claim 15.

17. The cancer is selected from the group consisting of lung cancer, bone cancer, pancreatic cancer, skin cancer, head cancer, neck cancer, cutaneous melanoma, intraocular melanoma, uterine cancer, ovarian cancer, endometrial cancer, rectal cancer, stomach cancer, colon cancer, breast cancer, triple-negative breast cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, non-small cell lung cancer, adrenal cancer, soft tissue sarcoma, osteosarcoma, selected from the group consisting of urethral cancer, prostate cancer, chronic leukemia, acute leukemia, acute myeloid leukemia, lymphocytic lymphoma, myeloid leukemia, myelomonocytic leukemia, hairy cell leukemia, pleural mesothelioma, bladder cancer, Burkitt's lymphoma, ureteral cancer, kidney cancer, renal cell carcinoma, renal pelvis cancer, central nervous system (CNS) neoplasms, primary CNS lymphoma, spinal axis tumors, brain stem glioma, pituitary adenoma, and gastroesophageal junction adenocarcinoma; The use according to any one of claims 13 to 16.

18. The use according to any one of claims 13 to 17, wherein the CAR has a recognition region, the recognition region being an anti-fluorescein antibody or a part thereof, optionally the recognition region being a single chain fragment variable (scFv) region of an anti-FITC antibody.

19. the compound or a pharma- ceutically acceptable salt thereof is administered continuously to a patient; The method further comprises terminating the continuous administration of the compound or a pharma- ceutically acceptable salt thereof to inhibit or prevent cytokine release syndrome in the patient. Use according to any one of claims 13 to 18.

20. 20. The use of any of claims 13 to 19, further comprising administering to the patient folic acid, a conjugate comprising folic acid without a targeting moiety, or an agent that blocks activation of CAR T cells.

21. The use according to any one of claims 13 to 20, wherein the compound or a pharma- ceutically acceptable salt thereof is administered to the patient once a week.

22. The use of any of claims 13 to 21, wherein the CAR T cell composition is administered to a patient prior to administration of the compound or a pharma- ceutically acceptable salt thereof.

23. 21. The use of claim 20, wherein the agent that blocks activation of CAR T cells is sodium fluorescein.

24. The compound has the formula: The use according to any one of claims 13 to 23, comprising:

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