BCMA-targeted CAR-T cell therapy for multiple myeloma

Abstract

The present application provides a method of treating a subject suffering from multiple myeloma with siltacabtadine autorucel suspension. The present application further provides a pharmaceutical product containing the siltacabtadine autorucel suspension, instructions for use of the siltacabtadine autorucel suspension, and a method for selling a pharmaceutical product containing the siltacabtadine autorucel suspension.

Description

Cross-reference of related applications

[0001] Book Out The application claims priority to U.S. Extraordinary Patent Application No. 63 / 314,968, filed on 28 February 2022, the disclosures of which are incorporated herein by reference in their entirety. Sequence List

[0002] Book Out The request is already in XML file format. Out This specification includes a computer-readable sequence listing filed with the application, the contents of which are incorporated herein by reference in their entirety. The sequence listing filed with the application has the XML file title "14651-054-228_SEQ_LISTING.xml", was created on 23 February 2023, and has a size of 21,916 bytes. [Background technology]

[0003] Multiple myeloma is an invasive plasma cell tumor. It is thought to be a B-cell tumor that grows uncontrollably in the bone marrow. Symptoms include one or more of the following: hypercalcemia, renal failure, anemia, bone lesions, bacterial infections, hyperviscosity, and amyloidosis. Treatment involves proteasome inhibitors, Immunomodulatory drugs While novel therapies, including monoclonal antibodies, have significantly improved patient outcomes, multiple myeloma remains considered an incurable disease. Most patients experience relapses. Either they do so, or they become refractory to treatment. Novel therapies for multiple myeloma are continuously needed. [Overview of the Initiative]

[0004] In one aspect, the patient is suffering from multiple myeloma. subject A method for treating the condition is provided, the method being a single intravenous injection Import Note, subject The method comprises administering a composition containing T cells, wherein the T cells contain a chimeric antigen receptor (CAR), and the chimeric antigen receptor is a) An extracellular antigen-binding domain comprising a first anti-BCMA binding moiety and a second BCMA binding moiety, b) Transmembrane domain and c) Including an intracellular signaling domain, As a result, T cells that express CAR (CAR-T cells) a certain dose The above subject To be delivered, Here, the first BCMA binding portion includes the amino acid sequence described in SEQ ID NO: 2, and the second BCMA binding portion includes the amino acid sequence described in SEQ ID NO: 4.

[0005] In some embodiments, the dose is 1.0 × 10 5 ~5.0×10 6 The number of CAR-T cells / kilogram subject It contains the mass of . In some examples, the dose is 5.0 × 10 5 ~1.0×10 6 The number of CAR-T cells / kilogram subject It contains the mass of . In some examples, the dose is about 0.75 × 10 6 The number of CAR-T cells / kilogram subject It contains the mass of 1. In some examples, the dose is 1 subject 1.0 x 10 per unit 8 This includes fewer than a certain number of the aforementioned CAR-T cells.

[0006] In some embodiments, the single intravenous Import Note: The administration is performed using one bag of the CAR-T cells. In some examples, the administration of one bag of the CAR-T cells is performed using one bag of the CAR-T cells melting It will be completed in three hours at the latest.

[0007] In some embodiments, the single intravenous ImportNote: The administration is performed using two bags of the CAR-T cells. In some examples, the administration of each bag of the two bags of CAR-T cells is performed using the two bags of CAR-T cells. melting It will be completed in three hours at the latest.

[0008] In some embodiments, the method is used for the CAR-T cells. Import The negative status of minimal residual disease (MRD) assessed in the bone marrow after injection is referred to as follows: subject Effectively obtained in the following cases. In some examples, the negative state of the MRD is the same as the CAR-T cells. Import Note: Between approximately 28 and 179 days after First tracking period It can be obtained from this.

[0009] In some examples, lymph ball The removal regimen is the removal of the CAR-T cells. Infusion This is performed prior to the following. In some embodiments, the lymph ball The elimination regimen includes the administration of cyclophosphamide or fludarabine. In some examples, lymph ball The removal regimen is administered intravenously. In some examples, the lymph ball The removal regimen is the aforementioned CAR-T cells Import Note: This is performed 5 to 7 days prior to the date. In some examples, the lymph ball The removal regimen is the aforementioned CAR-T cells Import Note: This includes intravenous administration of cyclophosphamide and fludarabine 5 to 7 days prior to the date of the note. In some examples, the cyclophosphamide was 300 mg / m². 2 It is administered intravenously. In some examples, the amount of fludarabine was 30 mg / m². 2 It is administered intravenously.

[0010] In some examples, the method did not significantly reduce the in vivo amplification of CAR-T cells. Import Note: More than 3 days after the above subjectFurther includes treating cytokine release syndrome (CRS) in some embodiments. Treatment teeth, subject This includes administering an IL-6R inhibitor. In some examples, the IL-6R inhibitor is an antibody. In some examples, the antibody inhibits IL-6R by binding to the extracellular domain of IL-6R. In some examples, the IL-6R inhibitor prevents the binding of IL-6 to IL-6R. In some examples, the IL-6R inhibitor is tocilizumab.

[0011] In some examples, CAR-T cells are included. Infusion 1 hour Previous to, Antipyretic and antihistamines and Pre-infusion medication in subject To treat the following. In some embodiments, the Antipyretic This includes paracetamol or acetaminophen. In some examples, the above Antipyretic teeth, subject It is administered orally or intravenously. In some examples, the above Antipyretic It is administered in doses ranging from 650 mg to 1000 mg. subject It is administered to the following. In some examples, the antihistamines It contains diphenhydramine. In some examples, the above antihistamines teeth, subject It is administered orally or intravenously. In some examples, the above antihistamines The dosage is 25 mg to 50 mg or equivalent dose It is administered as follows.

[0012] In some examples, CAR-T cells are included. Infusion The further comprises an excipient selected from dimethyl sulfoxide or dextran-40.

[0013] In some examples, subject teeth, At least 3 lines of prior treatment history Previous treatment including the above was received. In some examples, the above At least 3 lines of prior treatment historyAt least 1 type This includes drug therapy, and the at least 1 type The drugs are proteasome inhibitors (PIs), Immunomodulatory drugs It contains at least one of (IMiD) or an anti-CD38 antibody.

[0014] In some examples, subject The above A history of at least 3 lines of prior treatment It recurs later. In some cases, multiple myeloma is as described above. A history of at least 3 lines of prior treatment Later, at least 2 types Drugs It is difficult to treat. In some examples, It is intractable for the target. The at least 2 types The drug comprises PI and IMiD. In some examples, subject At least 3 types Drugs It is difficult to treat. In some examples, subject At least 4 types Drugs It is difficult to treat. In some examples, subject At least 5 types Drugs It is difficult to treat. .

[0015] In some embodiments, the method effectively obtains an overall response rate greater than 91%. In some embodiments, the method effectively obtains an overall response rate greater than 93%. In some embodiments, the method effectively obtains an overall response rate greater than 95%. In some embodiments, the method effectively obtains an overall response rate greater than 97%. In some embodiments, the method effectively obtains an overall response rate greater than 99%. In some embodiments, the CAR-T cells Import The overall response rate will be assessed at the median of a follow-up period of at least 12 months after the injection.

[0016] In some embodiments, the method achieved an initial response in less than 1.15 months. up to Effectively obtain the median duration. In some examples, the method achieves an initial response of less than 1.10 months. up toEffectively obtain the median duration. In some examples, the method achieves an initial response in less than 1.05 months. up to Effectively obtain the median duration. In some examples, the method achieves an initial response of less than 1.00 months. up to The median duration is effectively obtained. In some examples, the method achieves an initial response in less than 0.95 months. up to Effectively obtain the median of the period.

[0017] In some examples, the method achieved a best response of less than 2.96 months. up to The median duration is effectively obtained. In some examples, the method yielded a best response of less than 2.86 months. up to The median duration is effectively obtained. In some examples, the method yields a best response of less than 2.76 months. up to The median duration is effectively obtained. In some examples, the method yields a best response of less than 2.66 months. up to The median duration is effectively obtained. In some examples, the method yields a best response of less than 2.56 months. up to Effectively obtain the median of the period.

[0018] In some embodiments, the method is used for the CAR-T cells. Import A negative status for minimal residual disease (MRD) assessed in the bone marrow approximately 28 days or longer after the initial assessment is defined as follows: subject Effectively obtained in the CAR-T cells. In some examples, the method is used to obtain the CAR-T cells. Import The negative status of the aforementioned MRD, as assessed in the bone marrow approximately 12 months or longer after the injection, subject To maintain effectively in [location / area].

[0019] In some examples, the first BCMA binding moiety and / or the second BCMA binding moiety is anti-BCMA VHH. In some examples, the first BCMA binding moiety is the first anti-BCMA VHH, and the second BCMA binding moiety is the second anti-BCMA VHH. In some examples, the first BCMA binding moiety contains a polypeptide encoded by the nucleic acid sequence of SEQ ID NO: 10. In some examples, the second BCMA binding moiety contains a polypeptide encoded by the nucleic acid sequence of SEQ ID NO: 12. In some examples, the first BCMA binding moiety and the second BCMA binding moiety are linked to each other via a peptide linker.

[0020] In some examples, the peptide linker contains the amino acid sequence of SEQ ID NO: 3. In some examples, the peptide linker contains a polypeptide encoded by the nucleic acid sequence of SEQ ID NO: 11.

[0021] In some examples, the CAR polypeptide further comprises a signal peptide located at the N-terminus of the polypeptide. In some examples, the signal peptide is derived from CD8α. In some examples, the signal peptide comprises the amino acid sequence of SEQ ID NO: 1. In some examples, the signal peptide comprises a polypeptide encoded by the nucleic acid sequence of SEQ ID NO: 9.

[0022] In some examples, the transmembrane domain contains the amino acid sequence of SEQ ID NO: 6. In some examples, the transmembrane domain contains a polypeptide encoded by the nucleic acid sequence of SEQ ID NO: 14.

[0023] In some examples, the intracellular signaling domain includes the primary intracellular signaling domain of an immune effector cell. In some examples, the intracellular signaling domain is derived from CD3ζ. In some examples, the intracellular signaling domain includes one or more co-stimulatory signaling domains. In some examples, the intracellular signaling domain includes the amino acid sequence of SEQ ID NO: 8. In some examples, the intracellular signaling domain includes a polypeptide encoded by the nucleic acid sequence of SEQ ID NO: 16. In some examples, the intracellular signaling domain includes the amino acid sequence of SEQ ID NO: 7. In some examples, the intracellular signaling domain includes a polypeptide encoded by the nucleic acid sequence of SEQ ID NO: 15.

[0024] In some examples, the CAR polypeptide further comprises a hinge domain located between the C-terminus of the extracellular antigen-binding domain and the N-terminus of the transmembrane domain. In some examples, the hinge domain comprises the amino acid sequence of SEQ ID NO: 5. In some examples, the hinge domain comprises a polypeptide encoded by the nucleic acid sequence of SEQ ID NO: 13.

[0025] In some examples, the T cells are autologous T cells. In some examples, the T cells are allogeneic T cells.

[0026] In some examples, subject It is a human being.

[0027] In one aspect, the patient has multiple myeloma and Patients with a history of at least three lines of prior treatment. A method for treating the condition is provided, the method being a single intravenous injection Import Note: Compositions containing T cells subject The administration includes administering to T cells, wherein the T cells contain a chimeric antigen receptor (CAR), and the chimeric antigen receptor contains the amino acid sequence SEQ ID NO: 17, expressing the CAR in approximately 0.75 × 10⁻¹⁶ cells.6 number of T cells (CAR-T cells) per kilogram of subject mass dose of subject delivered to, where the method effectively achieves a negative state of minimal residual disease (MRD) in the subject and the negative state of minimal residual disease is evaluated in the bone marrow during a follow-up period of 28 days or more after the Import injection of the CAR-T cells.

[0028] In some embodiments, the method achieves, at a sensitivity threshold level of 10 Import during a follow-up period of about 12 months after the injection of the CAR-T cells, from about 44% to about 65% of -5 and, at a sensitivity threshold level of 10 ratio during a follow-up period of about 18 months after the injection of the CAR-T cells, from about 57% to about 76% of Import and, at a sensitivity threshold level of 10 -4 during a follow-up period of about 18 months after the injection of the CAR-T cells, from about 47% to about 68% of ratio or, at a sensitivity threshold level of 10 Import during a follow-up period of about 18 months after the injection of the CAR-T cells, from about 29% to about 50% of -5 to effectively achieve the negative state of the MRD. ratio Import ratio In some embodiments, the method achieves, at a sensitivity threshold level of 10 -6 during a follow-up period of about 12 months after the administration of the CAR-T cells, about 55% of ratio and, at a sensitivity threshold level of 10 <000056l> during a follow-up period of about 18 months after the injection of the CAR-T cells, about 67% of -5 and, at a sensitivity threshold level of 10 ratio during a follow-up period of about 18 months after the injection of the CAR-T cells, about 58% of Import or, at a sensitivity threshold level of 10 -4 during a follow-up period of about 18 months after the injection of the CAR-T cells, about 67% of ratio and, at a sensitivity threshold level of 10 Import during a follow-up period of about 18 months after the injection of the CAR-T cells, about 58% of <000,0016>or, at a sensitivity threshold level of 10 ratio during a follow-up period of about 18 months after the injection of the CAR-T cells, about 39% of Import at a sensitivity threshold level of 10 -6 during a follow-up period of about 18 months after the injection of the CAR-T cells. ratio This effectively achieves a negative MRD test result.

[0030] In some embodiments, the method is used for the CAR-T cells. Import During the follow-up period of approximately 12 months after the note, 10 -5 At the sensitivity threshold level, the sample has an evaluable sample. subject In that case, approximately 83% to approximately 98% ratio or the CAR-T cells Import Note: During a follow-up period of approximately 18 months, 10 -5 At the sensitivity threshold level, the sample has an evaluable sample. subject In that case, approximately 82% to approximately 97% ratio This effectively achieves a negative status for minimal residual disease (MRD).

[0031] In some embodiments, the method is used for the CAR-T cells. Import During the follow-up period of approximately 12 months after the note, 10 -5 At the sensitivity threshold level, the sample has an evaluable sample. subject In that case, approximately 93% ratio or the CAR-T cells Import Note: During a follow-up period of approximately 18 months, 10 -5 At the sensitivity threshold level, the sample has an evaluable sample. subject In that case, approximately 92% ratio This effectively achieves a negative status for minimal residual disease (MRD).

[0032] In some embodiments, the method is used for the CAR-T cells. Import Note: subject At least one response is effectively obtained, wherein the at least one response includes, in order from best to worst, a strict complete response, a complete response, a best partial response, a partial response, or a minimal response.

[0033] In some embodiments, the method is used for the CAR-T cells. ImportThe initial response is effectively obtained approximately 27 to 321 days after injection. In some examples, the method involves the CAR-T cells Import The initial response is effectively obtained approximately 27 to 89 days after injection. In some examples, the method involves the CAR-T cells Import The first response is effectively obtained approximately 42 days after injection. In some examples, the method involves the CAR-T cells Import Effective initial response is achieved approximately 29 days after administration.

[0034] In some embodiments, the method effectively obtains one of the best responses, which is minimal response, partial response, best partial response, complete response, or strict complete response. In some embodiments, the method obtains the CAR-T cells Import During a follow-up period of approximately 12 months after ordering, approximately 91% to 99% ratio or the CAR-T cells Import During a follow-up period of approximately 18 months after the order was placed, approximately 93% to 100% of the cases were reported. ratio The method effectively obtains one of the following best responses: minimal response, partial response, best partial response, complete response, or strict complete response. In some embodiments, the method is used to obtain the CAR-T cells Import During a follow-up period of approximately 12 months after ordering, approximately 97% ratio or the CAR-T cells Import During a follow-up period of approximately 18 months after ordering, approximately 98% ratio The patient effectively obtains one of the following best responses: minimal response, partial response, best partial response, complete response, or strict complete response.

[0035] In some embodiments, the method effectively obtains one of the best responses: partial response, best partial response, complete response, or severe complete response. In some embodiments, the method uses the CAR-T cells Import During a follow-up period of approximately 12 months after ordering, approximately 91% to 99% ratio or the CAR-T cells Import During a follow-up period of approximately 18 months after the order was placed, approximately 93% to 100% of the cases were reported. ratioThe method effectively obtains one of the following best responses: partial response, best partial response, complete response, or severe complete response. In some embodiments, the method involves the CAR-T cells Import During a follow-up period of approximately 12 months after ordering, approximately 97% ratio or the CAR-T cells Import During a follow-up period of approximately 18 months after the order was placed, approximately 97% ratio The patient effectively achieves one of the following outcomes: partial response, best partial response, complete response, or strict complete response.

[0036] In some embodiments, the method effectively obtains one of the best responses: best partial response, complete response, or severe complete response. In some embodiments, the method uses the CAR-T cells Import During a follow-up period of approximately 12 months after ordering, approximately 86% to 97% ratio or the CAR-T cells Import During a follow-up period of approximately 18 months after ordering, approximately 88% to 98% ratio The method effectively obtains one of the best responses, which is either a best partial response, a complete response, or a severe complete response. In some examples, the method is used to obtain the CAR-T cells Import During a follow-up period of approximately 12 months after ordering, approximately 93% ratio or the CAR-T cells Import During a follow-up period of approximately 18 months after the order was placed, approximately 95% ratio This effectively achieves one of the following best responses: best partial response, complete response, or strict complete response.

[0037] In some embodiments, the method effectively obtains the best response of complete response or strict complete response. In some embodiments, the method uses the CAR-T cells Import During a follow-up period of approximately 12 months after the note, approximately 57% to approximately 76% ratio or the CAR-T cells Import During a follow-up period of approximately 18 months after the note, approximately 73% to 89% ratioThus, the best response, which is complete response or strict complete response, is effectively obtained. In some examples, the method is used to obtain the CAR-T cells Import During a follow-up period of approximately 12 months after the order was placed, approximately 67% ratio or the CAR-T cells Import During a follow-up period of approximately 18 months after the order was placed, approximately 83% ratio This effectively achieves the best possible response, which is either a complete response or a strict complete response.

[0038] In some embodiments, the method effectively obtains the best response, which is a strict complete response. In some embodiments, the method uses the CAR-T cells Import During a follow-up period of approximately 12 months after the note, approximately 57% to approximately 76% ratio or the CAR-T cells Import During a follow-up period of approximately 18 months after the note, approximately 73% to 89% ratio Thus, the best response of strict complete response is effectively obtained. In some examples, the method is used to obtain the CAR-T cells Import During a follow-up period of approximately 12 months after the order was placed, approximately 67% ratio or the CAR-T cells Import During a follow-up period of approximately 18 months after the order was placed, approximately 83% ratio This effectively achieves the aforementioned best response, which is a strict complete response.

[0039] In some embodiments, the method is subject To effectively obtain the progression-free survival period of the CAR-T cells. In some examples, the method is used to obtain the progression-free survival period of the CAR-T cells. Import Note: The CAR-T cells Import Approximately 209 days after injection, the CAR-T cells Import Approximately 386 days after injection, the CAR-T cells Import Approximately 632 days after injection or the aforementioned CAR-T cells Import Note: During the period up to approximately 684 days after the date, subject To effectively obtain the aforementioned progression-free survival period.

[0040] In some embodiments, the method is used for the CAR-T cells. ImportDuring a follow-up period of approximately 6 months after ordering, approximately 79% to 93% ratio And the CAR-T cells Import During a follow-up period of approximately 12 months after the note, approximately 67% to approximately 84% ratio And the CAR-T cells Import During a follow-up period of approximately 18 months after the note, approximately 57% to approximately 75% ratio And the CAR-T cells Import During a follow-up period of approximately 21 months after the note, approximately 57% to approximately 75% ratio or the CAR-T cells Import During a follow-up period of approximately 24 months after the note, approximately 49% to approximately 70% ratio This effectively achieves the aforementioned progression-free survival period.

[0041] In some embodiments, the method is used for the CAR-T cells. Import During the follow-up period of approximately 6 months after the order was placed, approximately 88% ratio And the CAR-T cells Import During a follow-up period of approximately 12 months after the order was placed, approximately 76% ratio And the CAR-T cells Import During a follow-up period of approximately 18 months after the note, approximately 67% ratio And the CAR-T cells Import During a follow-up period of approximately 21 months after the note, approximately 67% ratio or the CAR-T cells Import During the follow-up period of approximately 24 months after the note, approximately 61% ratio This effectively achieves the aforementioned progression-free survival period.

[0042] In some embodiments, the method is used for the CAR-T cells. Import Note: More than approximately 1 day after the above subject The method further includes treating cytokine release syndrome. In some embodiments, the method effectively obtains a recovery rate of about 1% to about 99% of the cytokine release syndrome within a period of about 1, 3, 4, 6, 16, or 97 days from the first observation of the cytokine release syndrome.

[0043] In some embodiments, the method is used for the CAR-T cells. ImportNote: More than approximately 3 days after the above subject The method further includes treating neurotoxicity associated with immune effector cells. In some embodiments, the method effectively obtains a recovery rate of about 1% to about 17% of the neurotoxicity associated with immune effector cells over a period of about 1, 4, 5, 8, 12, or 16 days from the first observation of the neurotoxicity associated with immune effector cells.

[0044] In some embodiments, the method is used for the CAR-T cells. Import The best response is effectively obtained approximately 27 to 534 days after injection. In some examples, the method is used to obtain the CAR-T cells Import The best response is effectively obtained approximately 27 to 293 days after injection. In some examples, the method involves the CAR-T cells Import The best response is effectively obtained approximately 153 days after injection. In some examples, the method is used to obtain the CAR-T cells Import The best response is effectively achieved approximately 78 days after administration.

[0045] In some embodiments, the method involves the CAR-T cells from the time of the initial response. Import Approximately 180 days after injection, the CAR-T cells Import Approximately 357 days after injection, the CAR-T cells Import Approximately 606 days after injection or the aforementioned CAR-T cells Import During the tracking period of approximately 654 days after ordering, subject To effectively maintain efficacy in the CAR-T cells. In some examples, the method is used to maintain efficacy in the CAR-T cells. Import During a follow-up period of approximately 6 months after ordering, approximately 77% to 91% ratio And the CAR-T cells Import During a follow-up period of approximately 12 months after the note, approximately 63% to approximately 81% ratio And the CAR-T cells Import During a follow-up period of approximately 18 months after the note, approximately 56% to approximately 75% ratio And the CAR-T cells ImportDuring a follow-up period of approximately 21 months after the note, approximately 52% to approximately 72% ratio or the CAR-T cells Import During a follow-up period of approximately 24 months after the note, approximately 48% to approximately 70% ratio This effectively maintains the response. In some examples, the method involves the CAR-T cells Import During the follow-up period of approximately 6 months after the note, approximately 85% ratio And the CAR-T cells Import During a follow-up period of approximately 12 months after the order was placed, approximately 74% ratio And the CAR-T cells Import During a follow-up period of approximately 18 months after the note, approximately 67% ratio And the CAR-T cells Import During a follow-up period of approximately 21 months after the note, approximately 63% ratio or the CAR-T cells Import During the follow-up period of approximately 24 months after the note, approximately 60% ratio This effectively maintains the effectiveness of the treatment.

[0046] In some examples, the method involves 10 times from the time of administration of the CAR-T cells to approximately 3 months after the administration of the CAR-T cells. -5 The negative status of minimal residual disease (MRD) assessed in the bone marrow at the sensitivity threshold level is defined as follows: subject Effectively obtained in the CAR-T cells. In some examples, the method is used to obtain the CAR-T cells. Import During a follow-up period of approximately 12 months after the note, approximately 25% to 44% ratio or the CAR-T cells Import During a follow-up period of approximately 18 months after the note, approximately 33% to approximately 54% ratio This effectively obtains a negative complete response or a negative strict complete response for minimal residual disease (MRD). In some examples, the method is used to obtain the CAR-T cells Import During a follow-up period of approximately 12 months after the order was placed, approximately 34% ratio or the CAR-T cells Import During a follow-up period of approximately 18 months after the note, approximately 43% ratioThis effectively achieves negative complete response or negative strict complete response with minimal residual disease (MRD).

[0047] This disclosure will be furthered, Siltacabutagen autoleucel for intravenous infusion With respect to a pharmaceutical product containing a suspension, wherein the pharmaceutical product is packaged, the packaging includes a label, and the label is Siltacaptogen autoleucel suspension , proteasome inhibitors, Immunomodulatory drugs and an anti-CD38 monoclonal antibody Identify as an approved drug for the treatment of adult patients with relapsed or refractory multiple myeloma who have received four or more prior lines of treatment. .

[0048] This disclosure is, That need Let's assume In adult patients Relapsed or refractory It provides a method to treat multiple myeloma, and it is approved. Pharmaceuticals of Pharmaceuticals Labels and / or descriptions herein Treatment regimen In the quantities and methods described, Siltacaptagenautoleucyl Approved suspension Pharmaceuticals This includes administering [the drug].

[0049] This disclosure is, Siltacaptagenautoleucyl Approved suspension Pharmaceuticals Further providing a method for selling, the said method is The aforementioned pharmaceutical This includes selling, Drug label of the reference product of the aforementioned drug These are proteasome inhibitors and Immunomodulatory drugs and an anti-CD38 monoclonal antibody Includes information for treating patients with relapsed or refractory multiple myeloma who have received four or more prior treatments. .

[0050] This disclosure is, Siltacaptagenautoleucyl Includes suspension Pharmaceuticals Sales To make a request Further providing a method, the said method is The aforementioned pharmaceutical Sales To make a request Including, here, Drug label of the reference product of the aforementioned drug These are proteasome inhibitors and Immunomodulatory drugs and an anti-CD38 monoclonal antibody Includes information for treating patients with relapsed or refractory multiple myeloma who have received four or more prior treatments. . [Brief explanation of the drawing]

[0051] [Figure 1]This figure shows the expression of BCMA antigens on the surface of GC, memory, and plasmablast cells in lymph nodes, long-lived plasma cells in bone marrow LN and MALT, and multiple myeloma cells. BAFF-R antigen is not expressed in plasmablasts, long-lived plasma cells, or multiple myeloma cells. TACI is expressed in memory and plasmablasts, long-lived plasma cells, and multiple myeloma cells. CD138 is expressed only in long-lived plasma cells and multiple myeloma cells.

[0052] [Figure 2] This is a diagram showing the design of the siltacaptagene autoleucel CAR. Siltacaptagene autoleucel contains two VHH domains, unlike the single VL domain and single VH domain found in various other CARs. Siltacaptagene autoleucel contains intracellular CD137 and human CD3ζ domains.

[0053] [Figure 3] This is a schematic diagram showing the production of a virus encoding siltacaptagene autoleucel CAR, the transduction of the virus into a patient's T cells, and the production of CAR T cells expressing siltacaptagene autoleucel.

[0054] [Figure 4] This is a schematic diagram illustrating the study design for siltacabutagen autoleucel CAR T cells. The patient population includes patients with relapsed or refractory multiple myeloma who have received three lines of prior treatment or are refractory to both PIs / IMiDs and have been previously exposed to PIs, IMiDs, and anti-CD38. The primary objective is to establish safety and RP2D, e.g., to investigate the incidence and severity of adverse events (stage 1b). Another primary objective is efficacy, which is ORR-PR or better, as defined by the IMWG (stage 2). The following are secondary objectives: characterization of the incidence and severity of adverse events (stage 2) and any further efficacy.

[0055] [Figure 5A]This graph shows the response and duration of response (DOR) for the 50 most frequently followed-up patients across all treatment analysis populations, based on the assessment of an independent review committee (IRC), with a median follow-up period of 12.4 months. The data is arranged along the vertical axis in order of the duration of follow-up for each responder. [Figure 5B] This graph shows the response and duration of response (DOR) for the 44 responders with the fewest follow-up periods across all treatment analysis populations, based on assessments by an independent review committee (IRC), with a median follow-up period of 12.4 months. The data is arranged along the vertical axis in order of the duration of follow-up for responders.

[0056] [Figure 6] Based on assessments by an independent review committee (IRC), the Kaplan-Meier chart of the duration of response (DOR) in all treatment analysis populations, with a median follow-up period of 12.4 months, showed that approximately 80.2% and 68.2% of respondents maintained a response for 9 and 12 months, respectively.

[0057] [Figure 7] The Kaplan-Meier chart shows the overall survival (OS) for all subjects in all treatment analysis populations, with a median follow-up period of 12.4 months, indicating that the 9-month and 12-month survival rates were approximately 90.7% and 88.5%, respectively.

[0058] [Figure 8] , [Figure 9] , [Figure 10] , [Figure 11] , [Figure 12] , [Figure 13] , [Figure 14] and [Figure 15]This figure shows a description of the regimens and data obtained in the stage 1b-2 clinical trials described herein, with a median follow-up period of 12.4 months, in which patients with relapsed, refractory multiple myeloma were treated with siltacabutagene autoleucel.

[0059] [Figure 16] , [Figure 17] , [Figure 18] and [Figure 19] This figure illustrates the evaluation and assessment of cytokine release syndrome (CRS) in the stage 1b-2 clinical trial described herein, in which patients with relapsed, refractory multiple myeloma were treated with siltacabutagene autoleucel.

[0060] [Figure 20] This graph shows the response and duration of response (DOR) in all treatment analysis populations, based on assessments by an independent review committee (IRC), with a median follow-up period of 18 months.

[0061] [Figure 21] This is a Kaplan-Meier chart of the duration of response (DOR) in the treatment analysis population, based on assessments by an independent review committee (IRC), with a median follow-up period of 18 months.

[0062] [Figure 22] This is a Kaplan-Meier chart of progression-free survival (PFS) in all treatment analysis populations, based on assessments by an independent review committee (IRC), with a median follow-up period of 18 months.

[0063] [Figure 23] This is a Kaplan-Meier plot of overall survival (OS) for all subjects in all treatment analysis populations, with a median follow-up period of 18 months.

[0064] [Figure 24A] , [Figure 24B] And [Figure 24C] A forest plot showing subgroup analysis of overall response rate (ORR) in all treatment analysis populations based on the assessment of the Independent Review Committee (IRC), when the median follow-up period is 18 months.

[0065] [Figure 25A] , [Figure 25B] And [Figure 25C] A forest plot showing subgroup analysis of duration of response (DOR) in all treatment analysis populations based on the assessment of the Independent Review Committee (IRC), when the median follow-up period is 18 months.

[0066] [Figure 26A] , [Figure 26B] And [Figure 26C] A forest plot showing subgroup analysis of the overall MRD negativity rate of 10-5 in the bone marrow of all treatment analysis populations, when the median follow-up period is 18 months.

[0067] [Figure 27A] , [Figure 27B] And [Figure 27C] A forest plot showing subgroup analysis of the overall MRD negativity rate of 10-5 in the bone marrow of subjects with evaluable samples in all treatment analysis populations, when the median follow-up period is 18 months.

[0068] [Figure 28] A figure summarizing the selection of the comparison group for indirect treatment comparison (ITC) analysis.

[0069] [Figure 29A] And [Figure 29B]This figure shows a meta-analysis comparison of overall survival for patients treated with siltacaptagen autoleucel and patients treated with physician-initiated treatment, using all index dates.

[0070] [Figure 30] This figure shows a meta-analysis comparison of progression-free survival between patients treated with siltacabutagene autoleucel and patients treated with physician-initiated treatment, using all index dates.

[0071] [Figure 31] This figure shows a meta-analysis comparison of overall survival for patients treated with siltacaptagen autoleucel and patients treated by physician's choice of treatment, using the first index date.

[0072] [Figure 32] This figure shows a meta-analysis comparison of progression-free survival between patients treated with siltacabutagene autoleucel and patients treated by physician's choice of treatment, using the first index date. [Modes for carrying out the invention]

[0073] This disclosure further provides relevant nucleic acids, recombinant expression vectors, host cells, cell populations, antibodies or their antigen-binding moieties, and pharmaceutical compositions relating to immune cells and CAR-expressing T cells of this disclosure. Dosage regimens, dosage forms, and methods for therapeutic use of CAR-T cells are further provided.

[0074] In the following, several aspects of this disclosure will be described with reference to examples for illustrative purposes only. It should be understood that many specific details, relationships, and methods are provided to provide a comprehensive understanding of this disclosure. However, as will be readily apparent to those skilled in the art, this disclosure may be practiced without one or more specific details, or using other methods, regimens, reagents, cell lines, and animals. This disclosure is not limited to the order of the actions or events shown, as some actions may occur in different orders and / or simultaneously with other actions or events. Furthermore, not all actions, steps, or events shown are necessarily required to implement the methods of this disclosure.

[0075] Unless otherwise specified, all articulate terms, symbols, and other scientific or technical terms used herein are intended to have meanings generally understood by those skilled in the art. In some cases, for clarity and / or convenience of reference, this specification defines terms that have generally understood meanings, and this specification, including such definitions, should not necessarily be interpreted as indicating a significant difference from the meanings generally understood in the art. For further understanding, terms (such as those defined in a general dictionary) should be interpreted as having meanings consistent with their meanings in the context of the relevant art and / or meanings separately defined herein.

[0076] The term "about" or "approximately" refers to a range of values ​​that is statistically significant. Such a range may be of a certain order of value or range, preferably within 50%, more preferably within 20%, even more preferably within 10%, and still more preferably within 5%. The acceptable variation encompassed by the term "about" or "approximately" depends on the specific system under study and is readily understandable to those skilled in the art.

[0077] The term "antibody" includes monoclonal antibodies (including full-length four-chain antibodies having an immunoglobulin Fc region or heavy-chain-only full-length antibodies), antibody compositions having multiepitope specificity, multispecific antibodies (e.g., bispecific antibodies, biantibodies, and single-chain molecules), and antibody fragments (e.g., Fab, F(ab')2, and Fv). The terms "immunoglobulin" (Ig) and "antibody" are used interchangeably herein. Antibodies considered herein include single-domain antibodies, e.g., heavy-chain-only antibodies.

[0078] The term "heavy-chain only antibody" or "HCAb" includes functional antibodies that contain a heavy chain but lack the light chain typically found in four-chain antibodies. Camelids (e.g., camels, llamas, alpacas) are known to produce HCAbs.

[0079] The term “single-domain antibody” or “sdAb” refers to a single antigen-binding polypeptide having three complementarity-determining regions (CDRs). A single sdAb can bind to an antigen but does not pair with a corresponding polypeptide containing CDRs. In some cases, single-domain antibodies are engineered from camel HCAbs, and their heavy-chain variable domains are referred to herein as “VHH.” Some VHHs may also be called “nanoantibodies.” Camel sdAbs are among the smallest known antigen-binding antibody fragments (see, e.g., Hamers-Casterman et al., Nature 363:446-8 (1993), Greenberg et al., Nature 374:168-73 (1995), Hassanzadeh-Ghassabeh et al., Nanomedicine (Lond), 8:1013-26 (2013)). The basic VHH has a structure FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4 from the N-terminus to the C-terminus, where FR1 to FR4 refer to framework regions 1 to 4, respectively, and CDR1 to CDR3 refer to complementarity determination regions 1 to 3.

[0080] The "variable region" or "variable domain" of an antibody refers to the amino-terminal domain of the heavy or light chain of the antibody. The variable domains of the heavy and light chains may also be called "VH" and "VL," respectively. These domains are usually the most variable parts of the antibody (compared to other antibodies of the same class) and contain the antigen-binding site. Antibodies consisting only of heavy chains from camelid species have a single heavy chain variable region called the "VHH" domain. Therefore, VHH is a special type of variable region.

[0081] The term "variable" refers to the fact that the sequences of several segments of the variable domain differ significantly between antibodies. The V domain (i.e., the variable domain) mediates antigen binding and defines the specificity of a particular antibody to that particular antigen. However, variability is not uniformly distributed across the entire span of the variable domain. Rather, it is concentrated in three segments called hypervariable regions (HVRs) within the light and heavy chain variable domains. The more conserved parts of the variable domain are called framework regions (FRs). The variable domains of the native heavy and light chains each contain four FR regions, primarily using β-sheet structures, which are linked via three HVRs. These three HVRs link together to form loops that link β-sheet structures and, in some cases, form parts of the β-sheet structures. HVRs in each strand are tightly bound by the FR region and are favorable for the formation of antibody antigen-binding sites (along with HVRs from other strands if the antibody is not an sdAb or HCAb) (see Kabat et al., Sequences of Immunological Interest, Fifth Edition, National Institute of Health, Bethesda, Md. (1991)). The constant domain does not directly participate in antibody-antigen binding, but exhibits various effector functions, such as the involvement of antibodies in antibody-dependent cell-mediated cytotoxicity.

[0082] The terms "antibody fragment", "antibody fragment", "functional fragment of an antibody" and "antigen-binding portion" are used interchangeably herein and mean one or more fragments or portions of an antibody that retain the ability to specifically bind to an antigen (see generally Holliger et al., Nat. Biotech., 23(9): 1126-1129 (2005)). The antigen recognition portion of a CAR encoded by a nucleic acid sequence disclosed herein may contain any BCMA-binding antibody fragment. Antibody fragments preferably include, for example, one or more CDRs, variable regions (or portions thereof), constant regions (or portions thereof) or combinations thereof. Examples of antibody fragments include (i) a Fab fragment, which is a monovalent fragment composed of VL, VH, CL and CHI domains; (ii) an F(ab')2 fragment, which is a bivalent fragment containing two Fab fragments linked by a disulfide bond at the hinge region position; (iii) an Fv fragment, which is composed of the VL and VH domains of a single arm of an antibody; (iv) a single-chain Fv (scFv), which is a monovalent molecule composed of two domains (i.e., VL and VH) of an Fv fragment linked via a synthetic linker, which can synthesize the two domains into a single polypeptide chain (see, for example, Bird et al., Science, 242: 423-426 (1988), Huston et al., Proc. Natl. Acad. Sci. USA, 85: 5879-5883 (1988), and Osbourn et al., Nat. Biotechnol, 16: 778 (1998)); and (v) a diabody, which is a dimer of polypeptide chains, each polypeptide chain containing a VH linked to a VL via a peptide linker, the peptide linker being too short to allow pairing between VH and VL in the same polypeptide chain, thereby driving pairing of complementary domains in different VH-VL polypeptide chains to produce a dimer molecule having two functional antigen-binding sites, but are not limited thereto. Antibody fragments are known in the art and are described in more detail, for example, in U.S. Patent Application Publication No. 2009 / 0093024 A1.

[0083] As used herein, the terms “specific binding,” “specific recognition,” or “specific to…” refer to measurable and reproducible interactions, such as the binding of a target to an antigen-binding protein (e.g., CAR or VHH), which determines the presence of the target in the presence of a heteromolecular population including biomolecules.

[0084] The term "specificity" refers to the selective recognition of an antigen by an antigen-binding protein (e.g., CAR or VHH) against a specific epitope of an antigen. For example, natural antibodies are monospecific.

[0085] A "chimeric antigen receptor" or "CAR" is an artificially constructed hybrid protein or polypeptide containing an antigen-binding domain of an antibody (or antibody fragment) linked to a T cell signaling domain. A feature of the CAR may include the ability to redirect T cell specificity and reactivity to a selected target in a non-MHC-restrictive manner (utilizing the antigen-binding properties of a monoclonal antibody). Non-MHC-restrictive antigen recognition circumvents the main mechanism of tumor escape by conferring the ability of CAR-expressing T cells to recognize antigens (independent of antigen processing). Furthermore, when expressed on T cells, the non-dimerization of CAR with the endogenous T cell receptor (TCR) α and β chains is advantageous. T cells expressing CAR are referred to herein as CAR T cells, CAR-T cells, or CAR-modified T cells, and these terms are used interchangeably herein. These cells can be genetically modified to stably express an antibody-binding domain on their surface, thereby conferring novel MHC-independent antigen specificity. A "BCMA CAR" refers to a CAR that has an extracellular binding domain specific to BCMA. A "dual epitope CAR" refers to a CAR that has extracellular binding domains specific to two different epitopes of BCMA.

[0086] " Siltacaptagenautoleucyl"Cilta-cel" is a chimeric antigen receptor T-cell (CAR-T) therapy that contains two BCMA-targeting VHH domains designed to confer avidity to B-cell maturation antigen (BCMA). Siltacaptagenautoleucyl teeth, Siltacaptagenautoleucyl CAR (wrench) virus The vector may include T lymphocytes transduced by a vector-encoded CAR. The CAR targets human B cell maturation antigen (BCMA CAR). Siltacaptagenautoleucyl Wrench for coding CAR virus A schematic diagram of the vector is shown in Figure 2. Siltacaptagenautoleucyl The amino acid sequence of CAR is the amino acid sequence of SEQ ID NO: 17.

[0087] The terms "expression" and "expression" mean allowing or causing the generation of information in a gene or DNA sequence. For example, expression can take the form of producing a protein by activating cellular functions involved in the transcription and translation of the corresponding gene or DNA sequence. A DNA sequence forms "expression products," such as proteins, in a cell or through cellular expression. The expression product itself, for example, the resulting protein, may also be called "expressed" by the cell. Expression products may be characterized as intracellular, extracellular, or transmembrane.

[0088] The term “treat” or “treatment” refers to therapeutic treatment, where the objective is to alleviate or reduce undesirable physiological changes or disease, or to provide beneficial or desirable clinical outcomes during the course of treatment. Beneficial or desirable clinical outcomes include, whether detectable or undetectable, reduction of symptoms, reduction of disease severity, stabilization of the disease state (i.e., no worsening), delay or mitigation of disease progression, improvement or mitigation of the disease state, and / or remission (whether partial or complete remission). “Treatment” further means: subject This may also mean that the survival time is extended compared to the expected survival time if no treatment is received. subjectThis refers to a person who is already suffering from an undesirable physiological change or disease. subject , and a tendency to suffer from physiological changes or diseases subject This includes. Treatment may also refer to a therapeutic agent, as referred to herein as “medicament or medication,” which may be intended to help achieve a beneficial or desirable clinical outcome of interest through its action. Therapeutic agents or drugs can be administered through many routes. subject It can be administered via at least intravenous and oral routes. The term "intravenous" in relation to the administration of therapeutic agents or drugs refers to administering the therapeutic agent or drug into one or more veins. The term "oral" in relation to the administration of therapeutic agents or drugs refers to administering the therapeutic agent or drug through an oral passage such as the mouth.

[0089] As used herein, subject The term "animals" refers to animals. subject The terms "patient" and "patient" are subject In this specification, it is used interchangeably when referring to it. subject "Patients" refers to people who are being treated for a disease or are being prevented from developing a disease. The methods described herein do not belong to any classification. Animals It may be used to treat [condition]. Examples of such animals include mammals. Mammals include, but are not limited to, rodents such as mice and hamsters, and mammals of the order Logomorpha such as rabbits. Mammals may also be of the order Carnivora, which includes felines (cats) and canines (dogs). Mammals may also be of the order Artiodactyla, which includes bovines (cats) and pigs (pigs), or of the order Perissodactyla, which includes equids (horses). Mammals may also be of the order Primates, Ceboids, Simoids (monkeys), or Anthropoids (humans and monkeys). In some embodiments, the mammal is a human.

[0090] The term "effective" applied to dosage or quantity means that it is necessary subject This refers to the amount of compound or pharmaceutical composition sufficient to produce the desired activity after administration. When administering a combination of active ingredients, the effective amount of the combination may or may not include the amount of each individual ingredient that would be effective if administered individually. The exact amount required is: subject Depending on the species, age and general condition, the severity of the condition being treated, the one or more specific drugs used, and the administration pattern, subject It changes depending on the circumstances.

[0091] As used in conjunction with the compositions described herein, the term "pharmaceutically acceptable" refers to the molecular entities and other components of a composition that are physiologically acceptable and do not typically produce adverse reactions when administered to mammals (e.g., humans). Preferably, the term "pharmaceutically acceptable" means that it is approved by a federal or state regulatory authority or listed in the United States Pharmacopeia or other generally accepted pharmacopoeias for use in mammals, more specifically humans.

[0092] The term " " is used in conjunction with the treatment methods described herein. Treatment history "A planned treatment procedure" refers to one or more cycles of a planned treatment procedure, which may consist of one or more planned cycles of monotherapy or combination therapy and a treatment sequence administered in a planned manner. For example, a planned treatment method consisting of induction therapy followed by autologous stem cell transplantation followed by maintenance therapy is one Treatment history Therefore, if the planned course of treatment is modified to include other therapeutic agents or drugs (alone or in combination) due to disease progression, relapse, or toxicity, the new treatment may be necessary. Treatment history It is believed that this was initiated. Even if the planned observation period after therapy is interrupted because additional treatment for the disease is needed, new treatment is considered. Treatment history It is believed that this has been initiated.

[0093] As used herein in conjunction with treatment with a particular therapeutic agent or drug, the term "refractory" refers to a disease or condition that does not respond to the said therapeutic agent or drug. Disease TargetThis refers to a disease that does not respond to primary or emergency treatment, or that progresses within 60 days of the last treatment.

[0094] The term "refractory disease" refers to a condition in which minimal response is not achieved with treatment, or where the disease progresses to progression.

[0095] The terms used herein are for the purpose of describing specific embodiments only and are not intended to be limiting. As used herein, the indefinite articles “a / an” and “the / the said” should be understood to include multiple references unless the context otherwise explicitly indicates.

[0096] Throughout the disclosure, each aspect of the disclosure may be presented in the form of a scope. It should be understood that scope descriptions are merely for convenience and brevity and should not be interpreted as an inflexible limitation on the scope of the disclosure. Therefore, a scope description should be considered to have all possible sub-scopes that are precisely disclosed and the individual numbers within those scopes. For example, a scope description such as 1 to 6 should be considered to have precisely disclosed sub-scopes such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, and the individual numbers within those scopes, e.g., 1, 2, 2.7, 3, 4, 5, 5.3, and 6. As another example, a range such as 95%–99% identity includes subranges that have 95%, 96%, 97%, 98%, or 99% identity, and also include subranges such as 96%–99%, 96%–98%, 96%–97%, 97%–99%, 97%–98%, and 98%–99% identity. This applies regardless of the width of the range. vector

[0097] Using standard recombination techniques, Out The polynucleotide sequence encoding the CAR described in the application can be obtained. The desired polynucleotide sequence can be isolated and sequenced from antibody-producing cells such as hybridoma cells. Alternatively, polynucleotides can be synthesized using a nucleotide synthesizer or PCR technology.

[0098] This disclosure further provides vectors comprising nucleic acid sequences encoding the CARs disclosed herein. These vectors include, for example, plasmids, cosmids, virus Vector (for example, retro virus or adeno virus ) or phages may also be used. Suitable vectors and vector manufacturing methods are well known in this field (see, for example, Sambrook et al. and Ausubel et al.).

[0099] In addition to the nucleic acid sequences encoding the CARs disclosed herein, the vectors preferably include expression regulatory sequences that provide expression of the nucleic acid sequences in host cells, such as promoters, enhancers, polyadenylation signals, transcriptional terminators, and internal ribosome entry sites (IRESs). Exemplary expression regulatory sequences are known in the art and are described, for example, in Goddel, Gene Expression Technology: Methods in Enzymology, Vol. 185, Academic Press, San Diego, Calif. (1990).

[0100] In some examples, the vector contains a promoter. Numerous promoters recognized by many potential host cells are well known. The selected promoter is removed from the source DNA by restriction enzyme digestion, and the isolated promoter sequence is used as the base. Out By insertion into the vector of the application, it can be operably ligated to the cistron DNA encoding the CAR disclosed herein. Numerous promoters from many different sources are well known in the art, including constitutive, inducible, and inhibitory promoters. Representative promoter sources include, for example, virusThis includes mammals, insects, plants, yeasts, and bacteria, and suitable promoters from these sources are readily available or can be synthesized and manufactured based on publicly available sequences from depositary centers such as ATCC and other commercial or private sources. Promoters can be unidirectional (i.e., transcription starts in one direction) or bidirectional (i.e., transcription starts in the 3' or 5' direction). Non-limiting examples of promoters include, for example, the T7 bacterial expression system, the pBAD(araA) bacterial expression system, and cytomegalovirus. virus Examples include the (CMV) promoter, SV40 promoter, and RSV promoter. Examples of inducible promoters include the Tet system (US Patent Nos. 5,464,758 and 5,814,618), the ecdysone-inducible system (No et al., Proc. Natl. Acad. Sci., 93: 3346-3351 (1996)), the T-REX® system (Invitrogen, Carlsbad, CA), the LACSWITCH® system (Stratagene, San Diego, CA), and the Cre-ERT tamoxifen-inducible recombinase system (Indra et al., Nuc. Acid. Res., 27: 4324-4327 (1999); Nuc. Acid. Res., 28: e99 (2000), US Patent No. 7,112,715, and Kramer & Fussenegger, Methods Mol. Biol, 308: 123-144). (2005)) is included.

[0101] In some embodiments, the vector includes an “enhancer.” As used herein, the term “enhancer” refers, for example, to a DNA sequence that increases the transcription of a nucleic acid sequence to which it is operably ligated. The enhancer may be located several kilobases away from the coding region of the nucleic acid sequence and can mediate the binding of regulatory factors, changes in DNA methylation patterns, or changes in DNA structure. Numerous enhancers from various different sources are well known in the art and are available in cloned polynucleotides or within cloned polynucleotides (e.g., from depositary centers, e.g., ATCC, and other commercial or private sources). Many polynucleotides containing promoters (e.g., the commonly used CMV promoter) also contain enhancer sequences. The enhancer may be located upstream, within, or downstream of the coding sequence. The term “Ig enhancer” refers to an enhancer element derived from an enhancer region, which is mapped within an immunoglobulin (Ig) locus. Such Ig enhancers include, for example, heavy-chain (μ)5' enhancers, light-chain (κ)5' enhancers, κ and μ intron enhancers, and 3' enhancers (see, for general information, Paul WE (ed.), Fundamental Immunology, 3rd Edition, Raven Press, New York (1993), pp. 353-363, and U.S. Patent No. 5,885,827).

[0102] In some embodiments, the vector includes a “selectable marker gene.” As used herein, the term “selectable marker gene” refers to a nucleic acid sequence that enables cells expressing the nucleic acid sequence to be specifically selected or targeted in the presence of a corresponding selector. Appropriate selectable marker genes are known in this field and, for example, in international patent application publications WO 1992 / 08796 and WO 1994 / 28143, Wigler et al., Proc. Natl. Acad. Sci. USA, 77: 3567 (1980), O'Hare et al., Proc. Natl. Acad. Sci. USA, 78: 1527 (1981), Mulligan & Berg, Proc. Natl. Acad. Sci. USA, 78: 2072 (1981), Colberre-Garapin et al., J. Mol. Biol., 150: 1 (1981), Santerre et al., Gene, 30: 147 (1984), Kent et al., Science, 237: 901-903 (1987), Wigler et al. This is described in Cell, IP. 223 (1977), Szybalska & Szybalski, Proc. Natl. Acad. Sci. USA, 48: 2026 (1962), Lowy et al., Cell, 22: 817 (1980), and U.S. Patent Nos. 5,122,464 and 5,770,359.

[0103] In some examples, the vector is an "episome expression vector" or "episome," which is replicable in host cells and persists as an extrachromosomal segment of DNA within the host cell under appropriate selective pressure (see, for example, Conese et al., Gene Therapy, 11: 1735-1742 (2004)). A typical commercially available episome expression vector is Epstein-Burr. virus Derived nuclear antigen 1 (EBNA1) and Epstein-Barr virusThis includes, but is not limited to, episomal plasmids that utilize the (EBV) replication origin (oriP). Vectors pREP4, pCEP4, pREP7, and pcDNA3.1 from Invitrogen (Carlsbad, California) and pB-CMV from Stratagene (La Jolla, California) represent non-exclusive examples of episomal vectors that use the T antigen and SV40 replication origin instead of EBMAL and oriP.

[0104] In some embodiments, the vector is an "integrated expression vector," which may be randomly integrated into the host cell's DNA or may contain recombination sites to enable recombination between the expression vector and specific sites in the host cell's chromosomal DNA. Such integrated expression vectors can utilize endogenous expression regulatory sequences in the host cell chromosome to achieve the expression of a desired protein. Examples of site-specifically integrated vectors include, for example, the flp-in system component from Invitrogen (Carlsbad, CA) (e.g., pcDNA® 5 / FRT), or the cre-lox system, which can be found in, for example, the pExchange-6 core vector from Stratagene (La Jolla, CA). Examples of randomly integrated vectors in the host cell chromosome include, for example, pcDNA3.1 from Invitrogen (Carlsbad, CA) (introduced when the T antigen is absent), and pCI or pFNI OA (ACT) FLEXI® from Promega (Madison, WI).

[0105] In some embodiments, the vector is virus It is a vector. Typical. virus The expression vector is adeno virus Base vector (for example, adeno available from Crucell, Inc. (Leiden, The Netherlands)) virus Base (Per.C6 series), wrench virus Base vector (e.g., wrench from Life Technologies (Carlsbad, CA)) virus Base pLPl) and retro virus This includes, but is not limited to, vectors (e.g., pFB-ERV plus pCFB-EGSH from Stratagene (La Jolla, CA)). In preferred embodiments, virus Vector is a wrench virus It is a vector.

[0106] A vector containing the nucleic acid of the present invention encoding a CAR is introduced into a host cell, the host cell being capable of expressing the thereby encoded CAR, and includes any suitable prokaryotic or eukaryotic cell. Preferred host cells are those that can proliferate easily and reliably, have a reasonable and rapid growth rate, have a well-characterized expression system, and can be easily and effectively transformed or transfected.

[0107] As used herein, the term “host cell” refers to any type of cell that may contain an expression vector. The host cell may be a eukaryotic cell, e.g., a plant, animal, fungus, or algae, or a prokaryotic cell, e.g., a bacterium or protist. The host cell may be a cultured cell or a primary cell, i.e., directly isolated from a living organism, e.g., a human. The host cell may be an adherent cell or a suspension cell, i.e., a cell that grows in a suspension. Suitable host cells are known in the art and include, for example, DH5α Escherichia coli cells, Chinese hamster ovary cells, monkey VERO cells, COS cells, HEK 293 cells, etc. In preferred examples, the host cell is HEK 293 cells. In some examples, the HEK 293 cells are derived from the ATCC SD-3515 lineage. In some examples, the HEK 293 cells are derived from the IU-VPF MCB lineage. In some examples, the HEK 293 cells are derived from the IU-VPF MWCB lineage. In some embodiments, the host cells may be peripheral blood lymphocytes (PBLs), peripheral blood mononuclear cells (PBMCs), or natural killer cells (NKs). Preferably, the host cells are natural killer (NK) cells. More preferably, the host cells are T cells.

[0108] To amplify or replicate the recombinant expression vector, the host cell may be a prokaryotic cell, such as a DH5α cell. virus From the expression vector virus To produce CAR, the host cell may be a eukaryotic cell, such as a HEK 293 cell. To produce recombinant CAR, the host cell may be a mammalian cell. Preferably, the host cell is a human cell. The host cell may be any cell type, may come from any type of tissue, and may be at any developmental stage. Methods for selecting suitable mammalian host cells, and for transforming, culturing, amplifying, screening, and purifying cells are known in the art.

[0109] In some embodiments, the present disclosure provides isolated host cells expressing nucleic acid sequences encoding CARs as described herein.

[0110] In some embodiments, the host cell is a T cell. The T cells of this disclosure may be any T cells, such as cultured T cells such as primary T cells, or T cells from a cultured T cell line, or T cells obtained from a mammal. If obtained from a mammal, the T cells may be obtained from many sources, including, but not limited to, blood, bone marrow, lymph nodes, thymus, or other tissues or body fluids. Furthermore, the T cells may be concentrated or purified. The T cells are preferably human T cells (e.g., isolated from humans). The T cells may be at any developmental stage and include, but are not limited to, CD4+ / CD8+ double-positive T cells, CD4+ helper T cells, e.g., Th and Th2 cells, CD8+ T cells (e.g., cytotoxic T cells), tumor-infiltrating cells, memory T cells, naive T cells, etc. In one embodiment, the T cells are CD8+ T cells or CD4+ T cells. T cell lines are available, for example, from the American Type Culture Collection (ATCC, Manassas, VA) and the German Microbial Cell Culture Collection (DSMZ), and include, for example, Jurkat cells (ATCC TIB-152), Sup-Tl cells (ATCC CRL-1942), RPMI 8402 cells (DSMZ ACC-290), Karpas 45 cells (DSMZ ACC-545), and their derivatives.

[0111] In some embodiments, the host cells are natural killer (NK) cells. NK cells are cytotoxic lymphocytes that function in the innate immune system. Defined as macrogranular lymphocytes, NK cells constitute a third class of cells differentiated from common lymphoid progenitor cells, which also produce B lymphocytes and T lymphocytes (see, for example, Immunobiology, 5th edition, Janeway et al., eds., Garland Publishing, New York, NY (2001)). NK cells differentiate and mature in the bone marrow, lymph nodes, spleen, amygdala, and thymus. After maturation, NK cells enter the cycle as macro lymphocytes with distinctive cytotoxic granules. NK cells can kill several abnormal cells, such as some tumor cells. virusThey can recognize and kill infected cells and are considered important in innate immune defense against intracellular pathogens. As described above regarding T cells, NK cells may be any NK cells, such as cultured NK cells such as primary NK cells, or NK cells from cultured NK cell lines, or NK cells obtained from mammals. When obtained from mammals, NK cells can be obtained from many sources, including but not limited to blood, bone marrow, lymph nodes, thymus, or other tissues or body fluids. Furthermore, NK cells may be concentrated or purified. Preferably, NK cells are human NK cells (e.g., isolated from humans). NK cell lines are available, for example, from the American Type Culture Collection (ATCC, Manassas, VA), and include, for example, NK-92 cells (ATCC CRL-2407), NK92MI cells (ATCC CRL-2408), and their derivatives.

[0112] In some embodiments, nucleic acid sequences encoding CARs may be introduced into cells by “transfection,” “transformation,” or “transduction.” As used herein, “transfection,” “transformation,” or “transduction” refers to the introduction of one or more exogenous polynucleotides into host cells by physical or chemical means. Many transfection techniques are known in this field and include, for example, calcium phosphate DNA coprecipitation (e.g., Murray EJ (ed.), Methods in Molecular Biology, Vol. 7, Gene Transfer and Expression Protocols, Humana Press (1991)), DEAE-dextran, electroporation, cationic liposome-mediated transfection, tungsten particle-assisted microparticle impaction (Johnston, Nature, 346: 776-777 (1990)), and strontium phosphate DNA coprecipitation (Brash et al., Mol. Cell Biol., 7: 2031-2034 (1987)). After infected granules proliferate in appropriate packaging cells, phages or virus The vector may be introduced into host cells, and many packaging cells are commercially available. Chimeric antigen receptor

[0113] International Patent Publication WO 2018 / 028647 is incorporated herein by reference in its entirety. U.S. Patent Publication 2018 / 0230225 is incorporated herein by reference in its entirety.

[0114] This disclosure relates to cells expressing chimeric antigen receptors (CARs). subjectA method for treating [condition] is provided. The CAR comprises an extracellular antigen-binding domain containing one or more single-domain antibodies. In various examples, a BCMA-targeting CAR (also referred to herein as "BCMA CAR") is provided, comprising a polypeptide comprising (a) an extracellular antigen-binding domain containing an anti-BCMA binding moiety, (b) a transmembrane domain, and (c) an intracellular signaling domain. In some examples, the anti-BCMA binding moiety is camel, chimeric, human, or humanized. In some examples, the intracellular signaling domain comprises a primary intracellular signaling domain of an immune effector cell (e.g., a T cell). In some examples, the primary intracellular signaling domain is derived from CD4. In some examples, the primary intracellular signaling domain is derived from CD3ζ. In some examples, the intracellular signaling domain comprises a co-stimulatory signaling domain. In some examples, the co-stimulatory signaling domain is derived from a co-stimulatory molecule selected from the group consisting of ligands and combinations thereof for CD27, CD28, CD137, OX40, CD30, CD40, CD3, LFA-1, ICOS, CD2, CD7, LIGHT, NKG2C, B7-H3, and CD83. In some examples, the transmembrane domain is derived from CD137.

[0115] In some examples, BCMA CAR further comprises a hinge domain (e.g., CD8α hinge domain) located between the C-terminus of the extracellular antigen-binding domain and the N-terminus of the transmembrane domain. In some examples, BCMA CAR further comprises a signal peptide (e.g., CD8α signal peptide) located at the N-terminus of the polypeptide. In some examples, the polypeptide comprises, from N-terminus to C-terminus, a CD8α signal peptide, an extracellular antigen-binding domain, a CD8α hinge domain, a CD28 transmembrane domain, a first co-stimulatory signaling domain derived from CD28, a second co-stimulatory signaling domain derived from CD137, and a primary intracellular signaling domain derived from CD4. In some examples, the polypeptide comprises, from N-terminus to C-terminus, a CD8α signal peptide, an extracellular antigen-binding domain, a CD8α hinge domain, a CD8α transmembrane domain, a second co-stimulatory signaling domain derived from CD137, and a primary intracellular signaling domain derived from CD3ζ. In some examples, BCMA CAR is monospecific. In some examples, BCMA CAR is monovalent.

[0116] Book Out The invention further provides CARs having two or more binding sites (including, but not limited to, one of 2, 3, 4, 5, 6, or more) that specifically bind to antigens such as BCMA. In some examples, one or more binding sites are antigen-binding fragments. In some examples, one or more binding sites include a single-domain antibody. In some examples, one or more binding sites include a VHH.

[0117] In some examples, the CAR is a polyvalent (e.g., divalent, trivalent, or higher valency) CAR comprising a polypeptide, the polypeptide comprising (a) an extracellular antigen-binding domain comprising several binding sites (e.g., at least about 2, 3, 4, 5, 6, or more) that specifically bind to an antigen (e.g., a tumor antigen), (b) a transmembrane domain, and (c) an intracellular signaling domain.

[0118] In some embodiments, the binding portion, for example, VHH (containing multiple VHHs, or a first VHH and / or a second VHH) is camel, chimera, human, or humanized. In some embodiments, the binding portions or VHHs are linked to each other via peptide bonds or peptide linkers. In some embodiments, the length of each peptide linker is less than or equal to about 50 amino acids (e.g., less than or equal to one of about 35, 25, 20, 15, 10, or 5).

[0119] In some embodiments, the first BCMA binding moiety and / or the second BCMA binding moiety is anti-BCMA VHH. In some embodiments, the first BCMA binding moiety is the first anti-BCMA VHH, and the second BCMA binding moiety is the second anti-BCMA VHH.

[0120] In some examples, the first BCMA binding site and the second BCMA binding site are linked to each other via a peptide linker. In some examples, the peptide linker contains the amino acid sequence of SEQ ID NO: 3. In some examples, the peptide linker contains a polypeptide encoded by the nucleic acid sequence of SEQ ID NO: 11.

[0121] In some examples, the CAR further comprises a hinge domain (e.g., a CD8α hinge domain) located between the C-terminus of the extracellular antigen-binding domain and the N-terminus of the transmembrane domain. In some examples, the CAR further comprises a signal peptide (e.g., a CD8α signal peptide) located at the N-terminus of the polypeptide.

[0122] While we do not wish to be bound by theory, multivalent CARs or CARs containing extracellular antigen-binding domains with a first BCMA-binding moiety and a second BCMA-binding moiety may be particularly suitable for targeting multimeric antigens via synergistic binding of different antigen-binding sites, or for enhancing binding affinity or avidity to antigens. Improved avidity may allow for a significant reduction in the dose of CAR-T cells required to achieve therapeutic effects, for example, a dose range of 4.0 × 10⁻⁶ 4 From 1.0 × 10 6 individual CAR-T cells / kilogram subject The mass of, or 3.0 × 10 6 From 1.0 × 10 8 These are total CAR-T expressing cells. Monovalent CARs, such as bb2121, may need to be administered at 5 to 10 times these doses to achieve an equivalent effect. In various cases, the reduced dose range can provide a significant reduction in cytokine release syndrome (CRS) and other potentially dangerous side effects of CAR-T therapy.

[0123] Various binding sites in the CAR described herein (e.g., an extracellular antigen-binding domain including a first BCMA-binding site and a second BCMA-binding site) can be linked to one another via peptide linkers. The peptide linkers linking different binding sites (e.g., VHH) may be the same or different. Different domains of the CAR can also be linked to one another via peptide linkers. In some examples, the binding sites (e.g., VHH) are linked directly without any peptide linkers.

[0124] The peptide linker in the CAR described herein may have any suitable length. In some examples, the length of the peptide linker is at least one of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 50, 75, 100, or more amino acids. In some examples, the length of the peptide linker is less than or equal to one of about 100, 75, 50, 40, 35, 30, 25, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, or fewer amino acids. In some examples, the length of the peptide linker is one of the following: approximately 1 amino acid to approximately 10 amino acids, approximately 1 amino acid to approximately 20 amino acids, approximately 1 amino acid to approximately 30 amino acids, approximately 5 amino acids to approximately 15 amino acids, approximately 10 amino acids to approximately 25 amino acids, approximately 5 amino acids to approximately 30 amino acids, approximately 10 amino acids to approximately 30 amino acids, approximately 30 amino acids to approximately 50 amino acids, approximately 50 amino acids to approximately 100 amino acids, or approximately 1 amino acid to approximately 100 amino acids.

[0125] Book Out The CAR of the invention includes a transmembrane domain that can be directly or indirectly linked to an extracellular antigen-binding domain.

[0126] The CAR may include a T cell activating moiety. The T cell activating moiety may be derived from or obtained from any suitable molecule. In one embodiment, for example, the T cell activating moiety includes a transmembrane domain. The transmembrane domain may be derived from or obtained from any molecule known in the art. For example, the transmembrane domain may be obtained from or derived from the CD8a molecule or the CD28 molecule. While we do not wish to be bound by theory, CD8 is a transmembrane glycoprotein that functions as a co-receptor of the T cell receptor (TCR) and is mainly expressed on the surface of cytotoxic T cells. The most common form of CD8 exists as a dimer composed of CD8α and CD8β chains. CD28 is expressed on T cells and provides the co-stimulatory signals necessary for T cell activation. CD28 is a receptor for CD80(B7.1) and CD86(B7.2). In preferred embodiments, CD8α and CD28 are human.

[0127] In addition to the transmembrane domain, the T cell activation moiety may further include an intracellular (i.e., cytoplasmic) T cell signaling domain. The intercellular T cell signaling domain may be obtained from or derived from the CD28 molecule, the CD3ζ molecule or a modified form thereof, a human Fc receptor γ (FcRγ) chain, the CD27 molecule, the OX40 molecule, the 4-1BB molecule, or other intracellular signaling molecules known in the art. While we do not wish to be bound by theory, (1) CD28 is an important T cell marker for T cell costimulation, (2) CD3ζ associates with the TCR to produce a signal and contains an immune receptor tyrosine-based activation motif (ITAM), and (3) 4-1BB, also known as CD137, promotes T lymphocyte differentiation and improves the long-term survival of T lymphocytes by transmitting a potent costimulatory signal to T cells. In preferred embodiments, CD28, CD3ζ, 4-1BB, OX40, and CD27 are human.

[0128] The T cell activation domain of a CAR encoded by the nucleic acid sequences disclosed herein may comprise any combination of the above transmembrane domains and any one or more of the above intercellular T cell signaling domains. For example, the nucleic acid sequences disclosed herein can encode a CAR comprising a CD28 transmembrane domain and intracellular T cell signaling domains of CD28 and CD3ζ. Alternatively, for example, the nucleic acid sequences disclosed herein can encode a CAR comprising a CD8α transmembrane domain and intracellular T cell signaling domains of CD28, CD3ζ, Fc receptor γ (FcRγ) chain and / or 4-1BB.

[0129] In some examples, the CAR polypeptide further comprises a signal peptide located at the N-terminus of the polypeptide. In some examples, the signal peptide is derived from CD8α. In some examples, the signal peptide comprises the amino acid sequence of SEQ ID NO: 1. In some examples, the signal peptide comprises a polypeptide encoded by the nucleic acid sequence of SEQ ID NO: 9.

[0130] In some examples, the transmembrane domain contains the amino acid sequence of SEQ ID NO: 6. In some examples, the transmembrane domain contains a polypeptide encoded by the nucleic acid sequence of SEQ ID NO: 14.

[0131] In some examples, the intracellular signaling domain includes the primary intracellular signaling domain of an immune effector cell. In some examples, the intracellular signaling domain is derived from CD3ζ. In some examples, the intracellular signaling domain includes at least one co-stimulatory signaling domain. In some examples, the intracellular signaling domain includes the amino acid sequence of SEQ ID NO: 8. In some examples, the intracellular signaling domain includes a polypeptide encoded by the nucleic acid sequence of SEQ ID NO: 16. In some examples, the intracellular signaling domain includes the amino acid sequence of SEQ ID NO: 7. In some examples, the intracellular signaling domain includes a polypeptide encoded by the nucleic acid sequence of SEQ ID NO: 15.

[0132] In some examples, the CAR polypeptide further comprises a hinge domain located between the C-terminus of the extracellular antigen-binding domain and the N-terminus of the transmembrane domain. In some examples, the hinge domain comprises the amino acid sequence of SEQ ID NO: 5. In some examples, the hinge domain comprises a polypeptide encoded by the nucleic acid sequence of SEQ ID NO: 13.

[0133] In some examples, CAR includes one, more, or all of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8. In one example, CAR includes SEQ ID NO: 17. In some examples, CAR includes a polypeptide encoded by one, more, or all of the nucleic acid sequences of SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, and SEQ ID NO: 16. Immunoeffector cell composition

[0134] "Immune effector cells" refer to immune cells capable of exhibiting immune effector function. In some examples, immune effector cells express at least FcγRIII and exhibit ADCC effector function. Examples of ADCC-mediated immune effector cells include peripheral blood mononuclear cells (PBMCs), natural killer (NK) cells, mononuclear cells, cytotoxic T cells, neutrophils, and eosinophils. In some examples, immune effector cells are T cells. In some examples, T cells are autologous T cells. In some examples, T cells are allogeneic T cells. In some examples, T cells are CD4+ / CD8-, CD4- / CD8+, CD4+ / CD8+, CD4- / CD8-, or a combination thereof. In some examples, T cells express CARs and, after binding to target cells (e.g., CD20+ or ​​CD19+ tumor cells), produce IL-2, TFN, and / or TNF. In some examples, CD8+ T cells express CARs and bind to target cells, after which they lyse antigen-specific target cells.

[0135] Biological methods for introducing vectors into immune effector cells include the use of DNA and RNA vectors. virus Vectors have become the most widely used method for inserting genes into mammalian cells, such as human cells. Chemical methods for introducing vectors into immunoeffector cells include colloidal dispersion systems such as polymer complexes, nanocapsules, microspheres, and beads, and lipid-based systems including oil-in-water emulsions, micelles, mixed micelles, and liposomes. An exemplary colloidal system as an in vitro delivery vehicle is liposomes (e.g., artificial membrane vesicles).

[0136] The dosage form specified herein is 3.0 × 10 7 From 1.0 × 10 8The present invention comprises CAR-T cells, each CAR-T cell comprising a polypeptide-containing CAR, the polypeptide comprising (a) an extracellular antigen-binding domain including a first BCMA-binding moiety that specifically binds to a first epitope of BCMA and a second BCMA-binding moiety that specifically binds to a second epitope of BCMA, (b) a transmembrane domain, and (c) an intracellular signaling domain, where the first and second epitopes are different. In some examples, the dosage form is 3.0 × 10⁶ 7 From 4.0 x 10 7 Contains 10 CAR-T cells. In some examples, the dosage form is 3.5 × 10⁶. 7 From 4.5 x 10 7 Contains 10 CAR-T cells. In some examples, the dosage form is 4.0 × 10 7 From 5.0 x 10 7 Contains CAR-T cells. In some examples, the dosage form is 4.5 × 10⁶. 7 From 5.5 x 10 7 Contains 5.0 × 10⁶ CAR-T cells. In some examples, the dosage form is 5.0 × 10⁶. 7 From 6.0 x 10 7 Contains 5.5 × 10¹ CAR-T cells. In some examples, the dosage form is 5.5 × 10¹⁶. 7 From 6.5 x 10 7 Contains CAR-T cells. In some examples, the dosage form is 6.0 × 10⁶. 7 From 7.0 x 10 7 Contains CAR-T cells. In some examples, the dosage form is 6.5 × 10⁶. 7 From 7.5 x 10 7 Contains CAR-T cells. In some examples, the dosage form is 7.0 × 10⁶. 7 From 8.0 x 10 7 Contains CAR-T cells. In some examples, the dosage form is 7.5 × 10⁶. 7 From 8.5 x 10 7 Contains CAR-T cells. In some examples, the dosage form is 8.0 × 10⁶. 7 From 9.0 x 10 7 Contains CAR-T cells. In some examples, the dosage form is 8.5 × 107 From 9.5 x 10 7 Contains CAR-T cells. In some examples, the dosage form is 9.0 × 10⁶. 7 From 1.0 × 10 8 Contains 1 CAR-T cell.

[0137] In some embodiments, the provided dosage form is 3.0 × 10 7 From 1.0 × 10 8 The present invention comprises several engineered immune effector cells (e.g., T cells), the engineered immune effector cells comprising a polypeptide-containing CAR, the polypeptide comprising an extracellular antigen-binding domain including (a) a first anti-BCMA VHH that specifically binds to a first epitope of BCMA and a second anti-BCMA VHH that specifically binds to a second epitope of BCMA, (b) a transmembrane domain, and (c) an intracellular signaling domain, wherein the first and second epitopes are different. In some examples, the dosage form is 3.0 × 10⁶ 7 From 4.0 x 10 7 Contains 10 CAR-T cells. In some examples, the dosage form is 3.5 × 10⁶. 7 From 4.5 x 10 7 Contains 10 CAR-T cells. In some examples, the dosage form is 4.0 × 10 7 From 5.0 x 10 7 Contains CAR-T cells. In some examples, the dosage form is 4.5 × 10⁶. 7 From 5.5 x 10 7 Contains 5.0 × 10⁶ CAR-T cells. In some examples, the dosage form is 5.0 × 10⁶. 7 From 6.0 x 10 7 Contains 5.5 × 10¹ CAR-T cells. In some examples, the dosage form is 5.5 × 10¹⁶. 7 From 6.5 x 10 7 Contains CAR-T cells. In some examples, the dosage form is 6.0 × 10⁶. 7 From 7.0 x 10 7 Contains CAR-T cells. In some examples, the dosage form is 6.5 × 10⁶. 7 From 7.5 x 107 Contains CAR-T cells. In some examples, the dosage form is 7.0 × 10⁶. 7 From 8.0 x 10 7 Contains CAR-T cells. In some examples, the dosage form is 7.5 × 10⁶. 7 From 8.5 x 10 7 Contains CAR-T cells. In some examples, the dosage form is 8.0 × 10⁶. 7 From 9.0 x 10 7 Contains CAR-T cells. In some examples, the dosage form is 8.5 × 10 7 From 9.5 x 10 7 Contains CAR-T cells. In some examples, the dosage form is 9.0 × 10⁶. 7 From 1.0 × 10 8 Contains 1 CAR-T cell.

[0138] In some embodiments, the cell population of the CAR-T formulation described herein comprises T cells or T cell populations, for example, at different stages of differentiation. The stages of T cell differentiation include naive T cells, stem central memory T cells, central memory T cells, effector memory T cells, and terminal effector T cells, ranging from the lowest to the highest degree of differentiation. Antigen violence After exposure, naive T cells proliferate and differentiate into memory T cells, such as stem central memory T cells and central memory T cells, and then into effector memory T cells. After receiving appropriate T cell receptors, costimulatory signals, and inflammatory signals, memory T cells further differentiate into final effector T cells. See, for example, Restifo. Blood. 124.4(2014):476-77 and Joshi et al. J. Immunol. 180.3(2008):1309-15.

[0139] Naive T cells may have the expression pattern of the cell surface markers CCR7+, CD62L+, CD45RO-, and CD95-. Stem central memory T cells (Tscm) may have the expression pattern of the cell surface markers CCR7+, CD62L+, CD45RO-, and CD95+. Central memory T cells (Tcm) may have the expression pattern of the cell surface markers CCR7+, CD62L+, CD45RO+, and CD95+. Effector memory T cells (Tem) may have the expression pattern of the cell surface markers CCR7-, CD62L-, CD45RO+, and CD95+. Final effector T cells (Teff) may have the expression pattern of the cell surface markers CCR7-, CD62L-, CD45RO-, and CD95+. For example, see Gattinoni et al. Nat. Med. 17(2011):1290-7 and Flynn et al. Clin. Translat. Immunol. 3(2014):e20. Pharmaceutical compositions and preparations

[0140] Book Out The wish further provides a pharmaceutical composition comprising any one anti-BCMA antibody of the present disclosure or any one engineered immunoeffector cell of any one CAR (e.g., BCMA CAR) described herein, and a pharmaceutically acceptable vector. The pharmaceutical composition may be prepared in the form of a lyophilized preparation or an aqueous solution by mixing any immunoeffector cells of the desired purity as described herein with an optional pharmaceutically acceptable vector, excipient, or stabilizer (Remington's Pharmaceutical Sciences, 16th edition, edited by Osol, A. (1980)). In some examples, the CAR-T cell pharmaceutical composition further comprises an excipient selected from dimethyl sulfoxide or dextran-40.

[0141] The compositions described herein may be administered as part of a pharmaceutical composition comprising one or more vectors. The choice of vector is partially determined by a specific nucleic acid sequence, vector, or host cell expressing the CAR disclosed herein, and a specific method for administering the nucleic acid sequence, vector, or host cell expressing the CAR disclosed herein. Thus, multiple suitable formulations of the pharmaceutical compositions disclosed herein exist.

[0142] For example, a pharmaceutical composition may contain a preservative. Suitable preservatives may include, for example, methylparaben, propylparaben, sodium benzoate, and benzalkonium chloride. A mixture of two or more preservatives may be used at the discretion of the preservative. The preservative or mixture thereof is typically present in an amount of about 0.0001% to about 2% of the total weight of the composition.

[0143] Furthermore, buffering agents may be used in the composition. Suitable buffering agents include, for example, citric acid, sodium citrate, phosphoric acid, potassium phosphate, and various other acids and salts. Mixtures of two or more buffering agents may be used at the discretion of the parties. The buffering agent or mixture thereof is typically present in an amount of about 0.001% to about 4% of the total weight of the composition.

[0144] Compositions comprising a nucleic acid sequence encoding a CAR disclosed herein or a host cell expressing a CAR disclosed herein may be prepared as inclusion complexes, such as cyclodextrin inclusion complexes, or liposomes. Liposomes may be used to target host cells (e.g., T cells or NK cells) or the nucleic acid sequences disclosed herein to a particular tissue. Liposomes may also be used to increase the half-life of the nucleic acid sequences disclosed herein. For example, many methods, such as those described in Szoka et al., Ann. Rev. Biophys. Bioeng., 9: 467 (1980), and U.S. Patent Nos. 4,235,871, 4,501,728, 4,837,028, and 5,019,369, may be used in the manufacture of liposomes. The compositions may use timed-release delivery systems, delayed-release delivery systems, and sustained-release delivery systems such that delivery of the compositions disclosed herein occurs prior to sensitization of the site of treatment and has sufficient time to cause sensitization of the site of treatment. Many types of release delivery systems are available and are known to those of skill in the art. Such systems can increase convenience to the Target physician by avoiding repeated administration of the composition and can be particularly suitable for some of the embodiments of the present disclosure.

[0145] In some embodiments, the CAR-T cells are from about 1.0×10 5 to 2.0×10 5 cells / kg, 1.5×10 5 to 2.5×10 5 cells / kg, 2.0×10 5 to 3.0×10 5 cells / kg, 2.5×10 5 to 3.5×10 5 cells / kg, 3.0×10 5 to 4.0×10 5 cells / kg, 3.5×10 5 to 4.5×10 5 cells / kg, 4.0×10 5 to 5.0×10 5 cells / kg, 4.5×105 from 5.5×10 5 cells / kg, 5.0×10 5 to 6.0×10 5 cells / kg, 5.5×10 5 to 6.5×10 5 cells / kg, 6.0×10 5 to 7.0×10 5 cells / kg, 6.5×10 5 to 7.5×10 5 cells / kg, 7.0×10 5 to 8.0×10 5 cells / kg, 7.5×10 5 to 8.5×10 5 cells / kg, 8.0×10 5 to 9.0×10 5 cells / kg, 8.5×10 5 to 9.5×10 5 cells / kg, 9.0×10 5 to 1.0×10 6 cells / kg and formulated at a dosage. In a preferred embodiment, the dosage is about 0.75×10 6 cells / kg and formulated. In some embodiments, the CAR-T cells are formulated at a dosage of less than 1.0×10 8 cells / subject . Method of treatment

[0146] This Out application further relates to a method and a composition for use in cellular immunotherapy. In some embodiments, the cellular immunotherapy is for subject treating cancer, including but not limited to hematological malignancies and solid tumors. In some embodiments, subject is human. In some embodiments, the method is suitable for treating adult and pediatric populations, including all age subgroups, and can be used as any Treatment history including the first line or subsequent lines.

[0147] Any anti-BCMA VHH, CAR, and engineered immune effector cells (e.g., CAR-T cells) described herein can be used for use in methods of treating cancer. In some examples, the immune effector cells are autologous. In some examples, the immune effector cells are allogeneic.

[0148] In some cases, CAR-T cells were approximately 1.0 × 10⁶ 5 From 2.0 × 10 5 individual cells / kg, 1.5 × 10⁻⁶ 5 From 2.5 × 10 5 individual cells / kg, 2.0 × 10⁻⁶ 5 From 3.0 x 10 5 individual cells / kg, 2.5 × 10⁻⁶ 5 From 3.5 x 10 5 individual cells / kg, 3.0 × 10⁻⁶ 5 From 4.0 x 10 5 individual cells / kg, 3.5 × 10⁻⁶ 5 From 4.5 x 10 5 cells / kg, 4.0 × 10 5 From 5.0 x 10 5 cells / kg, 4.5 × 10⁻⁶ 5 From 5.5 x 10 5 cells / kg, 5.0 × 10 5 From 6.0 x 10 5 individual cells / kg, 5.5 × 10⁻⁶ 5 From 6.5 x 10 5 cells / kg, 6.0 × 10⁻⁶ 5 From 7.0 x 10 5 cells / kg, 6.5 × 10⁻⁶ 5 From 7.5 x 10 5 cells / kg, 7.0 × 10 5 From 8.0 x 10 5 individual cells / kg, 7.5 × 10⁻⁶ 5 From 8.5 x 10 5 cells / kg, 8.0 × 10 5 From 9.0 x 10 5 cells / kg, 8.5 × 10 5 From 9.5 x 10 5 cells / kg, 9.0 × 10 5From 1.0 × 10 6 cells / kg, 1.0 × 10⁻⁶ 6 From 2.0 × 10 6 individual cells / kg, 1.5 × 10⁻⁶ 6 From 2.5 × 10 6 individual cells / kg, 2.0 × 10⁻⁶ 6 From 3.0 x 10 6 individual cells / kg, 2.5 × 10⁻⁶ 6 From 3.5 x 10 6 individual cells / kg, 3.0 × 10⁻⁶ 6 From 4.0 x 10 6 individual cells / kg, 3.5 × 10⁻⁶ 6 From 4.5 x 10 6 cells / kg, 4.0 × 10 6 From 5.0 x 10 6 cells / kg, 4.5 × 10⁻⁶ 6 From 5.5 x 10 6 cells / kg or 5.0 × 10⁶ 6 From 6.0 x 10 6 It is administered at a dose of cells / kg. In preferred examples, the dose is approximately 0.75 × 10⁻⁶ 6 Contains 1 cell / kg. In some examples, CAR-T cells are 1 subject Approximately 1.0 x 10 8 It is administered in doses of individual cells.

[0149] In some cases, CAR-T cells were 1 subject 1.0 x 10 per unit 8 They are administered in doses of less than one cell. In some examples, CAR-T cells are approximately 3.0 to 4.0 × 10⁶ 7 They are administered in doses of individual cells. In some examples, CAR-T cells are administered in doses of approximately 3.5 to 4.5 × 10⁶ 7 They are administered in doses of individual cells. In some examples, CAR-T cells are administered in doses of approximately 4.0 to 5.0 × 10⁶ 7 They are administered in doses of individual cells. In some examples, CAR-T cells are administered in doses of approximately 4.5 to 5.5 × 10⁶ cells. 7 They are administered in doses of individual cells. In some examples, CAR-T cells were administered in doses of approximately 5.0 to 6.0 × 10⁶ 7They are administered in doses of individual cells. In some examples, CAR-T cells are administered in doses of approximately 5.5 to 6.5 × 10⁶ 7 They are administered in doses of individual cells. In some examples, CAR-T cells are administered in doses of approximately 6.0 to 7.0 × 10⁶ 7 They are administered in doses of individual cells. In some examples, CAR-T cells are administered in doses of approximately 6.5 to 7.5 × 10⁶ 7 They are administered in doses of individual cells. In some examples, CAR-T cells are administered in doses of approximately 7.0 to 8.0 × 10⁶ 7 They are administered in doses of individual cells. In some examples, CAR-T cells are administered in doses of approximately 7.5 to 8.5 × 10⁶ 7 They are administered in doses of individual cells. In some examples, CAR-T cells are administered in doses of approximately 8.0 to 9.0 × 10⁶ 7 They are administered in doses of individual cells. In some examples, CAR-T cells are administered in doses of approximately 8.5 to 9.5 × 10⁶ 7 They are administered in doses of individual cells. In some examples, CAR-T cells were approximately 9.0 × 10⁶ 7 From 1.0 × 10 8 It is administered in doses of individual cells.

[0150] In some cases, CAR-T cells were approximately 0.693 × 10⁶ 6 The cells are administered at a dose of CAR-positive live T cells / kg. In some cases, CAR-T cells were approximately 0.52 × 10⁶ 6 The cells are administered at a dose of CAR-positive live T cells / kg. In some examples, CAR-T cells were approximately 0.94 × 10⁶ 6 The cells are administered at a dose of CAR-positive live T cells / kg. In some examples, CAR-T cells were approximately 0.709 × 10⁶ 6 The cells are administered at a dose of CAR-positive live T cells / kg. In some examples, CAR-T cells were approximately 0.51 × 10⁶ 6 The cells are administered at a dose of CAR-positive live T cells / kg. In some examples, CAR-T cells were approximately 0.95 × 10⁶ 6 The cells are administered at a dose of [number] CAR-positive live T cells / kg. In some cases, CAR-T cells are administered in an outpatient setting.

[0151] In some embodiments, subject The composition containing CAR-T cells, administered to the patient, further comprises an excipient selected from dimethyl sulfoxide or dextran-40.

[0152] In some embodiments, one or more intravenous Import Note: CAR-T cells are administered (for example, in any of the aforementioned doses). In some examples, the administration of CAR-T cells is a single intravenous dose. Import Note: In some examples, a single intravenous injection Import Note: The administration is performed using one bag of CAR-T cells. In some examples, the administration of the one bag of CAR-T cells is performed when the one bag of CAR-T cells melting From the moment of occurrence, the CAR-T cells in the aforementioned bag melting The procedure is completed within 3 hours of the time of administration. In some embodiments, a single intravenous administration is performed using two bags of the CAR-T cells. In some embodiments, the administration of each bag of the two bags of CAR-T cells is performed using the first bag of the two bags of CAR-T cells. melting From the moment of occurrence, the CAR-T cells in the first bag melting It must be completed within 3 hours of being initiated.

[0153] In some examples, the time from initial apheresis to CAR-T cell administration was shorter than 41, 47, 54, 61, 68, 75, 82, 89, 96, 103, 110, 117, 124, 131, 138, 145, 152, 159, 166, or 167 days. In some examples, the time from initial apheresis to CAR-T cell administration was longer than 41, 47, 54, 61, 68, 75, 82, 89, 96, 103, 110, 117, 124, 131, 138, 145, 152, 159, 166, or 167 days.

[0154] In some examples, lymph ballThe elimination regimen is performed prior to the administration of CAR-T cells. In some examples, lymph ball The elimination regimen includes the administration of cyclophosphamide and / or fludarabine. In some examples, lymph ball The removal regimen is administered intravenously. In some cases, lymph ball The elimination regimen is performed 5 to 7 days before CAR-T cell administration. In some cases, lymph ball The elimination regimen is performed 2 to 4 days before CAR-T cell administration. In some cases, lymph ball The elimination regimen involves intravenous administration of cyclophosphamide and fludarabine 5 to 7 days prior to CAR-T cell administration. In some examples, lymph ball The elimination regimen involves intravenous administration of cyclophosphamide and fludarabine 2 to 4 days before CAR-T cell administration. In some examples, lymph ball The elimination regimen is 300 mg / m². 2 This includes intravenous administration of cyclophosphamide. In some examples, lymph ball The elimination regimen is 30 mg / m². 2 This includes administering fludarabine intravenously. In some examples, the lymph ball The elimination regimen is performed daily for 3 days. If the delay in CAR-T cell administration exceeds 14 days, lymphatic ball The removal regimen may be repeated.

[0155] In several cases, the treatment method with CAR-T cells showed that within 3 days of administering CAR-T cells, without significantly reducing the in vivo amplification of CAR-T cells, subject Further includes treating cytokine release syndrome (CRS). In some cases, the treatment of CRS is subjectThis includes administering an IL-6R inhibitor. In some examples, the IL-6R inhibitor is an antibody. In some examples, the IL-6 inhibitor inhibits IL-6R by binding to the extracellular domain of IL-6R. In some examples, the IL-6R inhibitor blocks the binding of IL-6 to IL-6R. In some examples, the IL-6R inhibitor is tocilizumab. CRS may be identified based on clinical symptoms [see the approved label herein]. In some examples, fever, low acid underlying disease And assess and treat other causes of hypotension. Laboratory tests may monitor disseminated intravascular coagulation, hematological parameters, and pulmonary, cardiac, renal, and hepatic function. CRS may be managed based on the suggestions in Table 1 of the approved label disclosed herein. These methods involve administering levetiracetam to patients experiencing CRS to treat seizure This may include taking preventive measures. In some embodiments, these methods use continuous cardiac telemetry and pulse oximetry to determine grade 2 or higher CRS (e.g., hypotension unresponsive to fluids, or requiring oxygenation supplementation). Hypoxia This includes monitoring patients experiencing ) in the ICU. In some embodiments, intensive care unit level monitoring and supportive care are provided for severe or life of threaten It may also be used for CRS. Frontline intervention (e.g., tocilizumab or tocilizumab and corticosteroids) It is difficult to treat. For CRS, these methods include alternative treatment regimens (i.e., higher corticosteroid doses, alternative anti-cytokine agents, e.g., anti-IL1 and / or anti-TNFα, anti-T cell therapy). Refractory CRS is characterized by fever and end-organ toxicity (e.g., Hypoxia The condition is that hypotension (or low blood pressure) does not improve within 12 hours of frontline intervention, or that HLH / MAS develops.

[0156] In some cases, the method of treatment with CAR-T cells was performed one hour before CAR-T cell administration. within to, Antipyretic and antihistamines and Pre-infusion medication in subject Further includes treating the following. In some embodiments, Antipyretic It contains paracetamol or acetaminophen. In some examples, Antipyretic teeth, subject It is administered orally or intravenously. In some examples, Antipyretic It is administered in doses ranging from 650 mg to 1000 mg. subject It is administered to the following: In some examples, antihistamines It contains diphenhydramine. In some examples, antihistamines teeth, subject It is administered orally or intravenously. In some examples, antihistamines The dosage is 25 mg to 50 mg or equivalent dose The composition may be administered to mammals using standard administration techniques, the composition comprising host cells expressing the CAR coding nucleic acid sequence disclosed herein, or a vector comprising the CAR coding nucleic acid sequence disclosed herein, the standard administration techniques comprising oral, intravenous, intraperitoneal, subcutaneous, pulmonary, transdermal, intramuscular, intranasal, transbuccal, sublingual, or suppository administration. The composition is preferably suitable for parenteral administration. As used herein, the term “parenteral” includes intravenous, intramuscular, subcutaneous, rectal, vaginal, and intraperitoneal administration. More preferably, the composition is administered to mammals by intravenous, intraperitoneal, or subcutaneous injection using peripheral systemic delivery. Most preferably, the composition is administered intravenously Import It is administered by injection.

[0157] A composition comprising host cells expressing a CAR coding nucleic acid sequence disclosed herein or a vector containing a CAR coding nucleic acid sequence disclosed herein may be administered together with one or more other therapeutic agents, which may be co-administered to mammals. "Co-administration" means administering one or more other therapeutic agents and a composition comprising the host cells or vector disclosed herein within a sufficiently close time frame so that the CAR disclosed herein may enhance the effects of one or more other therapeutic agents, or vice versa. In this embodiment, the composition comprising the host cells or vector disclosed herein may be administered first, and then one or more other therapeutic agents may be administered, or vice versa.

[0158] The CAR-expressing cells described herein and at least one other therapeutic agent may be administered simultaneously (in the same or separate compositions) or sequentially. In the case of sequential administration, the CAR-expressing cells described herein may be administered first, followed by the other agent, or the order of administration may be reversed.

[0159] In some examples, lymph ball The elimination regimen is performed prior to the administration of CAR-T cells. In some examples, lymph ball The removal regimen is performed approximately 2 to 7 days before the administration of the CAR-T cells. In some examples, lymph ball The removal regimen is administered intravenously. In some examples, the lymph ball The elimination regimen includes the administration of cyclophosphamide or fludarabine. In some examples, the cyclophosphamide is 300 mg / m². 2 It is administered intravenously. In some examples, the amount of fludarabine was 30 mg / m². 2 It is administered intravenously.

[0160] In some examples, cyclophosphamide was administered at a dose of 300 mg / m². 2 Intravenous administration and fludarabine 30 mg / m² 2Intravenous administration and lymphatic ball The removal regimen is performed approximately 2 to 7 days before the CAR-T cells are removed.

[0161] In some embodiments, subject Furthermore, Bridging therapy In response, here, The aforementioned bridging therapy apheresis and the lymph ball at least one between the removal regimen Bridging drugs Including short-term treatment by, at least one Bridging drugs Previously, subject Disease stabilization, minimal response, partial response, best partial response, complete response, or strict complete response have already been achieved. In some examples, The aforementioned bridging therapy Despite this happening, subject The tumor burden increased. In some cases, The aforementioned bridging therapy Despite this happening, subject The tumor burden increased by more than approximately 25%. Bridging therapy This includes, for example, dexamethasone, bortezomib, cyclophosphamide, and pomalidomide. In some examples, Bridging therapy It contains dexamethasone. In some examples, Bridging therapy It contains bortezomib. In some examples, Bridging therapy It contains cyclophosphamide. In some examples, Bridging therapy It contains pomalidomide.

[0162] In some examples, approximately one hour before the administration of the CAR-T cells within to, Antipyretic and antihistamines and Premedication in subject To treat the following. In some embodiments, the Antipyretic This includes paracetamol or acetaminophen. In some examples, the above Antipyretic teeth, subject It is administered orally or intravenously. In some examples, the above Antipyretic It is administered in doses ranging from 650 mg to 1000 mg. subjectIt is administered to the following. In some examples, the antihistamines It contains diphenhydramine. In some examples, the above antihistamines teeth, subject It is administered orally or intravenously. In some examples, the above antihistamines The dosage is 25 mg to 50 mg or equivalent dose It is administered by [method]. In some examples, the above Antipyretic This comprises paracetamol or acetaminophen, and the above Antipyretic It is available in doses ranging from 650 mg to 1000 mg. subject It is administered orally or intravenously, and the above antihistamines It contains diphenhydramine, and the above antihistamines The dosage is 25 mg to 50 mg or equivalent dose in, subject It is administered orally or intravenously.

[0163] In some examples, the method involved administering 300 mg / m² of cyclophosphamide daily for three days prior to CAR-T cell administration. 2 Intravenous administration (IV) and fludarabine 30 mg / m² 2 Includes IV Lymphocyte depletion chemotherapy regimen of implementation death, Antipyretic (For example, administering 650 to 1000 mg of acetaminophen orally or intravenously) antihistamines (For example, administering 25 to 50 mg of diphenhydramine or an equivalent orally or intravenously) Pre-infusion medication of implementation And here, CAR-T cells are lymphatic ball It is administered 2 to 4 days after the completion of depletion chemotherapy. CAR-T cells are Since pre-infusion medication has been administered It is administered 30-60 minutes later.

[0164] In some cases, CAR-T cell administration was withheld or delayed if the patient had any of the following: clinically significant active infection or inflammatory disorder, or non-hematological toxicity of ≥grade 3, conditioned with cyclophosphamide and fludarabine, excluding grade 3 nausea, vomiting, diarrhea, or constipation. CAR-T cell administration should be delayed until these events have resolved to ≤grade 1. In some cases, prophylactic systemic corticosteroids were not administered.

[0165] In some embodiments, the method is subject This further includes the diagnosis of cytokine release syndrome (CRS). In preferred embodiments, the diagnosis is based on the American Society for Transplantation and Cell Therapy (ASTCT) Consensus Classification, which was previously the American Society for Blood and Marrow Transplantation (ASBMT). Table 13 provides a non-restrictive summary of the ASTCT Consensus Classification for CRS diagnosis. In some embodiments, CRS is assessed by assessing the levels of one, more, or all of the following: IL-6, IL-10, IFN-□, C-reactive protein (CRP), and ferritin.

[0166] In some embodiments, the method is subject Further includes treating cytokine release syndrome (CRS). In some examples, Antipyretic CRS is treated with anti-cytokine therapy. In some cases, CRS is treated with anti-cytokine therapy. In some cases, the treatment of CRS is Import It occurs approximately 3 days or more after administration. In some cases, CRS is treated without significantly reducing the in vivo amplification of CAR-T cells. In some cases, the method does not significantly reduce the in vivo amplification of CAR-T cells, and the CRS occurs approximately 3 days or more after administration of CAR-T cells. subject Further includes treating cytokine release syndrome. In some cases, the treatment of CRS is subjectThis includes administering an IL-6R inhibitor. In some examples, the IL-6R inhibitor is an antibody. In some examples, the antibody inhibits IL-6R by binding to the extracellular domain of IL-6R. In some examples, the IL-6R inhibitor blocks the binding of IL-6 to IL-6R. In some examples, the IL-6R inhibitor is tocilizumab. In some examples, anti-cytokine therapy includes the administration of tocilizumab. In some examples, anti-cytokine therapy includes the administration of steroids. In some examples, treatment of CRS includes treatment with a monoclonal antibody other than tocilizumab. In some examples, the antibody other than tocilizumab targets a cytokine. In some examples, the cytokine targeted by the antibody other than tocilizumab is IL-1. In some examples, the antibody targeting IL-1 is anakinra. In some examples, the cytokine targeted by the antibody other than tocilizumab is TNFα. In some examples, treatment of CRS includes, subject This includes administering corticosteroids. In some examples, treatment of CRS includes the use of vasoconstrictors. In some examples, treatment of CRS includes intubation or mechanical ventilation. In some examples, treatment of CRS includes, subject This includes administering cyclophosphamide. In some examples, the treatment of CRS is subject This includes administering etanercept. In some examples, the treatment of CRS is subject This includes administering levetiracetam. In some examples, treatment of CRS includes supportive care.

[0167] In some embodiments, the method is subjectThis further includes diagnosing immune cell effector-associated neurotoxicity (ICANS). In some cases, the diagnosis is based on the National Cancer Institute Common Terminology Standard for Adverse Events (NCI CTCAE). In some cases, the diagnosis is based on NCI CTCAE standard version 5.0. In some cases, the diagnosis is based on the American Society for Transplantation and Cell Therapy (ASTCT) Consensus Classification System. In some cases, the cases have neurotoxicity consistent with ICAN. Table 14 provides a non-limiting summary of the ASTCT Consensus Classification System for ICAN diagnosis. In some cases, the treatment of ICAN is subject This includes administering an IL-6R inhibitor. In some examples, the IL-6R inhibitor is an antibody. In some examples, the antibody inhibits IL-6R by binding to the extracellular domain of IL-6R. In some examples, the IL-6R inhibitor blocks the binding of IL-6 to IL-6R. In some examples, the IL-6R inhibitor is tocilizumab. In some examples, the treatment of ICANs is subject This involves administering an IL-1 inhibitor. In some examples, the IL-1 inhibitor is an antibody. In preferred examples, the IL-1 inhibitory antibody is anakinra. In some examples, the treatment of ICANs is subject This includes administering corticosteroids. In some examples, treatment of ICANs is subject This includes administering levetiracetam. In some examples, treatment of ICANs is subject This includes administering dexamethasone. In some examples, treatment of ICANs is subject This includes administering sodium methylprednisolone succinate. In some examples, the treatment of ICANs is subject This includes administering pethidine. In some examples, the treatment of ICANs is subjectThis includes administering one, more, or all of the following: tocilizumab, anakinra, corticosteroids, levetiracetam, dexamethasone, methylprednisolone sodium succinate, or pethidine.

[0168] If neurotoxicity is suspected to occur during the CRS period, or vice versa, the above method may include administering the following: • More invasive interventions with corticosteroids, based on the approval labels disclosed herein, with CRS and neurotoxicity levels as shown in Tables 1 and 2. • CRS in Table 1 of the approval labels disclosed herein grade Tocilizumab • Anti-neurotoxicity in Table 2 of the approval label disclosed herein seizure medicine

[0169] In some embodiments, the method is subject This further includes diagnosing cytopenia. In some examples, cytopenia includes one, more, or all of lymphopenia, neutropenia, and thrombocytopenia. Although not bound by theory, lymphopenia of grade 3 or grade 4, rather than grade 2 or lower, is defined as a lymphocyte count of 0.5 × 10⁶. 9 individual cells / liter Target blood Neutropenia is characterized by having fewer than 1000 cells / microliter, and is not grade 2 or lower, but grade 3 or grade 4. Target blood Characterized by a sample size of less than 50,000 cells / microliter, thrombocytopenia of grade 3 or grade 4, rather than grade 2 or lower, is characterized by a platelet count of 50,000 cells / microliter. Target blood Characterized by being less than a sample size. In some examples, patients suffered from grade 3 or grade 4 lymphopenia after CAR-T cell administration. subject Over 75% of them experienced a decline in 60 minutes after CAR-T cell administration. days The patients recovered to lymphopenia of grade 2 or lower. In some cases, patients developed grade 3 or grade 4 lymphopenia after CAR-T cell administration. subjectOver 80% of them were 60 days after CAR-T cell administration. days The patients recovered to lymphopenia of grade 2 or lower. In some cases, patients developed grade 3 or grade 4 lymphopenia after CAR-T cell administration. subject Over 85% of them were 60 days after CAR-T cell administration. days The patients recovered to lymphopenia of grade 2 or lower. In some cases, patients developed grade 3 or grade 4 lymphopenia after CAR-T cell administration. subject Over 90% of them were 60 days after CAR-T cell administration. days The patients recovered to lymphopenia of grade 2 or lower. In some cases, patients developed grade 3 or grade 4 neutropenia after CAR-T cell administration. subject Over 70% of them were 60 days after CAR-T cell administration. days The neutropenia improved to grade 2 or lower. In some cases, patients developed grade 3 or grade 4 neutropenia after CAR-T cell administration. subject Over 75% of them experienced a decline in 60 minutes after CAR-T cell administration. days The neutropenia improved to grade 2 or lower. In some cases, patients developed grade 3 or grade 4 neutropenia after CAR-T cell administration. subject Over 80% of them were 60 days after CAR-T cell administration. days The neutropenia improved to grade 2 or lower. In some cases, patients developed grade 3 or grade 4 neutropenia after CAR-T cell administration. subject Over 85% of them were 60 days after CAR-T cell administration. days The neutropenia improved to grade 2 or lower. In some cases, patients developed grade 3 or grade 4 thrombocytopenia after CAR-T cell administration. subject Over 30% of them were 60 days after CAR-T cell administration. days The thrombocytopenia recovered to grade 2 or lower. In some cases, patients developed grade 3 or grade 4 thrombocytopenia after CAR-T cell administration. subject Over 34% of them experienced a decline in 60 days after CAR-T cell administration. daysThe thrombocytopenia recovered to grade 2 or lower. In some cases, patients developed grade 3 or grade 4 thrombocytopenia after CAR-T cell administration. subject Over 38% of them experienced a decline in 60 days after CAR-T cell administration. days The thrombocytopenia recovered to grade 2 or lower. In some cases, patients developed grade 3 or grade 4 thrombocytopenia after CAR-T cell administration. subject Over 42% of them experienced a decline in 60 minutes after CAR-T cell administration. days The thrombocytopenia recovered to grade 2 or lower.

[0170] When a host cell expressing the CAR coding nucleic acid sequence disclosed herein or a composition comprising a vector containing the CAR coding nucleic acid sequence disclosed herein is administered to a mammal (e.g., human), the biological activity of the CAR can be measured by any suitable method known in the art. According to the method disclosed herein, the CAR binds to BCMA in multiple myeloma cells, and these multiple myeloma cells are destroyed. The binding of the CAR to BCMA on the surface of multiple myeloma cells can be measured by any suitable method known in the art, including, for example, ELISA and flow cytometry. The ability of the CAR to destroy multiple myeloma cells can be measured by any suitable method known in the art, such as cytotoxic assays described, for example, Kochenderfer et al., J. Immunotherapy, 32(7): 689-702 (2009) and Herman et al., J. Immunological Methods, 285(1): 25-40 (2004). The biological activity of CAR can also be measured by assays of the expression of several cytokines, such as CD107a, IFNγ, IL-2, and TNF.

[0171] The methods described herein may be used to treat a variety of cancers, including solid tumors and liquid tumors. In some examples, these methods are for the treatment of multiple myeloma. The methods described herein may be used in combination with the first, second, third, or other types of cancer therapies known in the art (e.g., chemotherapy, surgery, radiation, gene therapy, immunotherapy, bone marrow transplantation, stem cell transplantation, targeted therapy, cryotherapy, ultrasound therapy, photodynamic therapy, radiofrequency ablation, etc.) in adjuvant therapy or novel adjuvant therapy.

[0172] In some examples, the cancer is multiple myeloma. In some examples, the cancer is stage I, stage II, or stage III, and / or stage A or stage B, according to the Durie-Salmon classification system. In some examples, the cancer is stage I, stage II, or stage III, according to the international classification system published by the International Myeloma Working Group (IMWG). In some examples, the multiple myeloma is progressive.

[0173] In some embodiments, subject teeth, At least 3 lines of prior treatment history Prior treatment including was received. In some cases, Prior medical history The median is 6. In some examples, Prior medical history This includes surgery, radiotherapy, or autologous or allogeneic transplantation, or any combination thereof. In some examples, At least 3 lines of prior treatment history This includes drug therapy, the drug being a proteasome inhibitor (PI). Non-limiting examples of PIs include bortezomib, carbenzomib, and izomib. In some examples, At least 3 lines of prior treatment history This includes drug therapy, and such drug is Immunomodulatory drugs It is an IMiD. Non-limiting examples of IMiDs include lenalidomide, pomalidomide, and thalidomide. In some examples, At least 3 lines of prior treatment historyThis includes drug therapy, the drug being a corticosteroid. Non-limiting examples of corticosteroids include dexamethasone and prednisone. In some examples, At least 3 lines of prior treatment history This includes drug therapy, wherein the drug is an alkylating agent. In some examples, At least 3 lines of prior treatment history This includes drug therapy, wherein the drug is an anthracycline. In some examples, At least 3 lines of prior treatment history This includes drug therapy, the drug being an anti-CD38 antibody. Non-limiting examples of anti-CD38 antibodies include daratumumab, isatuximab, and the research antibody TAK-079. In some examples, At least 3 lines of prior treatment history This includes drug therapy, the drug being elotuzumab. In some examples, At least 3 lines of prior treatment history This includes drug therapy, the drug being panobinostat. In some examples, At least 3 lines of prior treatment history At least 1 type This includes drug therapy, and the at least 1 type The drug comprises at least one of PI, IMiD, and anti-CD38 antibody. In some examples, At least 3 lines of prior treatment history At least 1 type This includes drug therapy, and the at least 1 type The drug comprises at least one of PI, IMiD, and alkylating agent. In some examples, subject The above A history of at least 3 lines of prior treatment It recurs later. In some cases, multiple myeloma was treated with one, more or all of the following: bortezomib, carbenzomib, izomib, lenalidomide, pomalidomide, thalidomide, dexamethasone, prednisone, alkylating agents, daratumumab, isatuximab, TAK-079, elotuzumab, and panobinostat. It is difficult to treat. In some examples, multiple myeloma is described as A history of at least 3 lines of prior treatment Later, at least 2 types Drugs It is difficult to treat. In some cases, multiple myeloma It is intractable for at least 2 types The drug comprises PI and IMiD. In some examples, multiple myeloma is treated as described above. A history of at least 3 lines of prior treatmentLater, at least 3 types Drugs It is difficult to treat. In some examples, multiple myeloma is described as A history of at least 3 lines of prior treatment Later, at least 4 types Drugs It is difficult to treat. In some embodiments, at least 4 line Previous medical history At least 1 type This includes drug therapy, and the at least 1 type The drug comprises at least one of PI, IMiD, anti-CD38 antibody, and alkylating agent. In some examples, multiple myeloma is treated as described above. A history of at least 3 lines of prior treatment Later, at least 5 types Drugs It is difficult to treat. .

[0174] In some embodiments, subject Prior to the administration of the CAR-T cells, the cells contain approximately 10% to 30% myeloid plasma cells.

[0175] In some embodiments, bone marrow aspiration or biopsy may be performed for clinical assessment, or bone marrow aspiration may be performed for biomarker assessment. In some embodiments, clinical classification (morphology, cytogenetics, immunohistochemistry or immunofluorescence or flow cytometry) may be performed. In some embodiments, immunophenotypic analysis may be performed on a portion of the bone marrow aspirate to monitor checkpoint ligand expression in BCMA, CD138-positive multiple myeloma cells and checkpoint expression in T cells. In some embodiments, next-generation sequencing (NGS) of bone marrow aspirate DNA may be used. subjectMinimally invasive residual disease (MRD) can be monitored in this manner. NGS of bone marrow aspirate DNA is known to those skilled in the art. In some examples, NGS is performed via clonoSeq. In some examples, myeloma clones can be defined using baseline bone marrow aspirates, and MRD negativity can be assessed using post-treatment samples. In some examples, MRD negativity may be based on an evaluable sample. In some examples, an evaluable sample is obtained by one, more or all of the following: correction, quality control, and evaluable cell suitability under a specific sensitivity level. In some examples, the sensitivity level is 10 -6 In some embodiments, the sensitivity level is 10 -6 The sensitivity level is 10 -5 In some embodiments, the sensitivity level is 10 -4 In some embodiments, the sensitivity level is 10 -3 That is the case.

[0176] In some cases, efficacy criteria based on the International Myeloma Working Group (IMWG) were used for the treatment method. subject The response was evaluated, and these criteria are summarized in Table 6. In some cases, the response may be classified as a strict complete response (sCR). In some cases, the response may be classified as a complete response (CR), which is worse than a strict complete response (sCR). In some cases, the response may be classified as a best partial response (VGPR), which is worse than a complete response (CR). In some cases, the response may be classified as a partial response (PR), which is worse than a best partial response (VGPR). In some cases, the response may be classified as a minimal response (MR), which is worse than a partial response (PR). In some cases, the response may be classified as disease stabilization (SD), which is worse than a minimal response (MR). In some cases, the response may be classified as disease progression (PD), which is worse than disease stabilization.

[0177] In some cases, the tests used to assess efficacy criteria based on the International Myeloma Working Group (IMWG) included measurement of myeloma protein (M-protein) in serum and urine, serum calcium corrected for albumin, bone marrow examination, bone survey, and documentation of extramedullary plasmacytoma.

[0178] Non-limiting examples of tests for the measurement of M-protein in blood and urine are known to those skilled in the art and include serum quantitative Ig, serum protein electrophoresis (SPEP), serum immunofixation electrophoresis, serum FLC assay, 24-hour urinary M-protein electrophoresis (UPEP), urinary immunofixation electrophoresis, and serum β2-microglobulin.

[0179] It is known to those skilled in the art that, in order to detect hypercalcemia, serum calcium levels in a blood sample must be corrected for albumin. While we do not wish to be bound by theory, calcium is biologically active only when bound to albumin, and only unbound (free) calcium possesses biological activity; therefore, serum calcium levels must be adjusted for abnormal albumin levels ("corrected serum calcium").

[0180] In some embodiments, a bone survey of one or all of the skull, the entire spine, the pelvis, the chest, the humerus, the femur, and any other bones may be performed and evaluated by radiography ("X-rays") or low-dose computed tomography (CT) diagnostic quality scans without the use of IV contrast, both of which are known to those skilled in the art. In some embodiments, localized X-ray or CT scans may be performed after T-cell administration and before disease progression is confirmed, with or without symptomatic clinical instruction, to record response or progression. In some embodiments, magnetic resonance imaging (MRI) may be used to evaluate bone disease, but it is not a substitute for a bone survey. MRI is known to those skilled in the art. In some embodiments, disease status can be recorded in two ways by using a radionuclide bone scan at screening in addition to a complete bone survey. Radionuclide bone scans are known to those skilled in the art. In some embodiments, a radionuclide bone scan and a complete bone survey may be performed simultaneously. In some embodiments, a radionuclide bone scan may not be a substitute for a complete bone survey. In some embodiments, subject If the disease progression is manifested by pain symptoms due to bone changes, subject Depending on the symptoms experienced, the progression of the disease can be recorded through bone examination or other radiographic imaging.

[0181] In some cases, extramedullary plasmacytoma can be recorded by clinical examination or MRI. In some cases, if there are no contraindications for the use of IV contrast, extramedullary plasmacytoma can be recorded by CT scan. In some cases, if the CT portion has sufficient diagnostic quality, extramedullary plasmacytoma can be recorded by fusion of positron emission tomography (PET) scan and CT scan. In some cases, until confirmed complete remission or confirmed disease progression occurs, subject In addition, local assessment, measurement, or evaluation of measurable sites of extramedullary disease may be performed every four weeks. In some examples, evaluation of extramedullary plasmacytoma may be performed every 12 weeks.

[0182] In some embodiments, to conform to VGPR, PR, or MR, the sum of the vertical diameter products of conventional extramedullary plasmacytomas may be reduced by more than 90% or at least 50%, respectively. In some embodiments, to conform to disease progression, the sum of the vertical diameter products of conventional extramedullary plasmacytomas must be increased by at least 50%, or the longest diameter of previous lesions >1 cm on the short axis must be increased by at least 50%, or a new plasmacytoma must have developed. In some embodiments, if not all present extramedullary plasmacytomas are reported, the sum of the vertical diameter products of reported plasmacytomas was increased by at least 50% to conform to disease progression. In some embodiments, if the study treatment interferes with the immunofixation assay, CR may be defined as the disappearance of the original M protein associated with multiple myeloma at immunofixation.

[0183] In some examples, the treatment method was determined based on changes in disease burden or tumor burden. subject The response in this regard will be assessed. Disease burden or tumor burden is, subjectThis represents the type of measurable disease in the context. In some examples, the change in tumor burden can be assessed based on the change in paraprotein levels after treatment. In some examples, paraprotein is M-protein in serum. In some examples, paraprotein is M-protein in serum. In some examples, the change in tumor burden can be assessed based on the difference between impaired free light chains and unimpaired free light chains (dFLC). In some examples, the change in tumor burden is assessed based on the maximum paraprotein reduction relative to baseline, i.e., before CAR-T cell administration. In some examples, the change in tumor burden is assessed at a median follow-up period of 28 days or more after CAR-T cell administration. In some examples, the change in tumor burden is assessed at a median follow-up period of 1 month or more after CAR-T cell administration. In some examples, the change in tumor burden is assessed at a median follow-up period of 3 months or more after CAR-T cell administration. In some examples, the change in tumor burden is assessed at a median follow-up period of 6 months or more after CAR-T cell administration. In some cases, the change in tumor burden was assessed at a median follow-up period of 9 months or more after CAR-T cell administration. In some cases, the change in tumor burden was assessed at a median follow-up period of 12 months or more after CAR-T cell administration.

[0184] In some cases, a second dose of CAR-T cells was administered intravenously. Import By administration via injection, subject The patient is retreated. In some cases, the retreatment dose was 1.0 × 10⁻⁶. 5 From 5.0 x 10 6 individual CAR-T cells / kilogram Target mass This includes. In some examples, the retreatment dose was approximately 0.75 × 10⁻⁶. 5 individual CAR-T cells / kilogram Target mass Includes. In some embodiments, subject The first CAR-T cell Import After injection, if disease progression occurs after the best response (minimal response or better response), retreatment is administered. In some cases, the first CAR-T cells Infusion The time from the initial diagnosis to the detection of disease progression includes at least six months.

[0185] In one aspect, the patient is suffering from multiple myeloma. subject A method for treating the condition is provided, the method being a single intravenous injection Import Note: The composition containing a therapeutically effective number of T cells including a chimeric antigen receptor (CAR) is described above. subject Administered to express CAR A certain dosage The T cells (CAR-T cells) subject This includes delivering to [the specified address].

[0186] In some embodiments, subject teeth, At least 3 lines of prior treatment history The patient received prior treatment including the above. In some cases, the above At least 3 lines of prior treatment history At least 1 type This includes drug therapy, and the at least 1 type The drug comprises at least one of PI, IMiD, and anti-CD38 antibody. In some examples, subject The above At least 3 lines of prior treatment history It recurs after that.

[0187] In some examples, multiple myeloma is described as A history of at least 3 lines of prior treatment Later, at least 2 types Drugs It is difficult to treat. In some embodiments, It is intractable for the target. The at least 2 types The drug comprises PI and IMiD. In some examples, multiple myeloma is treated as described above. A history of at least 3 lines of prior treatment Later, at least 3 types Drugs It is difficult to treat. In some examples, multiple myeloma is described as A history of at least 3 lines of prior treatment Later, at least 4 types Drugs It is difficult to treat. In some examples, multiple myeloma is described as A history of at least 3 lines of prior treatment Later, at least 5 types Drugs It is difficult to treat. .

[0188] In some embodiments, Target ageIt is greater than 65 years old. In some cases, subject They are Black or African American. In some instances, subject teeth, The patient has a history of three prior treatments. In some embodiments, subject teeth, The patient has a history of at least four lines of prior treatment. In some examples, multiple myeloma or subject teeth, 3 types against drugs It is difficult to treat. , that is, multiple myeloma or subject teeth, It is a triple-class refractory disease. In some examples, multiple myeloma or subject teeth, 5 types against medications or drugs It is difficult to treat. , that is, multiple myeloma or subject teeth, 5 types Drugs It is difficult to treat. In some embodiments, subject This has a standard cytogenetic risk. In some cases, subject This carries a high cytogenetic risk. In some examples, Target or Multiple myeloma is characterized as stage III according to the international classification system. In some cases, subject The cells have about 10% to about 30% myeloid plasma cells prior to the administration of the CAR-T cells. In some examples, subject The cells have approximately 31% to 59% myeloid plasma cells prior to the administration of the CAR-T cells. In some examples, subject The cells have approximately 60% to 100% myeloid plasma cells prior to the administration of the CAR-T cells. In some examples, subject BCMA expression in these tumors is lower than the median in the multiple myeloma patient population or any randomly selected population. In some examples, subject BCMA expression in the tumor is above the median in the multiple myeloma patient population or any randomly selected population. In some cases, plasmacytoma is subjectIt exists in [location]. In some examples, the plasmacytoma is bone-based. In some examples, the plasmacytoma is extramedullary. In some examples, the plasmacytoma is bone-based and extramedullary.

[0189] In some cases, the treatment method was subject In this, a reduced tumor burden is effectively obtained. In some cases, the treatment method is subject In this case, a reduction in tumor burden of approximately 1% to approximately 100%, approximately 60% to approximately 100%, approximately 65% ​​to approximately 100%, approximately 70% to approximately 100%, approximately 75% to approximately 100%, approximately 80% to approximately 100%, approximately 85% to approximately 100%, approximately 90% to approximately 100%, approximately 92% to approximately 100%, approximately 95% to approximately 100%, approximately 96% to approximately 100%, approximately 97% to approximately 100%, approximately 98% to approximately 100%, or approximately 99% to approximately 100% can be effectively obtained. In some examples, the treatment method is subject In this case, a tumor burden reduced by approximately 100% is effectively obtained. In some cases, the treatment method is subject In this case, approximately 1% to approximately 100% ratio This effectively reduces tumor burden by approximately 1% to approximately 100%. In some cases, the treatment method is subject In this case, approximately 1% to approximately 100% ratio This effectively reduces tumor burden by approximately 60% to 100%. In some cases, the treatment method is subject In this case, approximately 1% to approximately 92% ratio This effectively reduces tumor burden by approximately 65% ​​to 100%. In some cases, the treatment method is subject In this case, approximately 1% to approximately 88% ratio This effectively reduces tumor burden by approximately 70% to 100%. In some cases, the treatment method is subject In this case, approximately 1% to approximately 88% ratio This effectively reduces tumor burden by approximately 90% to 100%. In some cases, the treatment method is subject In this case, approximately 1% to approximately 88% ratioThis effectively reduces tumor burden by approximately 95% to 100%. In some cases, the treatment method is subject In this case, approximately 1% to approximately 88% ratio This effectively reduces tumor burden by approximately 99% to 100%. In some cases, the treatment method is subject In this case, approximately 1% to approximately 83% ratio This effectively reduces the tumor burden by approximately 100%.

[0190] In some cases, the treatment method was subject In this, the goal is to effectively achieve a negative status for minimal residual disease (MRD) or to effectively maintain the MRD status. In some embodiments, the treatment method is 10 -6 at the sensitivity level subject In this case, a negative status for minimal residual disease (MRD) is effectively obtained. In some cases, the treatment method was 10 -5 at the sensitivity level subject In this case, a negative status for minimal residual disease (MRD) is effectively obtained. In some cases, the treatment method was 10 -4 at the sensitivity level subject In this case, a negative status for minimal residual disease (MRD) is effectively obtained. In some cases, the treatment method was 10 -3 at the sensitivity level subject In some cases, the treatment method effectively obtains a negative status for minimal residual disease (MRD) when assessed in the bone marrow. In some cases, when assessed in an evaluable bone marrow sample, the treatment method effectively maintains a negative status for MRD. In some cases, when assessed in bone marrow DNA, the treatment method effectively obtains a negative status for MRD. In some cases, the method determines the negative status for minimal residual disease (MRD) assessed in the bone marrow during a follow-up period of approximately 28 days or more after the administration of the CAR-T cells, approximately 2 months or more after the administration of the CAR-T cells, approximately 3 months or more after the administration of the CAR-T cells, approximately 6 months or more after the administration of the CAR-T cells, approximately 9 months or more after the administration of the CAR-T cells, or approximately 12 months or more after the administration of the CAR-T cells. subject Effectively obtained in the following cases. In some examples, the negative status of minimal residual disease (MRD) is obtained in the CAR-T cells. Import Note: Between approximately 28 and 179 days after First tracking period It can be obtained from this.

[0191] In some cases, the treatment method was subject In this context, the negative status of minimal residual disease (MRD) obtained for the first time is effectively maintained. In some examples, the treatment method was 10 -5 It effectively maintains a negative MRD status at the sensitivity level. In some examples, the treatment method is 10 -6 at the sensitivity level subject In this case, a negative status for minimal residual disease (MRD) is effectively obtained. In some cases, the treatment method was 10 -4 It effectively maintains a negative MRD status at the sensitivity level. In some examples, the treatment method is 10 -3 The method effectively maintains a negative MRD status at the sensitivity level. In some examples, when assessed using bone marrow samples, the treatment method effectively maintains a negative MRD status. In some examples, when assessed using evaluable bone marrow samples, the treatment method effectively maintains a negative MRD status. In some examples, when assessed using bone marrow DNA, the treatment method effectively maintains a negative MRD status. In some examples, the method maintains a negative minimal residual disease (MRD) status assessed in the bone marrow during a second follow-up period of approximately 29 to 359 days after the administration of the CAR-T cells, approximately 29 to 9 months after the administration of the CAR-T cells, approximately 29 to 6 months after the administration of the CAR-T cells, approximately 29 to 3 months after the administration of the CAR-T cells, or approximately 29 to 2 months after the administration of the CAR-T cells. subject To effectively maintain in the CAR-T cells. In some examples, the method is used to maintain the CAR-T cells. Import Note: The negative status of minimal residual disease (MRD) assessed in the bone marrow during the second follow-up period, approximately 180 to 359 days after the initial assessment, is defined as follows: subjectTo effectively maintain in the CAR-T cells. In some examples, the method is used to maintain the CAR-T cells. Import Note: The negative status of minimal residual disease (MRD) assessed in the bone marrow during the second follow-up period, approximately 360 to 539 days after the initial assessment, is defined as follows: subject To maintain effectively in [location / area].

[0192] In some examples, the MRD negative state was subject The effectiveness of the treatment method is assessed by evaluating the proportion of [percentage]. In some examples, 10 -6 At the sensitivity level, the MRD negative status is present. subject The effectiveness of the treatment method is assessed by evaluating the proportion of [percentage]. In some examples, 10 -5 At the sensitivity level, the MRD negative status is present. subject The effectiveness of the treatment method is assessed by evaluating the proportion of [percentage]. In some examples, 10 -4 At the sensitivity level, the MRD negative status is present. subject The effectiveness of the treatment method is assessed by evaluating the proportion of [percentage]. In some examples, 10 -3 At the sensitivity level, the MRD negative status is present. subject The effectiveness of the treatment method is assessed by evaluating the proportion of patients who exhibit negative MRD status. In several cases, patients exhibited negative MRD status at the median follow-up periods of approximately 359 days after CAR-T cell administration, approximately 9 months after CAR-T cell administration, approximately 6 months after CAR-T cell administration, approximately 3 months after CAR-T cell administration, approximately 2 months after CAR-T cell administration, or approximately 29 days after CAR-T cell administration. subject The effectiveness of the treatment method is assessed by evaluating the proportion of the CAR-T cells. In some examples, the method involves the CAR-T cells. Import During the follow-up period of approximately 12 months after the note, 10 -5 At the sensitivity threshold level, approximately 44% or less ratio Then, during the follow-up period of approximately 12 months after the administration of the CAR-T cells, 10 -5At the sensitivity threshold level, approximately 55% ratio And the CAR-T cells Import During the follow-up period of approximately 12 months after the note, 10 -5 At the sensitivity threshold level, approximately 65% ​​or less. ratio And the CAR-T cells Import Note: During a follow-up period of approximately 18 months, 10 -4 At the sensitivity threshold level, approximately 57% or less. ratio And the CAR-T cells Import Note: During a follow-up period of approximately 18 months, 10 -4 At the sensitivity threshold level, approximately 67% ratio And the CAR-T cells Import Note: During a follow-up period of approximately 18 months, 10 -4 At the sensitivity threshold level, approximately 76% or less. ratio And the CAR-T cells Import Note: During a follow-up period of approximately 18 months, 10 -5 At the sensitivity threshold level, approximately 47% or less ratio And the CAR-T cells Import Note: During a follow-up period of approximately 18 months, 10 -5 At the sensitivity threshold level, approximately 58% ratio And the CAR-T cells Import Note: During a follow-up period of approximately 18 months, 10 -5 At the sensitivity threshold level, approximately 68% or less. ratio And the CAR-T cells Import Note: During a follow-up period of approximately 18 months, 10 -6 At the sensitivity threshold level, approximately 29% or less ratio And the CAR-T cells Import Note: During a follow-up period of approximately 18 months, 10 -6 At the sensitivity threshold level, approximately 39% ratio or the CAR-T cells Import Note: During a follow-up period of approximately 18 months, 10 -6 At the sensitivity threshold level, approximately 50% or less ratio This effectively obtains a negative state for minimal residual disease (MRD). In some examples, the method is used to obtain the CAR-T cells Import During the follow-up period of approximately 12 months after the note, 10 -5At the sensitivity threshold level, approximately 44% to approximately 65% ratio And the CAR-T cells Import Note: During a follow-up period of approximately 18 months, 10 -4 At the sensitivity threshold level, approximately 57% to approximately 76% ratio And the CAR-T cells Import Note: During a follow-up period of approximately 18 months, 10 -5 At the sensitivity threshold level, approximately 47% to approximately 68% ratio or the CAR-T cells Import Note: During a follow-up period of approximately 18 months, 10 -6 At the sensitivity threshold level, approximately 29% to approximately 50% ratio This effectively obtains a negative status for minimal residual disease (MRD). In some examples, the method involves a follow-up period of approximately 12 months after the administration of the CAR-T cells. -5 At the sensitivity threshold level, approximately 55% ratio And the CAR-T cells Import Note: During a follow-up period of approximately 18 months, 10 -4 At the sensitivity threshold level, approximately 67% ratio And the CAR-T cells Import Note: During a follow-up period of approximately 18 months, 10 -5 At the sensitivity threshold level, approximately 58% ratio or the CAR-T cells Import Note: During a follow-up period of approximately 18 months, 10 -6 At the sensitivity threshold level, approximately 39% ratio This effectively achieves a negative status for minimal residual disease (MRD).

[0193] In some examples, evaluable bone marrow and MRD-negative status were observed. subject The effectiveness of the treatment method is assessed by evaluating the proportion of [percentage]. In some examples, 10 -6 At the sensitivity level, it is possible to evaluate bone marrow and has a negative MRD status subject The effectiveness of the treatment method is assessed by evaluating the proportion of [percentage]. In some examples, 10 -5 At the sensitivity level, it is possible to evaluate bone marrow and has a negative MRD status subject The effectiveness of the treatment method is assessed by evaluating the proportion of [percentage]. In some examples, 10 -4 At the sensitivity level, it is possible to evaluate bone marrow and has a negative MRD status subject The effectiveness of the treatment method is assessed by evaluating the proportion of [percentage]. In some examples, 10 -3 At the sensitivity level, it is possible to evaluate bone marrow and has a negative MRD status subject The effectiveness of the treatment method is assessed by evaluating the proportion of [specific criteria]. In several cases, at median follow-up periods of approximately 359 days after CAR-T cell administration, approximately 9 months after CAR-T cell administration, approximately 6 months after CAR-T cell administration, approximately 3 months after CAR-T cell administration, approximately 2 months after CAR-T cell administration, or approximately 29 days after CAR-T cell administration, [specific criteria] were met, indicating that evaluable bone marrow and MRD-negative status were present. subject The effectiveness of the treatment method is assessed by evaluating the proportion of the CAR-T cells. In some examples, the method involves the CAR-T cells. Import During the follow-up period of approximately 12 months after the note, 10 -5 At the sensitivity threshold level, the sample has an evaluable sample. subject In that case, approximately 83% or less ratio And the CAR-T cells Import During the follow-up period of approximately 12 months after the note, 10 -5 At the sensitivity threshold level, the sample has an evaluable sample. subject In that case, approximately 93% ratio And the CAR-T cells Import During the follow-up period of approximately 12 months after the note, 10 -5 At the sensitivity threshold level, the sample has an evaluable sample. subject In that case, approximately 98% ratio And the CAR-T cells Import Note: During a follow-up period of approximately 18 months, 10 -5 At the sensitivity threshold level, the sample has an evaluable sample. subject In that case, approximately 82% or less ratio And the CAR-T cells Import Note: During a follow-up period of approximately 18 months, 10 -5 At the sensitivity threshold level, the sample has an evaluable sample. subject In that case, approximately 92% ratio or the CAR-T cells Import Note: During a follow-up period of approximately 18 months, 10 -5 At the sensitivity threshold level, the sample has an evaluable sample. subject In that case, approximately 97% or less ratio This effectively obtains a negative state for minimal residual disease (MRD). In some examples, the method is used to obtain the CAR-T cells Import During the follow-up period of approximately 12 months after the note, 10 -5 At the sensitivity threshold level, the sample has an evaluable sample. subject In that case, approximately 83% to approximately 98% ratio or the CAR-T cells Import Note: During a follow-up period of approximately 18 months, 10 -5 At the sensitivity threshold level, the sample has an evaluable sample. subject In that case, approximately 82% to approximately 97% ratio This effectively obtains a negative state for minimal residual disease (MRD). In some examples, the method is used to obtain the CAR-T cells Import During the follow-up period of approximately 12 months after the note, 10 -5 At the sensitivity threshold level, the sample has an evaluable sample. subject In that case, approximately 93% ratio or the CAR-T cells Import Note: During a follow-up period of approximately 18 months, 10 -5 At the sensitivity threshold level, the sample has an evaluable sample. subject In that case, approximately 92% ratio This effectively achieves a negative status for minimal residual disease (MRD).

[0194] In some embodiments, the method is used for the CAR-T cells. Import Note: subject At least one response is effectively obtained, wherein the at least one response includes, in order from best to worst, a strict complete response, a complete response, a best partial response, a partial response, or a minimal response.

[0195] In some embodiments, the method is used for the CAR-T cells. Import The initial response is effectively obtained within a period of approximately 27 days or more, approximately 29 days or more, approximately 42 days or more, approximately 89 days or more, or approximately 321 days or more after injection. In some examples, the method is used to obtain the aforementioned CAR-T cells. Import The initial response is effectively obtained approximately 27 to 321 days after injection. In some examples, the method involves the CAR-T cells Import The initial response is effectively obtained approximately 27 to 89 days after injection. In some examples, the method involves the CAR-T cells Import The first response is effectively obtained approximately 42 days after injection. In some examples, the method involves the CAR-T cells Import Effective initial response is achieved approximately 29 days after administration.

[0196] In some examples, a strict complete response was achieved. subject The effectiveness of the treatment method is assessed by evaluating the percentage of complete response or better response. In some cases, complete response or better response was observed. subject The effectiveness of the treatment method is assessed by evaluating the percentage of the best partial response or better response. In some cases, the best partial response or better response was observed. subject The effectiveness of the treatment method is assessed by evaluating the proportion of partial responses or better responses. In some cases, partial responses or better responses were observed. subject The effectiveness of the treatment method is assessed by evaluating the proportion of [specific percentages]. In some cases, [specific percentages] showed minimal response or better response. subject The effectiveness of the treatment method is assessed by evaluating the percentage of [specific percentage].

[0197] In some embodiments, the method effectively obtains one of the best responses among minimal response, partial response, best partial response, complete response, or strict complete response, i.e., the best response of minimal response or better response. In some embodiments, the method effectively obtains the best response of minimal response or better response. ratio This is referred to as the clinical utility rate. In some examples, the method is used for the CAR-T cells. Import During the follow-up period of approximately 12 months after ordering, less than 91% ratio And the CAR-T cells Import During a follow-up period of approximately 12 months after ordering, less than 97% ratio And the CAR-T cells Import During a follow-up period of approximately 12 months after ordering, less than 99% ratio And the CAR-T cells Import During a follow-up period of approximately 18 months after ordering, less than 93% ratio And the CAR-T cells Import During a follow-up period of approximately 18 months after ordering, less than 98% ratio or the CAR-T cells Import During the approximately 18-month follow-up period after ordering, less than 100% ratio This effectively obtains the best response, which is the minimum response or a better response. In some examples, the method is used to obtain the CAR-T cells Import During a follow-up period of approximately 12 months after ordering, approximately 91% to 99% ratio or the CAR-T cells Import During a follow-up period of approximately 18 months after the order was placed, approximately 93% to 100% of the cases were reported. ratio The method effectively obtains one of the following best responses: minimal response, partial response, best partial response, complete response, or strict complete response. In some embodiments, the method is used to obtain the CAR-T cells Import During a follow-up period of approximately 12 months after ordering, approximately 97% ratio or the CAR-T cells Import During a follow-up period of approximately 18 months after ordering, approximately 98% ratio The patient effectively obtains one of the following best responses: minimal response, partial response, best partial response, complete response, or strict complete response.

[0198] In some embodiments, the method effectively obtains one of the best responses, i.e., a partial response or a better response, among partial response, best partial response, complete response, or strict complete response. ratio This is referred to as the overall survival rate or overall response rate. In some examples, the method is used for the CAR-T cells. Import During the follow-up period of approximately 12 months after ordering, less than 91% ratio And the CAR-T cells Import During a follow-up period of approximately 12 months after ordering, less than 97% ratio And the CAR-T cells Import During a follow-up period of approximately 12 months after ordering, less than 99% ratio And the CAR-T cells Import During a follow-up period of approximately 18 months after ordering, less than 93% ratio And the CAR-T cells Import During a follow-up period of approximately 18 months after ordering, less than 97% ratio or the CAR-T cells Import During the approximately 18-month follow-up period after ordering, less than 100% ratio This effectively obtains the best response, which is a partial response or a better response. In some examples, the method is used to obtain the CAR-T cells Import During a follow-up period of approximately 12 months after ordering, approximately 91% to 99% ratio or the CAR-T cells Import During a follow-up period of approximately 18 months after the order was placed, approximately 93% to 100% of the cases were reported. ratio The method effectively obtains one of the following best responses: partial response, best partial response, complete response, or severe complete response. In some embodiments, the method involves the CAR-T cells Import During a follow-up period of approximately 12 months after ordering, approximately 97% ratio or the CAR-T cells Import During a follow-up period of approximately 18 months after the order was placed, approximately 97% ratio The patient effectively achieves one of the following outcomes: partial response, best partial response, complete response, or strict complete response.

[0199] In some embodiments, the method effectively obtains one of the best responses, i.e., the best partial response or a better response, among the best partial response, complete response, or severe complete response. In some embodiments, the method obtains the best response of the CAR-T cells Import During the follow-up period of approximately 12 months after ordering, less than 86% ratio And the CAR-T cells Import During a follow-up period of approximately 12 months after ordering, less than 93% ratio And the CAR-T cells Import During a follow-up period of approximately 12 months after ordering, less than 97% ratio And the CAR-T cells Import During a follow-up period of approximately 18 months after ordering, less than 88% ratio And the CAR-T cells Import During a follow-up period of approximately 18 months after ordering, less than 95% ratio or the CAR-T cells Import During a follow-up period of approximately 18 months after ordering, less than 98% ratio The best response, which is the best partial response or a better response, is effectively obtained. In some examples, the method is used to obtain the CAR-T cells Import During a follow-up period of approximately 12 months after ordering, approximately 86% to 97% ratio or the CAR-T cells Import During a follow-up period of approximately 18 months after ordering, approximately 88% to 98% ratio The method effectively obtains one of the best responses, which is either a best partial response, a complete response, or a severe complete response. In some examples, the method for the CAR-T cells Import During a follow-up period of approximately 12 months after ordering, approximately 93% ratio or the CAR-T cells Import During a follow-up period of approximately 18 months after the order was placed, approximately 95% ratio This effectively achieves one of the following best responses: best partial response, complete response, or strict complete response.

[0200] In some embodiments, the method effectively obtains complete response or the best response of strict complete response, i.e., complete response or the best response of better response. In some embodiments, the method effectively obtains the CAR-T cells Import During a follow-up period of approximately 12 months after ordering, less than 57% ratio And the CAR-T cells Import During the follow-up period of approximately 12 months after ordering, less than 67% ratio And the CAR-T cells Import During the follow-up period of approximately 12 months after ordering, less than 76% ratio And the CAR-T cells Import During a follow-up period of approximately 18 months after ordering, less than 73% ratio And the CAR-T cells Import During a follow-up period of approximately 18 months after ordering, less than 83% ratio or the CAR-T cells Import During a follow-up period of approximately 18 months after ordering, less than 89% ratio Thus, the best response, which is complete response or a better response, is effectively obtained. In some examples, the method is used to obtain the CAR-T cells Import During a follow-up period of approximately 12 months after the note, approximately 57% to approximately 76% ratio or the CAR-T cells Import During a follow-up period of approximately 18 months after the note, approximately 73% to 89% ratio Thus, the best response, which is complete response or strict complete response, is effectively obtained. In some examples, the method is used to obtain the CAR-T cells Import During a follow-up period of approximately 12 months after the order was placed, approximately 67% ratio or the CAR-T cells Import During a follow-up period of approximately 18 months after the order was placed, approximately 83% ratio This effectively achieves the best possible response, which is either a complete response or a strict complete response.

[0201] In some embodiments, the method effectively obtains the best response, which is a strict complete response. In some embodiments, the method uses the CAR-T cells Import During a follow-up period of approximately 12 months after ordering, less than 57% ratio And the CAR-T cells Import During the follow-up period of approximately 12 months after ordering, less than 67% ratio And the CAR-T cells Import During the follow-up period of approximately 12 months after ordering, less than 76% ratio And the CAR-T cells Import During a follow-up period of approximately 18 months after ordering, less than 73% ratio And the CAR-T cells Import During a follow-up period of approximately 18 months after ordering, less than 83% ratio or the CAR-T cells Import During a follow-up period of approximately 18 months after ordering, less than 89% ratio Thus, the best response of strict complete response is effectively obtained. In some examples, the method is used to obtain the CAR-T cells Import During a follow-up period of approximately 12 months after the note, approximately 57% to approximately 76% ratio or the CAR-T cells Import During a follow-up period of approximately 18 months after the note, approximately 73% to 89% ratio Thus, the best response of strict complete response is effectively obtained. In some examples, the method is used to obtain the CAR-T cells Import During a follow-up period of approximately 12 months after the order was placed, approximately 67% ratio or the CAR-T cells Import During a follow-up period of approximately 18 months after the order was placed, approximately 83% ratio This effectively achieves the aforementioned best response, which is a strict complete response.

[0202] In some embodiments, the method is used for the CAR-T cells. Import The best response is effectively obtained during a period of approximately 27 days or more, 78 days or more, 153 days or more, 293 days or more, or approximately 534 days or more after injection. In some examples, the method is used to obtain the best response of the CAR-T cells. Import The best response is effectively obtained approximately 27 to 534 days after injection. In some examples, the method is used to obtain the CAR-T cells Import The best response is effectively obtained approximately 27 to 293 days after injection. In some examples, the method involves the CAR-T cells ImportThe best response is effectively obtained approximately 153 days after injection. In some examples, the method is used to obtain the CAR-T cells Import The best response is effectively achieved approximately 78 days after administration.

[0203] In some embodiments, the method is described as follows: Import Up to approximately 180 days after injection, from the time of the initial response, the CAR-T cells Import Up to approximately 357 days after injection, from the time of the initial response, the CAR-T cells Import Up to approximately 606 days after injection, or from the time of the first response, the CAR-T cells Import During the tracking period of approximately 654 days after ordering, subject To effectively maintain efficacy in the CAR-T cells. In some examples, the method is used to maintain efficacy in the CAR-T cells. Import During the follow-up period of approximately 6 months after ordering, less than 77% ratio And the CAR-T cells Import During the follow-up period of approximately 6 months after ordering, less than 85% ratio And the CAR-T cells Import During a follow-up period of approximately 6 months after ordering, less than 91% ratio And the CAR-T cells Import During a follow-up period of approximately 12 months after ordering, less than 63% ratio And the CAR-T cells Import During the follow-up period of approximately 12 months after ordering, less than 74% ratio And the CAR-T cells Import During a follow-up period of approximately 12 months after ordering, less than 81% ratio And the CAR-T cells Import During a follow-up period of approximately 18 months after the note was issued, less than 56% ratio And the CAR-T cells Import During a follow-up period of approximately 18 months after ordering, less than 67% ratio And the CAR-T cells Import During a follow-up period of approximately 18 months after ordering, less than 75% ratio And the CAR-T cells Import During a follow-up period of approximately 21 months after ordering, less than 52% ratioAnd the CAR-T cells Import During a follow-up period of approximately 21 months after ordering, less than 63% ratio And the CAR-T cells Import During a follow-up period of approximately 21 months after ordering, less than 72% ratio And the CAR-T cells Import During the follow-up period of approximately 24 months after the note, less than 48% ratio And the CAR-T cells Import During the follow-up period of approximately 24 months after ordering, less than 60% ratio or the CAR-T cells Import During the follow-up period of approximately 24 months after ordering, less than 70% ratio This effectively maintains the response. In some examples, the method involves the CAR-T cells Import During a follow-up period of approximately 6 months after ordering, approximately 77% to 91% ratio And the CAR-T cells Import During a follow-up period of approximately 12 months after the note, approximately 63% to approximately 81% ratio And the CAR-T cells Import During a follow-up period of approximately 18 months after the note, approximately 56% to approximately 75% ratio And the CAR-T cells Import During a follow-up period of approximately 21 months after the note, approximately 52% to approximately 72% ratio or the CAR-T cells Import During a follow-up period of approximately 24 months after the note, approximately 48% to approximately 70% ratio This effectively maintains the response. In some examples, the method involves the CAR-T cells Import During the follow-up period of approximately 6 months after the note, approximately 85% ratio And the CAR-T cells Import During a follow-up period of approximately 12 months after the order was placed, approximately 74% ratio And the CAR-T cells Import During a follow-up period of approximately 18 months after the note, approximately 67% ratio And the CAR-T cells Import During a follow-up period of approximately 21 months after the note, approximately 63% ratio or the CAR-T cells Import During the follow-up period of approximately 24 months after the note, approximately 60% ratioThis effectively maintains the effectiveness of the treatment.

[0204] In some embodiments, the method described herein involves 10 -5 At the sensitivity threshold level, the negative status of minimal residual disease (MRD) assessed in the bone marrow is defined as follows: subject Effectively obtained in the CAR-T cells. In some examples, the method is used to obtain the CAR-T cells. Import During the follow-up period of approximately 12 months after ordering, less than 25% ratio And the CAR-T cells Import During the follow-up period of approximately 12 months after ordering, less than 34% ratio And the CAR-T cells Import During the follow-up period of approximately 12 months after ordering, less than 44% ratio And the CAR-T cells Import During a follow-up period of approximately 18 months after ordering, less than 33% ratio And the CAR-T cells Import During a follow-up period of approximately 18 months after ordering, less than 43% ratio or the CAR-T cells Import During a follow-up period of approximately 18 months after ordering, less than 54% ratio This effectively obtains a negative complete response or a negative strict complete response for minimal residual disease (MRD). In some examples, the method is used to obtain the CAR-T cells Import During a follow-up period of approximately 12 months after the note, approximately 25% to 44% ratio or the CAR-T cells Import During a follow-up period of approximately 18 months after the note, approximately 33% to approximately 54% ratio This effectively obtains a negative complete response or a negative strict complete response for minimal residual disease (MRD). In some examples, the method is used to obtain the CAR-T cells Import During a follow-up period of approximately 12 months after the order was placed, approximately 34% ratio or the CAR-T cells Import During a follow-up period of approximately 18 months after the note, approximately 43% ratioThis effectively achieves negative complete response or negative strict complete response with minimal residual disease (MRD).

[0205] In some embodiments, the method is subject To effectively obtain the progression-free survival period of the CAR-T cells. In some examples, the method is used to obtain the progression-free survival period of the CAR-T cells. Import Note: The CAR-T cells Import Approximately 209 days after injection, the CAR-T cells Import Note: The CAR-T cells Import Approximately 386 days after injection, the CAR-T cells Import Note: The CAR-T cells Import Approximately 632 days after injection or the aforementioned CAR-T cells Import Note: The CAR-T cells Import Within approximately 684 days after the note, subject The aforementioned progression-free survival period is effectively obtained. In some examples, the method is used to obtain the aforementioned progression-free survival period of the CAR-T cells. Import During the follow-up period of approximately 6 months after ordering, less than 79% ratio And the CAR-T cells Import During the follow-up period of approximately 6 months after ordering, less than 88% ratio And the CAR-T cells Import During a follow-up period of approximately 6 months after ordering, less than 93% ratio And the CAR-T cells Import During the follow-up period of approximately 12 months after ordering, less than 67% ratio And the CAR-T cells Import During the follow-up period of approximately 12 months after ordering, less than 76% ratio And the CAR-T cells Import During a follow-up period of approximately 12 months after ordering, less than 84% ratio And the CAR-T cells Import During a follow-up period of approximately 18 months after the order was placed, less than 57% ratio And the CAR-T cells Import During a follow-up period of approximately 18 months after ordering, less than 67% ratio And the CAR-T cells Import During a follow-up period of approximately 18 months after ordering, less than 75% ratioAnd the CAR-T cells Import During a follow-up period of approximately 21 months after ordering, less than 57% ratio And the CAR-T cells Import During a follow-up period of approximately 21 months after the order was placed, less than 67% ratio And the CAR-T cells Import During a follow-up period of approximately 21 months after ordering, less than 75% ratio And the CAR-T cells Import During the follow-up period of approximately 24 months after ordering, less than 49% ratio And the CAR-T cells Import During the follow-up period of approximately 24 months after ordering, less than 61% ratio or the CAR-T cells Import During the follow-up period of approximately 24 months after ordering, less than 70% ratio This effectively obtains the aforementioned progression-free survival period. In some examples, the method is used to obtain the aforementioned CAR-T cells. Import During a follow-up period of approximately 6 months after ordering, approximately 79% to 93% ratio And the CAR-T cells Import During a follow-up period of approximately 12 months after the note, approximately 67% to approximately 84% ratio And the CAR-T cells Import During a follow-up period of approximately 18 months after the note, approximately 57% to approximately 75% ratio And the CAR-T cells Import During a follow-up period of approximately 21 months after the note, approximately 57% to approximately 75% ratio or the CAR-T cells Import During a follow-up period of approximately 24 months after the note, approximately 49% to approximately 70% ratio This effectively obtains the aforementioned progression-free survival period. In some examples, the method is used to obtain the aforementioned CAR-T cells. Import During the follow-up period of approximately 6 months after the order was placed, approximately 88% ratio And the CAR-T cells Import During a follow-up period of approximately 12 months after the order was placed, approximately 76% ratio And the CAR-T cells Import During a follow-up period of approximately 18 months after the note, approximately 67% ratio And the CAR-T cells Import During a follow-up period of approximately 21 months after the note, approximately 67% ratioor the CAR-T cells Import During the follow-up period of approximately 24 months after the note, approximately 61% ratio This effectively achieves the aforementioned progression-free survival period.

[0206] In some embodiments, the method is used for the CAR-T cells. Import Note: More than approximately 1 day after the above subject The method further includes treating cytokine release syndrome. In some embodiments, the method effectively obtains a recovery rate of about 1% to about 99% of the cytokine release syndrome within a period of about 1, 3, 4, 6, 16, or 97 days from the first observation of the cytokine release syndrome.

[0207] In some embodiments, the method is used for the CAR-T cells. Import Note: More than approximately 3 days after the above subject The method further includes treating neurotoxicity associated with immune effector cells. In some embodiments, the method effectively obtains a recovery rate of about 1% to about 17% of the neurotoxicity associated with immune effector cells over a period of about 1, 4, 5, 8, 12, or 16 days from the first observation of the neurotoxicity associated with immune effector cells.

[0208] In some cases, the treatment method was subject In this context, a reduction in tumor burden is effectively achieved. In some cases, the treatment method was more than 90%. subject In this approach, a reduction in tumor burden is effectively achieved. In some cases, the treatment method was more than 91%. subject In this approach, a reduction in tumor burden is effectively achieved. In some cases, the treatment method was more than 92%. subject In this approach, a reduction in tumor burden is effectively achieved. In some cases, the treatment method was more than 93%. subject In this approach, a reduction in tumor burden is effectively achieved. In some cases, the treatment method was more than 94%. subject In this context, a reduction in tumor burden is effectively achieved. In some cases, the treatment method was more than 95%. subject In this approach, a reduction in tumor burden is effectively achieved. In some cases, the treatment method was more than 96%. subject In this approach, a reduction in tumor burden is effectively achieved. In some cases, the treatment method was more than 97%. subject In this approach, a reduction in tumor burden is effectively achieved. In some cases, the treatment method was more than 98% effective. subject In this approach, a reduction in tumor burden is effectively achieved. In some cases, the treatment method was more than 99% effective. subject In this, a reduced tumor burden is effectively obtained. In some cases, the treatment method is 100% subject In this context, the reduced tumor burden is effectively obtained.

[0209] In some cases, the treatment method was subject In this, the goal is to effectively achieve a negative status for minimal residual disease (MRD) or to effectively maintain the MRD status. In some embodiments, the treatment method is subject In this, a negative status for minimal residual disease (MRD) is effectively obtained. In some cases, the treatment method was 10 -6 at the sensitivity level subject In this case, a negative status for minimal residual disease (MRD) is effectively obtained. In some cases, the treatment method was 10 -5 at the sensitivity level subject In this case, a negative status for minimal residual disease (MRD) is effectively obtained. In some cases, the treatment method was 10 -4 at the sensitivity level subject In this case, a negative status for minimal residual disease (MRD) is effectively obtained. In some cases, the treatment method was 10 -3 at the sensitivity level subjectIn some cases, the treatment method effectively achieves a negative status for minimal residual disease (MRD). In some cases, when assessment is performed in the bone marrow, the treatment method effectively achieves a negative status for MRD. In some cases, when assessment is performed using an evaluable bone marrow sample, the treatment method effectively maintains a negative status for MRD. In some cases, when assessment is performed using bone marrow DNA, the treatment method effectively achieves a negative status for MRD. In some cases, when assessment is performed during a follow-up period of 28 days or more after CAR-T cell administration, the treatment method effectively achieves a negative status for MRD. In some cases, when assessment is performed during a follow-up period of 1 month or more after CAR-T cell administration, the treatment method effectively achieves a negative status for MRD. In some cases, when assessment is performed during a follow-up period of 3 months or more after CAR-T cell administration, the treatment method effectively achieves a negative status for MRD. In some cases, when assessment is performed during a follow-up period of 6 months or more after CAR-T cell administration, the treatment method effectively achieves a negative status for MRD. In some cases, when assessments were conducted during a follow-up period of 9 months or more after CAR-T cell administration, the treatment method effectively achieved a negative MRD status. In some cases, when assessments were conducted during a follow-up period of 12 months or more after CAR-T cell administration, the treatment method effectively achieved a negative MRD status.

[0210] In some cases, the treatment method was subject In this context, the negative status of minimal residual disease (MRD) obtained for the first time is effectively maintained. In some examples, the treatment method was 10 -5 It effectively maintains a negative MRD status at the sensitivity level. In some examples, the treatment method is 10 -6 at the sensitivity level subject In this case, a negative status for minimal residual disease (MRD) is effectively obtained. In some cases, the treatment method was 10 -4 It effectively maintains a negative MRD status at the sensitivity level. In some examples, the treatment method is 10 -3The treatment effectively maintains an MRD-negative state at the sensitivity level. In some cases, when assessed using bone marrow samples, the treatment effectively maintains an MRD-negative state. In some cases, when assessed using evaluable bone marrow samples, the treatment effectively maintains an MRD-negative state. In some cases, when assessed using bone marrow DNA, the treatment effectively maintains an MRD-negative state. In some cases, when assessed during a follow-up period of more than one month after CAR-T cell administration, the treatment effectively maintains an MRD-negative state. In some cases, when assessed during a follow-up period of more than three months after CAR-T cell administration, the treatment effectively maintains an MRD-negative state. In some cases, when assessed during a follow-up period of more than six months after CAR-T cell administration, the treatment effectively maintains an MRD-negative state. In some cases, when assessed during a follow-up period of more than nine months after CAR-T cell administration, the treatment effectively maintains an MRD-negative state. In some cases, when evaluation was conducted during a follow-up period of 12 months or more after CAR-T cell administration, the treatment method was effective in maintaining a negative MRD status.

[0211] In some examples, the MRD negative state was subject The effectiveness of the treatment method is assessed by evaluating the proportion of [percentage]. In some examples, 10 -6 At the sensitivity level, the MRD negative status is present. subject The effectiveness of the treatment method is assessed by evaluating the proportion of [percentage]. In some examples, 10 -5 At the sensitivity level, the MRD negative status is present. subject The effectiveness of the treatment method is assessed by evaluating the proportion of [percentage]. In some examples, 10 -4 At the sensitivity level, the MRD negative status is present. subject The effectiveness of the treatment method is assessed by evaluating the proportion of [percentage]. In some examples, 10 -3 At the sensitivity level, the MRD negative status is present. subjectThe effectiveness of the treatment method is assessed by evaluating the proportion of [specific percentage]. In some cases, the median follow-up period of 28 days or more after CAR-T cell administration was negative for MRD. subject The effectiveness of the treatment method is assessed by evaluating the proportion of [specific percentage]. In some cases, the median follow-up period of more than one month after CAR-T cell administration was negative for MRD. subject The effectiveness of the treatment method is assessed by evaluating the proportion of [specific percentage]. In some cases, the median follow-up period of 3 months or more after CAR-T cell administration was negative for MRD. subject The effectiveness of the treatment method is assessed by evaluating the proportion of [specific percentage]. In some cases, the median follow-up period of 6 months or more after CAR-T cell administration was negative for MRD. subject The effectiveness of the treatment method is assessed by evaluating the proportion of [specific percentage]. In some cases, the median follow-up period of 9 months or more after CAR-T cell administration was negative for MRD. subject The effectiveness of the treatment method is assessed by evaluating the proportion of [specific percentage]. In some cases, the median follow-up period of 12 months or more after CAR-T cell administration was negative for MRD. subject The effectiveness of the treatment method is assessed by evaluating the percentage of [specific percentage].

[0212] In some examples, evaluable bone marrow and MRD-negative status were observed. subject The effectiveness of the treatment method is assessed by evaluating the proportion of [percentage]. In some examples, 10 -6 At the sensitivity level, it is possible to evaluate bone marrow and has a negative MRD status subject The effectiveness of the treatment method is assessed by evaluating the proportion of [percentage]. In some examples, 10 -5 At the sensitivity level, it is possible to evaluate bone marrow and has a negative MRD status subject The effectiveness of the treatment method is assessed by evaluating the proportion of [percentage]. In some examples, 10 -4 At the sensitivity level, it is possible to evaluate bone marrow and has a negative MRD status subjectThe effectiveness of the treatment method is assessed by evaluating the proportion of [percentage]. In some examples, 10 -3 At the sensitivity level, it is possible to evaluate bone marrow and has a negative MRD status subject The effectiveness of the treatment method is assessed by evaluating the proportion of [specific criteria]. In some cases, [specific criteria] were met, with a median follow-up period of 28 days or more after CAR-T cell administration, [specific criteria] showed evaluable bone marrow and MRD-negative status. subject The effectiveness of the treatment method is assessed by evaluating the proportion of [specific criteria]. In some cases, the median follow-up period of more than one month after CAR-T cell administration included [specific criteria] with evaluable bone marrow and MRD-negative status. subject The effectiveness of the treatment method is assessed by evaluating the proportion of [specific criteria]. In some cases, [specific criteria] were met, with a median follow-up period of 3 months or more after CAR-T cell administration, [specific criteria] showed evaluable bone marrow and MRD-negative status. subject The effectiveness of the treatment method is assessed by evaluating the proportion of [specific criteria]. In some cases, [specific criteria] were met, with a median follow-up period of 6 months or more after CAR-T cell administration, [specific criteria] showed evaluable bone marrow and MRD-negative status. subject The effectiveness of the treatment method is assessed by evaluating the proportion of [specific criteria]. In some cases, [specific criteria] were met, with a median follow-up period of 9 months or more after CAR-T cell administration, [specific criteria] showed evaluable bone marrow and MRD-negative status. subject The effectiveness of the treatment method is assessed by evaluating the proportion of [specific criteria]. In some cases, [specific criteria] were met, with a median follow-up period of 12 months or more after CAR-T cell administration, [specific criteria] showed evaluable bone marrow and MRD-negative status. subject The effectiveness of the treatment method is assessed by evaluating the percentage of [specific percentage].

[0213] In some examples, a strict complete response was achieved. subject The effectiveness of the treatment method is assessed by evaluating the percentage of complete response or better response. In some cases, complete response or better response was observed. subject The effectiveness of the treatment method is assessed by evaluating the percentage of the best partial response or better response. In some cases, the best partial response or better response was observed. subjectThe effectiveness of the treatment method is assessed by evaluating the proportion of partial responses or better responses. In some cases, partial responses or better responses were observed. subject The effectiveness of the treatment method is assessed by evaluating the percentage of responses. In some cases, the effectiveness of the treatment method is assessed using the overall response rate. In some cases, the overall response rate is the percentage of partial response or better response. subject This is the proportion.

[0214] In some embodiments, the method is 10 -5 At the sensitivity threshold level, a minimal residual disease (MRD) negativity rate greater than 39% is effectively obtained. In some examples, the method is 10 -5 At the sensitivity threshold level, a minimal residual disease (MRD) negativity rate greater than 44% is effectively obtained. In some examples, the method is 10 -5 At the sensitivity threshold level, a minimal residual disease (MRD) negativity rate greater than 49% is effectively obtained. In some examples, the method is 10 -5 At the sensitivity threshold level, a minimal residual disease (MRD) negativity rate greater than 54% is effectively obtained. In some examples, the method is 10 -5 At the sensitivity threshold level, a minimal residual disease (MRD) negativity rate greater than 59% is effectively obtained. In some examples, the method is 10 -5 At the sensitivity threshold level, a minimal residual disease (MRD) negativity rate greater than 64% is effectively obtained. In some examples, the method is 10 -5 At the sensitivity threshold level, a minimal residual disease (MRD) negativity rate greater than 69% is effectively obtained. In some examples, the method is 10 -5 At the sensitivity threshold level, a minimal residual disease (MRD) negativity rate greater than 74% is effectively obtained. In some examples, the method is 10 -5 At the sensitivity threshold level, a minimal residual disease (MRD) negativity rate greater than 70% is effectively obtained. In some examples, the method is used to assess bone marrow In the middle, 10 -5At the sensitivity threshold level, a minimal residual disease (MRD) negativity rate greater than 75% is effectively obtained. In some examples, the method is used to assess bone marrow In the middle, 10 -5 At the sensitivity threshold level, a minimal residual disease (MRD) negativity rate greater than 80% is effectively obtained. In some examples, the method is used to assess bone marrow In the middle, 10 -5 At the sensitivity threshold level, a minimal residual disease (MRD) negativity rate greater than 85% is effectively obtained. In some examples, the method is used to assess bone marrow In the middle, 10 -5 At the sensitivity threshold level, a minimal residual disease (MRD) negativity rate greater than 90% is effectively obtained. In some examples, the method is used to assess bone marrow In the middle, 10 -5 At the sensitivity threshold level, a minimal residual disease (MRD) negativity rate greater than 95% is effectively obtained. In some examples, the method is used to assess bone marrow In the middle, 10 -5 At this sensitivity threshold level, a 100% minimal residual disease (MRD) negativity rate is effectively achieved.

[0215] In some examples, the treatment method effectively achieves an overall response rate greater than 90%. In some examples, the treatment method effectively achieves an overall response rate greater than 91%. In some examples, the method effectively achieves an overall response rate greater than 93%. In some examples, the method effectively achieves an overall response rate greater than 95%. In some examples, the method effectively achieves an overall response rate greater than 97%. In some examples, the method effectively achieves an overall response rate greater than 99%. In some examples, the method effectively achieves an overall response rate of 100%. In some examples, the CAR-T cells Import The overall response rate will be assessed at a median follow-up period of at least 6 months after injection. In some examples, the CAR-T cells Import The overall response rate will be assessed at the median of a follow-up period of at least 12 months after the injection.

[0216] In some examples, more than 70% subject The treatment is effective at 9 months after CAR-T cell administration. In some cases, more than 72% responded to the treatment. subject The treatment is effective 9 months after CAR-T cell administration. In some cases, more than 74% responded to the treatment. subject The treatment is effective at 9 months after CAR-T cell administration. In some cases, more than 76% responded to the treatment. subject The treatment is effective at 9 months after CAR-T cell administration. In some cases, more than 78% responded to the treatment. subject The treatment is effective at 9 months after CAR-T cell administration. In some cases, more than 80% responded to the treatment. subject The treatment is effective 9 months after CAR-T cell administration. In some cases, more than 82% responded to the treatment. subject The treatment is effective at 9 months after CAR-T cell administration. In some cases, more than 84% responded to the treatment. subject The treatment is effective 9 months after CAR-T cell administration. In several cases, over 86% responded to the therapy. subject The treatment is effective 9 months after CAR-T cell administration.

[0217] In some examples, more than 54% Target of response The treatment is effective 12 months after CAR-T cell administration. In some cases, more than 58% responded to the treatment. Target of response The treatment is effective 12 months after CAR-T cell administration. In some cases, more than 62% responded to the treatment. Target of response The treatment is effective 12 months after CAR-T cell administration. In some cases, more than 66% responded to the treatment. Target of response The treatment is effective 12 months after CAR-T cell administration. In some cases, more than 70% responded to the treatment. Target of response The treatment is effective 12 months after CAR-T cell administration. In some cases, more than 74% responded to the treatment. Target of response The treatment is effective 12 months after CAR-T cell administration. In some cases, more than 78% responded to the treatment. Target of responseThe treatment is effective 12 months after CAR-T cell administration.

[0218] In some embodiments, the treatment method effectively achieves a duration of response longer than 9, 10, 11, 12, 13, 14, or 15 months. In some embodiments, the treatment method effectively achieves a duration of response longer than 12.4 months. In some embodiments, the treatment method effectively achieves a duration of response longer than 15.9 months.

[0219] In some cases, the treatment method effectively achieves a median duration of response longer than 9, 10, 11, 12, 13, 14, or 15 months. In some cases, the treatment method effectively achieves a median duration of response longer than 12.4 months. In some cases, the treatment method effectively achieves a median duration of response longer than 15.9 months.

[0220] In some cases, the treatment method was greater than 60% subject In this context, complete remission or a better response is effectively obtained. In some cases, the treatment method yielded a success rate of more than 61%. subject In this context, complete remission or a better response is effectively obtained. In some cases, the treatment method yielded a success rate greater than 62%. subject In this context, complete remission or a better response is effectively obtained. In some cases, the treatment method yielded a success rate greater than 63%. subject In this context, complete remission or a better response is effectively achieved. In some cases, the treatment method yielded a success rate greater than 64%. subject In this context, complete remission or a better response is effectively obtained. In some cases, the treatment method yielded a success rate of more than 65%. subject In this context, complete remission or a better response is effectively obtained. In some cases, the treatment method yielded a success rate greater than 66%. subject In this context, complete remission or a better response is effectively obtained. In some cases, the treatment method yielded a success rate of more than 67%. subjectIn this context, complete response or a better response was effectively obtained. In some cases, complete response or a better response was assessed less than 1 month after CAR-T cell administration. In some cases, complete response or a better response was assessed less than 3 months after CAR-T cell administration. In some cases, complete response or a better response was assessed less than 6 months after CAR-T cell administration. In some cases, complete response or a better response was assessed less than 9 months after CAR-T cell administration. In some cases, complete response or a better response was assessed less than 12 months after CAR-T cell administration. In some cases, complete response or a better response was assessed less than 15 months after CAR-T cell administration. In some cases, complete response or a better response was assessed more than 15 months after CAR-T cell administration.

[0221] In some cases, the treatment method was greater than 85% subject In this context, the best partial response or better response is effectively obtained. In some cases, the treatment method achieved a success rate greater than 86%. subject In this context, the best partial response or better response is effectively obtained. In some cases, the treatment method achieved a success rate greater than 87%. subject In this context, the best partial response or better response is effectively obtained. In some cases, the treatment method achieved a success rate greater than 88%. subject In this context, the best partial response or better response is effectively obtained. In some cases, the treatment method achieved a success rate greater than 89%. subject In this context, the best partial response or better response is effectively obtained. In some cases, the treatment method achieved a success rate of more than 90%. subject In this context, the best partial response or better response is effectively obtained. In some cases, the treatment method achieved a success rate of more than 91%. subject In this context, the best partial response or better response is effectively obtained. In some cases, the treatment method achieved a success rate greater than 92%. subjectIn this context, the best partial response or better response is effectively obtained. In some cases, the best partial response or better response was assessed less than 1 month after CAR-T cell administration. In some cases, the best partial response or better response was assessed less than 3 months after CAR-T cell administration. In some cases, the best partial response or better response was assessed less than 6 months after CAR-T cell administration. In some cases, the best partial response or better response was assessed less than 9 months after CAR-T cell administration. In some cases, the best partial response or better response was assessed less than 12 months after CAR-T cell administration. In some cases, the best partial response or better response was assessed less than 15 months after CAR-T cell administration. In some cases, the best partial response or better response was assessed more than 15 months after CAR-T cell administration.

[0222] In some cases, the treatment method was effective for an initial response in less than 1.15 months. up to Effectively obtain the median duration. In some cases, the treatment method achieved an initial response in less than 1.10 months. up to Effectively obtain the median duration. In some cases, the treatment method achieved an initial response in less than 1.05 months. up to Effectively obtain the median duration. In some cases, the treatment method achieved an initial response of less than 1.00 months. up to Effectively obtain the median duration. In some cases, the treatment method achieved an initial response in less than 0.95 months. up to Effectively obtain the median of the period.

[0223] In some cases, the treatment method showed a best response of less than 2.96 months. up to Effectively obtain the median duration. In some cases, the treatment method achieved the best response in less than 2.86 months. up to Effectively obtain the median duration. In some cases, the treatment method achieved the best response in less than 2.76 months. up to Effectively obtain the median duration. In some cases, the treatment method achieved the best response in less than 2.66 months. up toEffectively obtain the median duration. In some cases, the treatment method achieved the best response in less than 2.56 months. up to Effectively obtain the median of the period.

[0224] In some examples, the method effectively achieves an overall survival rate greater than 80% at 9 months after CAR-T cell administration. In some examples, the method effectively achieves an overall survival rate greater than 82% at 9 months after CAR-T cell administration. In some examples, the method effectively achieves an overall survival rate greater than 85% at 9 months after CAR-T cell administration. In some examples, the method effectively achieves an overall survival rate greater than 87% at 9 months after CAR-T cell administration. In some examples, the method effectively achieves an overall survival rate greater than 90% at 9 months after CAR-T cell administration. In some examples, the method effectively achieves an overall survival rate greater than 92% at 9 months after CAR-T cell administration. In some examples, the method effectively achieves an overall survival rate greater than 95% at 9 months after CAR-T cell administration.

[0225] In some examples, the method effectively achieves an overall survival rate greater than 80% at 12 months after CAR-T cell administration. In some examples, the method effectively achieves an overall survival rate greater than 83% at 12 months after CAR-T cell administration. In some examples, the method effectively achieves an overall survival rate greater than 86% at 12 months after CAR-T cell administration. In some examples, the method effectively achieves an overall survival rate greater than 89% at 12 months after CAR-T cell administration. In some examples, the method effectively achieves an overall survival rate greater than 92% at 12 months after CAR-T cell administration. In some examples, the method effectively achieves an overall survival rate greater than 93% at 12 months after CAR-T cell administration.

[0226] In some examples, the method effectively achieves a progression-free survival rate greater than 70% at 9 months after CAR-T cell administration. In some examples, the method effectively achieves a progression-free survival rate greater than 72% at 9 months after CAR-T cell administration. In some examples, the method effectively achieves a progression-free survival rate greater than 75% at 9 months after CAR-T cell administration. In some examples, the method effectively achieves a progression-free survival rate greater than 77% at 9 months after CAR-T cell administration. In some examples, the method effectively achieves a progression-free survival rate greater than 80% at 9 months after CAR-T cell administration. In some examples, the method effectively achieves a progression-free survival rate greater than 82% at 9 months after CAR-T cell administration. In some examples, the method effectively achieves a progression-free survival rate greater than 85% at 9 months after CAR-T cell administration. In several examples, the method effectively achieves a progression-free survival rate of 87% or higher at 9 months after CAR-T cell administration.

[0227] In some examples, the method effectively achieves a progression-free survival rate greater than 66% at 12 months after CAR-T cell administration. In some examples, the method effectively achieves a progression-free survival rate greater than 69% at 12 months after CAR-T cell administration. In some examples, the method effectively achieves a progression-free survival rate greater than 72% at 12 months after CAR-T cell administration. In some examples, the method effectively achieves a progression-free survival rate greater than 76% at 12 months after CAR-T cell administration. In some examples, the method effectively achieves a progression-free survival rate greater than 80% at 12 months after CAR-T cell administration. In some examples, the method effectively achieves a progression-free survival rate greater than 84% at 12 months after CAR-T cell administration.

[0228] In some cases, the treatment method was more effective than the 86% who recovered from cytokine release syndrome. subjectTo effectively obtain [results]. In some cases, the treatment method resulted in a greater than 88% recovery rate from cytokine release syndrome. subject To effectively obtain [results]. In some cases, the treatment method resulted in a greater than 90% recovery rate from cytokine release syndrome. subject To obtain effectively. In some cases, the treatment method resulted in a greater than 92% recovery rate from cytokine release syndrome. subject To effectively obtain [results]. In some cases, the treatment method resulted in a greater than 94% recovery rate from cytokine release syndrome. subject To obtain effectively. In some cases, the treatment method resulted in a greater than 96% recovery rate from cytokine release syndrome. subject To effectively obtain [results]. In some cases, the treatment method resulted in a greater than 98% recovery rate from cytokine release syndrome. subject To obtain effectively. In some cases, the treatment method resulted in a greater than 99% recovery rate from cytokine release syndrome. subject To effectively obtain [result]. In some cases, the treatment method resulted in 100% recovery from cytokine release syndrome. subject To obtain it effectively.

[0229] In some cases, the treatment method resulted in recovery from more than 90% of the neurotoxicity (if any) associated with immune effector cells. subject This effectively obtains the desired result. In some cases, the treatment method resulted in recovery from more than 92% of the neurotoxicity (if any) associated with immune effector cells. subject This effectively obtains the desired result. In several cases, the treatment method resulted in recovery from more than 94% of the neurotoxicity (if present) associated with immune effector cells. subject This effectively obtains the desired result. In several cases, the treatment method resulted in recovery from more than 96% of the neurotoxicity (if any) associated with immune effector cells. subject This effectively obtains the desired result. In several cases, the treatment method resulted in recovery from more than 98% of the neurotoxicity (if any) associated with immune effector cells. subjectTo effectively obtain. In some cases, the treatment method resulted in 100% recovery from neurotoxicity (if any) associated with immunoeffector cells. subject To obtain it effectively.

[0230] In some embodiments, the method is subject This further includes diagnosing cytopenia. In some examples, cytopenia includes one, more, or all of lymphopenia, neutropenia, and thrombocytopenia. Although not bound by theory, lymphopenia of grade 3 or grade 4, rather than grade 2 or lower, is defined as a lymphocyte count of 0.5 × 10⁶. 9 individual cells / liter Target blood Neutropenia is characterized by having fewer than 1000 cells / microliter, and is not grade 2 or lower, but grade 3 or grade 4. Target blood Characterized by a sample size of less than 50,000 cells / microliter, thrombocytopenia of grade 3 or grade 4, rather than grade 2 or lower, is characterized by a platelet count of 50,000 cells / microliter. Target blood Characterized by being less than a sample size. In some examples, patients suffered from grade 3 or grade 4 lymphopenia after CAR-T cell administration. subject Over 75% of them experienced a decline in 60 minutes after CAR-T cell administration. days The patients recovered to lymphopenia of grade 2 or lower. In some cases, patients developed grade 3 or grade 4 lymphopenia after CAR-T cell administration. subject Over 80% of them were 60 days after CAR-T cell administration. days The patients recovered to lymphopenia of grade 2 or lower. In some cases, patients developed grade 3 or grade 4 lymphopenia after CAR-T cell administration. subject Over 85% of them were 60 days after CAR-T cell administration. days The patients recovered to lymphopenia of grade 2 or lower. In some cases, patients developed grade 3 or grade 4 lymphopenia after CAR-T cell administration. subject Over 90% of them were 60 days after CAR-T cell administration. daysThe patients recovered to lymphopenia of grade 2 or lower. In some cases, patients developed grade 3 or grade 4 neutropenia after CAR-T cell administration. subject Over 70% of them were 60 days after CAR-T cell administration. days The neutropenia improved to grade 2 or lower. In some cases, patients developed grade 3 or grade 4 neutropenia after CAR-T cell administration. subject Over 75% of them experienced a decline in 60 minutes after CAR-T cell administration. days The neutropenia improved to grade 2 or lower. In some cases, patients developed grade 3 or grade 4 neutropenia after CAR-T cell administration. subject Over 80% of them were 60 days after CAR-T cell administration. days The neutropenia improved to grade 2 or lower. In some cases, patients developed grade 3 or grade 4 neutropenia after CAR-T cell administration. subject Over 85% of them were 60 days after CAR-T cell administration. days The neutropenia improved to grade 2 or lower. In some cases, patients developed grade 3 or grade 4 thrombocytopenia after CAR-T cell administration. subject Over 30% of them were 60 days after CAR-T cell administration. days The thrombocytopenia recovered to grade 2 or lower. In some cases, patients developed grade 3 or grade 4 thrombocytopenia after CAR-T cell administration. subject Over 34% of them experienced a decline in 60 days after CAR-T cell administration. days The thrombocytopenia recovered to grade 2 or lower. In some cases, patients developed grade 3 or grade 4 thrombocytopenia after CAR-T cell administration. subject Over 38% of them experienced a decline in 60 days after CAR-T cell administration. days The thrombocytopenia recovered to grade 2 or lower. In some cases, patients developed grade 3 or grade 4 thrombocytopenia after CAR-T cell administration. subject Over 42% of them experienced a decline in 60 minutes after CAR-T cell administration. days The thrombocytopenia recovered to grade 2 or lower.

[0231] In some cases, a second dose of CAR-T cells was administered intravenously. Import By administration via injection, subject The patient is retreated. In some cases, the retreatment dose was 1.0 × 10⁻⁶. 5 From 5.0 x 10 6 individual CAR-T cells / kilogram Target mass This includes. In some examples, the retreatment dose was approximately 0.75 × 10⁻⁶. 5 individual CAR-T cells / kilogram Target mass Includes. In some embodiments, subject The first CAR-T cell Import After injection, if disease progression occurs after the best response (minimal response or better response), retreatment is administered. In some cases, the first CAR-T cells Infusion The time from the initial diagnosis to the detection of disease progression includes at least six months. Sets (kits) and products

[0232] Any composition described herein may be included in the set. In some examples, engineered immortalized CAR-T cells are provided in the set, which may further include reagents suitable for cell amplification, such as culture media.

[0233] In non-limiting examples, these include a chimeric receptor expression construct, one or more reagents for producing a chimeric receptor expression construct, cells for transfecting the expression construct, and / or one or more instruments for obtaining immortalized T cells for transfecting the expression construct (such instruments may be syringes, pipettes, forceps, and / or any such medically approved device).

[0234] In some embodiments, the set includes reagents or apparatus for cell electroporation.

[0235] In some embodiments, the set includes artificial antigen-presenting cells.

[0236] A set may comprise one or more appropriately divided compositions of the present disclosure or reagents for producing compositions of the present disclosure. The components of the set may be packaged in aqueous media or lyophilized form. The container apparatus of the set may comprise at least one vial, test tube, flask, bottle, syringe or other container apparatus (in which the components can be placed and preferably appropriately divided). If the set contains more than one component, the set usually further comprises a second, third or other additional container in which the additional components may be placed separately. However, various combinations of components may be contained in a vial. A set of the present disclosure usually further comprises apparatus for commercially selling the chimeric receptor constructs and any other reagent containers in a sealed container. Such containers may comprise, for example, injection-molded or blow-molded plastic containers in which the desired vials are held. Approved Pharmaceuticals

[0237] This disclosure is, Adult patients with relapsed or refractory multiple myeloma It provides further methods to treat it, and it is approved. Pharmaceuticals of Pharmaceuticals In the amounts and manner described on the label and / or in the administration and / or treatment regimen described herein, Siltacaptagenautoleucyl Approved suspension Pharmaceuticals This includes administering the above to the patient.

[0238] This disclosure will be furthered, Siltacaptagenautoleucyl With respect to a pharmaceutical product comprising a suspension, wherein the pharmaceutical product is packaged, the packaging includes a label, and the label is Siltacaptogen autoleucel suspension , proteasome inhibitors, Immunomodulatory drugs and an anti-CD38 monoclonal antibody Identify as an approved drug for the treatment of adult patients with relapsed or refractory multiple myeloma who have received four or more prior lines of treatment. .

[0239] This disclosure is, Siltacaptagenautoleucyl Approved suspension Pharmaceuticals Further methods of selling are provided, and the said methods are approved. Pharmaceuticals This includes selling, and hereby approved Drug label of a reference product for a pharmaceutical product These are proteasome inhibitors and Immunomodulatory drugsand an anti-CD38 monoclonal antibody Includes information for treating patients with relapsed or refractory multiple myeloma who have received four or more prior treatments. .

[0240] In some examples, the sales method is Siltacaptagenautoleucyl Approved suspension Pharmaceuticals The method includes selling a biosimilar of the reference product of the biosimilar, wherein the method includes selling the biosimilar, wherein the reference product of the biosimilar Pharmaceutical label These are proteasome inhibitors and Immunomodulatory drugs and an anti-CD38 monoclonal antibody Includes information for treating patients with relapsed or refractory multiple myeloma who have received four or more prior treatments. .

[0241] This disclosure is, Siltacaptagenautoleucyl Includes suspension Pharmaceuticals Sales To make a request Further providing a method, the said method is The aforementioned pharmaceutical Sales To make a request Including, here, Drug label of the reference product of the aforementioned drug These are proteasome inhibitors and Immunomodulatory drugs and an anti-CD38 monoclonal antibody Includes information for treating patients with relapsed or refractory multiple myeloma who have received four or more prior treatments. .

[0242] In some cases, sales To make a request The method is, Siltacaptagenautoleucyl Sales of biosimilars of approved drugs, including suspensions. To make a request The method includes the sale of biosimilars. To make a request Including, here, the reference product of the biosimilar. Pharmaceutical label These are proteasome inhibitors and Immunomodulatory drugs and an anti-CD38 monoclonal antibody Includes information for treating patients with relapsed or refractory multiple myeloma who have received four or more prior treatments. .

[0243] As used herein, the terms “to put up for sale” or “to sell” are: Pharmaceuticals For example, this refers to the transfer of a pharmaceutical composition or dosage form from a seller to a buyer.

[0244] The term "sale" as used herein To make a request The term " " is used by a seller to indicate to a buyer. Pharmaceuticals For example, this refers to proposing the sale of a pharmaceutical composition or dosage form. These methods are Pharmaceuticals Sales To make a request include.

[0245] " Pharmaceuticals The term "food" is used by government authorities, for example, in the context of food. Pharmaceuticals This refers to products containing active drug ingredients that have already been approved for sale by the bureau or a similar authority in another country.

[0246] "Label" or " Pharmaceuticals "Label" refers to the information provided to the patient, and it is, Pharmaceuticals This provides information about the following: Pharmaceuticals Description, clinical pharmacology, indications ( Pharmaceuticals Uses), contraindications (who Pharmaceuticals Should you take this drug?), warnings, precautions, adverse events (side effects), drug abuse and dependence, dosage and administration, use during pregnancy, use by breastfeeding mothers, use in children and the elderly, Pharmaceuticals This includes, but is not limited to, the method of supply, patient safety information, or any combination thereof. In some embodiments, the label or Pharmaceuticals The label is for patients who need BCMA CAR T cells. use Instructions were provided. In further examples, labels or Pharmaceuticals The label is, Siltacaptagenautoleucyl Identify the suspension and for patients who require BCMA CAR T cells. use Instructions will be provided.

[0247] The term "reference product" refers to an FDA-approved bioproduct compared to a proposed biosimilar product. Pharmaceuticals This refers to [the specified product]. In addition, approval of the reference product is based on the complete supplementation of safety and efficacy data. The proposed biosimilar product is compared and evaluated with the reference product to ensure that the product is highly similar and has no clinical significance.

[0248] "Biosimilars" are conventional FDA-approved reference products (approved PharmaceuticalsThis refers to a bioproduct that is highly similar to the reference product and has no clinical significance. The high degree of similarity between the biosimilar and the reference product can be demonstrated by broadly analyzing (i.e., characterizing) the structure and function of the reference product and the submitted biosimilar, and by comparing the product characteristics, such as purity, chemical properties, and biological activity. Minor differences in clinically inactive components between the reference product and the submitted biosimilar product (e.g., minor differences compared to stabilizers or buffers used in the reference product) are acceptable. The FDA carefully assesses any differences between the submitted biosimilar product and the reference product to ensure that the biosimilar meets the FDA's high approval standards. Minor differences (i.e., acceptable intra-product variations) are expected during the manufacturing of bioproducts, whether the product is a biosimilar or a reference product. Manufacturers must further demonstrate that the submitted biosimilar product has no clinical significance difference from the reference product in terms of safety, purity, and potency (safety and efficacy), which usually involves human pharmacokinetics. exposure This is demonstrated by pharmacodynamic (response) studies, clinical immunogenicity assessments, and (if necessary) additional clinical studies.

[0249] The manufacturer of the submitted biosimilar product will generate data and compare the submitted product to an FDA-approved reference product to demonstrate biosimilarity. The application for a biosimilar product must include data demonstrating biosimilarity with the reference product, where, - Clinically Although there are no significant differences in the active ingredients, the bio-product and the reference product are highly similar. Analytical research that demonstrated this , - Animal studies including toxicity assessment, and - The submitted biosimilar product must be sufficient to demonstrate that it achieves the safety, purity, and efficacy of one or more indications approved for the reference product, and may include comparative clinical studies, typically including assessments of immunogenicity, pharmacokinetics (PK), and possibly pharmacodynamics (PD). There is also one or more clinical studies Includes data from.

[0250] Rather than generating complete non-clinical and clinical data identical to the reference product, manufacturers who demonstrate that the submitted biosimilar is highly similar to the FDA-approved reference product and has no clinically significant differences may rely partly on the FDA's previous approval of safety and efficacy for the reference product. Therefore, biosimilar manufacturers may not need to conduct as many clinical trials.

[0251] This specification is, Siltacaptagenautoleucyl Approved suspension Pharmaceuticals Methods for supplying, storing, and processing the material are further disclosed. Siltacaptagenautoleucyl Approved suspension Pharmaceuticals This is frozen in 5% DMSO. Siltacaptagenautoleucyl The solution is provided in an infusion bag containing a suspension, either as a 70 mL suspension in the infusion bag and metal case (NDC 57894-111-01) or a 30 mL suspension in the infusion bag and metal case (NDC 57894-111-02). Each infusion bag is individually packaged in an aluminum freezer case. The infusion bags are stored, transported, and approved in a container stored at a low temperature of -120°C or below, for example, in a liquid nitrogen vapor phase. Pharmaceuticals The product is stored in its original packaging, which includes a protective case for the infusion bag. In some embodiments, the time from leukocyte apheresis to product availability may be 27 to 66 days. In some embodiments, the time from leukocyte apheresis to product availability may be 32 days.

[0252] The following exemplary embodiments are intended to be merely examples of the disclosure and should not be considered to limit the disclosure in any way. Exemplary Example (Example 1) subject A method for treating the aforementioned subject This includes T cells containing chimeric antigen receptors (CARs). A certain dose The composition single infusion This includes doing Here, the CAR contains the amino acid sequence of SEQ ID NO: 17, Here, the aforementioned dosage is 0.5 x 10 per kg of body weight of the subject 6 From 1.0 × 10 6 Contains fruit, Here, the method involves the following: subject Completing the administration of the aforementioned dose of T cells to subject How to treat it. (Example 2) The above subject teeth, Relapsed or refractory I have multiple myeloma, which is... The patient has a history of multiple prior treatments. Optionally, the above subject teeth, Patients with a history of 3 or more prior treatment lines The method described in Example 1. (Example 3) The above subject teeth, Patients with a history of 4 or more prior treatment lines The method described in Example 1 or 2. (Example 4) Before Previous medical history These are proteasome inhibitors and Immunomodulatory drugs The method according to Example 2 or 3, comprising an anti-CD38 monoclonal antibody. (Example 5) The method according to any one of Examples 1 to 4, wherein the T cells are autologous T cells. (Example 6) The method described above subject Before administering the T cells, subject to Lymphocyte depletion chemotherapy regimen of implementation The method according to any one of Examples 1 to 5, further comprising doing the following. (Example 7) The above Lymphocyte depletion chemotherapy regimen The above subject The method according to Example 6, comprising administering cyclophosphamide and fludarabine to the patient. (Example 8) The above Lymphocyte depletion chemotherapy regimen The above subject The method according to Example 7, comprising intravenous administration of cyclophosphamide and fludarabine. (Example 9) The above Lymphocyte depletion chemotherapy regimen The above The target group received approximately 300 mg / m² of cyclophosphamide. 2 The dosage, and fludarabine 30 mg / m² 2 Administer intravenously daily at this dose. The method according to Example 8, which includes doing the following. (Example 10) The above Lymphocyte depletion chemotherapy regimenIt is approximately 3 days The method according to any one of Examples 6 to 9. (Example 11) The method described above subject Before administering the T cells, subject to the above Lymphocyte depletion chemotherapy regimen for at least 2-4 days implementation The method according to any one of Examples 6 to 10, including the action of (Example 12) The above method is Premedication is administered to the subject within 60 minutes prior to the administration of the T cells to the subject. This further includes, and the premedication is, Antipyretic and antihistamines The method according to any one of Examples 1 to 11, including the above. (Example 13) The above method The premedication is administered approximately 30 to 60 minutes before the administration of the T cells to the subject. The method according to Example 12, which includes doing the following. (Example 14) The above Antipyretic The method according to Example 12 or 13, comprising paracetamol or acetaminophen. (Example 15) The above Antipyretic This is the method according to Example 14, which contains acetaminophen in a dose of approximately 650 mg to 1000 mg. (Example 16) The above antihistamines This is the method according to any one of Examples 12 to 15, comprising diphenhydramine. (Example 17) The dose of diphenhydramine is approximately 25 mg to 50 mg or equivalent dose The method described in Example 16. (Example 18) The premedication is administered orally or intravenously. That is or the method described in any one of Examples 12 to 17. (Example 19) The premedication is the method according to any one of Examples 12 to 18, wherein the premedication does not include a systemic corticosteroid. (Example 20) The above method involves administering the above dose of T cells before administration. melting This includes, and here, the aforementioned melting The method according to any one of Examples 1 to 19, which is completed within approximately 15 minutes. (Example 21) The above dose of T cells was heated at a temperature of approximately 37°C ± 2°C. melting The method described in Example 20. (Example 22) The above method involves administering the above dose of T cells, and then the above subject The method according to any one of Examples 1 to 21, further comprising treating cytokine release syndrome (CRS). (Example 23) CRS is exothermic, high fever Hypotension, elevated aspartate aminotransferase, chills, elevated alanine aminotransferase, sinus tachycardia, hyperbilirubinemia, Hypoxia , respiratory failure, acute kidney disease hindrance , disseminated intravascular coagulation and bleeding (for example, Retroperitoneal hemorrhage, intracerebral hemorrhage, or (Gastrointestinal bleeding), hemophagocytic lymphohistiocytosis (HLH), macrophage activation syndrome (MAS), angina pectoris, supraventricular Tachycardia and ventricular tachycardia, fatigue muscle pain, C-reactive protein Quality improvement ferritin rise , blood alkaline phosphatase rise γ-glutamyltransferase rise The method according to Example 22, including organ toxicity or any combination thereof. (Example 24) The above subject Treating CRS is the aforementioned subject The method according to Example 22 or 23, comprising administering an anti-cytokine agent or a corticosteroid. (Example 25) The method according to Example 24, wherein the anti-cytokine agent comprises a monoclonal antibody that targets cytokines. (Example 26) The method according to Example 25, wherein the monoclonal antibody targeting the cytokine is an IL-6R inhibitor. (Example 27) The method according to Example 26, wherein the IL-6R inhibitor is tocilizumab. (Example 28) The above method takes about 1 hour Below The method according to Example 27, comprising intravenous administration of tocilizumab at a dose of approximately 8 mg / kg. (Example 29) The method according to Example 28, wherein the dose of tocilizumab does not exceed approximately 800 mg. (Example 30) The dose of tocilizumab was administered over 24 hours Below 3 inside It is less than or equal to the prescribed dose., the method described in Example 28 or 29. (Example 31) The total dose of tocilizumab was 4 It is less than or equal to the prescribed dose. or the method described in any one of Examples 28 to 30. (Example 32) The method according to Example 24, further comprising an anti-cytokine agent other than tocilizumab. (Example 33) The method according to Example 24, wherein the anti-cytokine agent further comprises a monoclonal antibody that targets cytokines other than tocilizumab. (Example 34) The method according to any one of Examples 24 to 33, wherein the corticosteroid comprises dexamethasone or methylprednisolone. (Example 35) The method according to Example 34, wherein the corticosteroid is dexamethasone. (Example 36) The above method is The target was given approximately 10 mg of dexamethasone. The method according to Example 35, comprising administering intravenously approximately every 12 to 24 hours. (Example 37) The above method is subject Dexamethasone Approximately 10mg of Approximately every 12 hours The method according to Example 36, including intravenous administration. (Example 38) The above method is The target was given approximately 20 mg of dexamethasone. The method according to Example 35, comprising intravenous administration approximately every 6 to 12 hours. (Example 39) The above method is subject Dexamethasone Approximately 20mg of Approximately every 6 hours The method according to Example 38, including intravenous administration. (Example 40) The method according to Example 34, wherein the corticosteroid is methylprednisolone. (Example 41) The method described above subject methylprednisolone Approximately 2mg / kg of Approximately every 12 hours The method according to Example 40, including intravenous administration. (Example 42) The above method is subject methylprednisolone Approximately 1~2g of Approximately every 24 hours The method according to Example 40, including intravenous administration. (Example 43) The above method is subject to Immunosuppressants The method according to Example 22 or 23, comprising administering [the specified substance]. (Example 44) The method described above involves administering the T cells in the aforementioned dose, and then... subject The method according to any one of Examples 1 to 43, further comprising treating the neurotoxicity of the following. (Example 45) The neurotoxicity is immunoeffector cell-associated neurotoxicity syndrome (ICANS), per Kinsonism , Gillan · Ballet - The method according to Example 44, comprising (Guillain-Barré) syndrome, immune-mediated myelitis, peripheral neuropathy, cranial nerve palsy, or any combination thereof. (Example 46) The neurotoxicity includes ICANS, and the ICANS causes encephalopathy, aphasia, headache, and altered level of consciousness. of decline, seizure , Findings related to the motor system The method according to Example 45, comprising motor finding, increased intracranial pressure (ICP), cerebral edema, or any combination thereof. (Example 47) The ICANS is focal or Generalized seizures , on electroencephalogram (EEG) Nonconvulsive seizures, life-threatening persistent seizures, recurrent clinical or electrical seizures, deep focal motor dysfunction, hemiplegia, paraplegia, neuroimaging Focal / localized edema, stupor, Coma, neuroimaging Diffuse cerebral edema, decerebrate rigidity Alternatively, decorticate rigidity, cranial nerve palsy (c4th cranial nerve palsy), optic disc edema, Cushing's syndrome. The three signs and The method according to Example 46, which includes any combination thereof. (Example 48) The above method is performed every 12 to 24 hours subject Approximately 10 mg of dexamethasone for about 2-3 days. 、 The method according to Example 46 or 47, including intravenous administration. (Example 49) The above method 、 Approximately every 12 hours subject Approximately 10 mg of dexamethasone for 2-3 days or more. 、 The method according to Example 48, including intravenous administration. (Example 50) The above method is performed every 6 hours subjectThe method according to Example 46 or 47, comprising administering approximately 10-20 mg of dexamethasone intravenously. (Example 51) The above method is performed every 24 hours The target is methylprednisolone. Approximately 1-2g / day in The method according to any one of Examples 46 to 50, including administration. (Example 52) The ICANs is the method according to any one of Examples 46 to 50, including cerebral edema. (Example 53) The above method is subject to Hyperventilation and high Osmotic pressure Therapy implementation The method of Example 52, which includes doing the following. (Example 54) The method described above Target non-sedating antisecution drugs The method according to any one of Examples 46 to 53, comprising administering [the specified substance]. (Example 55) The non-sedating agent seizure The drug is levetiracetam, as described in Example 54. (Example 56) The neurotoxicity is per Kinsonism The method according to Example 45, including the method described in Example 45. (Example 57) The part Kinsonism The method according to Example 56, including Parkinsonian symptoms or non-Parkinsonian symptoms. (Example 58) The Parkinsonian symptoms or non-Parkinsonian symptoms include tremor, bradykinesia, involuntary movements, stereotypic behavior, loss of spontaneous movement, masked face, apathy, flatness, fatigue, Muscle rigidity, psychomotor restriction, micrographia , writing disorder, apraxia, apathy, confusion , sleepiness, consciousness Disappear Loss of reflexes, delayed reflexes, hyperreflexes, memory loss, difficulty swallowing, fecal incontinence, falls, Bent forward posture, short, shuffling steps , muscle weakness and Muscle atrophy , motor dysfunction, loss of motor and sensory functions, Akinetic mutism, frontal lobe release sign, or The method according to Example 57, which includes any combination thereof. (Example 59) The above method is subject Treatment implementation and Kinsonism The method according to any one of Examples 56 to 58, which includes reducing [the specified amount]. (Example 60) The neurotoxicity is Guillain VolleyballThe method according to Example 45, including the syndrome. (Example 61) Guillain Volleyball The syndrome is Guillain Volleyball Mira's Syndrome -· Fischer (Miller-Fisher) subtype Symptoms consistent with encephalopathy, motor weakness, speech disorders, multiple sex The method according to Example 60, comprising radiculitis or any combination thereof. (Example 62) The above method is subject Treatment implementation Gillan Volleyball The method according to Example 61, including alleviating the syndrome. (Example 63) The neurotoxicity is the method according to Example 45, including immune-mediated myelitis. (Example 64) The method according to Example 63, wherein the symptoms of immune-mediated myelitis include decreased sensation in the lower extremities or lower abdomen accompanied by sphincter dysregulation. (Example 65) The method described above subject Treatment implementation The method according to Example 63 or 64, comprising reducing immune-mediated myelitis, wherein the treatment optionally comprises a corticosteroid or immunoglobulin, and optionally the method comprises intravenous administration of the immunoglobulin. (Example 66) The neurotoxicity is the method according to Example 45, including peripheral neuropathy. (Example 67) The method according to Example 66, wherein the peripheral neuropathy includes sensory neuropathy, motor neuropathy, sensorimotor neuropathy, or any combination thereof. (Example 68) The method described above subject Treatment implementation The method according to Example 66 or 67, which includes reducing peripheral neuropathy. (Example 69) The neurotoxicity is the method according to Example 45, including cranial nerve paralysis. (Example 70) The method according to Example 69, wherein the cranial nerve palsy includes cranial nerve palsy of the third cranial nerve, cranial nerve palsy of the sixth cranial nerve, cranial nerve palsy of the seventh cranial nerve, or bilateral cranial nerve palsy of the seventh cranial nerve. (Example 71) The above method is subject Treatment implementationThe method according to Example 69 or 70, which includes reducing cranial nerve paralysis. (Example 72) CRS includes hemophagocytic lymphohistiocytosis (HLH) or macrophage activation syndrome (MAS), where the symptoms of HLH or MAS are accompanied by hypotension and diffuse alveolar damage. Hypoxia The method according to Example 23, comprising, , coagulation disorders, cytopenia, renal dysfunction, and any combination thereof, multi-organ dysfunction. (Example 73) The above method is subject Treatment implementation The method according to Example 72, which includes reducing HLH or MAS. (Example 74) The above method is subject Before administering T cells containing CAR, subject to Lymphocyte depletion chemotherapy regimen of implementation After or after administering the aforementioned dose of T cells containing CAR, subject The method according to any one of Examples 1 to 73, further comprising treating long-term or recurrent cytopenia. (Example 75) Before Long-term or recurrent cytopenia The method according to Example 74, which includes long-term neutropenia, long-term thrombocytopenia, recurrent neutropenia, thrombocytopenia, lymphopenia, anemia, or any combination thereof. (Example 76) The method described above subject The method according to Examples 1 to 75, further comprising treating the infection. (Example 77) Infection virus Sexual, bacterial, fungal or unspecified The method according to Example 76, wherein the infection is caused by a pathogen and, optionally, includes lung abscess, sepsis, pneumonia, bronchopulmonary aspergillosis, Pneumocystis pneumonia, CMV colitis (with HSV-1 hepatitis), fungal aneurysm, cerebral aspergillosis, or COVID-19 infection. (Example 78) The method according to Example 76, wherein the infection causes febrile neutropenia or subarachnoid hemorrhage. (Example 79) The above method is subject to Antibiotics The method according to any one of Examples 76 to 78, comprising administering [the specified substance]. (Example 80) Before Antibiotics The method described in Example 79 is an antibiotic. (Example 81) The method according to Example 80, wherein the antibiotic is a broad-spectrum antibiotic. (Example 82) The infection described above is virus The method described in Example 77, which is of a sexual nature. (Example 83) The method described above subject against virus The method according to Example 82, comprising administering a therapy or vaccine. (Example 84) The method described above subject The method according to any one of Examples 1 to 83, further comprising treating hypogammaglobulinemia. (Example 85) The method of Example 84, wherein after administration of T cells in the aforementioned dose containing CAR, hypogammaglobulinemia includes laboratory IgG levels lower than approximately 500 mg / dL. (Example 86) The method involves administering the aforementioned dose of T cells containing CAR, and then... Target dosage The method according to Example 84 or 85, comprising administering intravenous immunoglobulin (IVIG). (Example 87) The method described above subject The method according to any one of Examples 1 to 86, further comprising treating a hypersensitivity reaction. (Example 88) The hypersensitivity reaction included flushing, chest discomfort, tachycardia, wheezing , tremors, burning sensation, Anaphylaxis or The method according to Example 87, which includes any combination thereof. (Example 89) The method described above subject Treatment implementation The method according to Example 87 or 88, comprising reducing the aforementioned hypersensitivity reaction. (Example 90) The above method is subject of Secondary malignant tumors The method according to any one of Examples 1 to 89, further comprising treating the condition. (Example 91) The method according to any one of Examples 1 to 90, further comprising an excipient selected from dimethyl sulfoxide or dextran-40. (Example 92) The method according to Example 91, wherein the excipient is dimethyl sulfoxide. (Example 93) The method according to Example 92, wherein the excipient is about 1% to 10% dimethyl sulfoxide. (Example 94) The method according to Example 93, wherein the excipient is about 5% dimethyl sulfoxide. (Example 95) Siltacabutagen autoleucel for intravenous infusion A pharmaceutical product comprising a suspension, wherein the pharmaceutical product is packaged, the packaging includes a label, and the label is Siltacaptogen autoleucel suspension , proteasome inhibitors, Immunomodulatory drugs and an anti-CD38 monoclonal antibody Identify as an approved drug for the treatment of adult patients with relapsed or refractory multiple myeloma who have received four or more prior lines of treatment. , pharmaceutical products. (Example 96) That need Patients In Relapsed or refractory A method for treating multiple myeloma, which has been approved. Pharmaceuticals of Pharmaceuticals Use the quantity and method indicated on the label. Siltacaptagenautoleucyl Approved suspension Pharmaceuticals A method including administering [a substance]. (Example 97) Siltacaptagenautoleucyl Approved suspension Pharmaceuticals A method of selling, The aforementioned pharmaceutical This includes selling, Drug label of the reference product of the aforementioned drug These are proteasome inhibitors and Immunomodulatory drugs and an anti-CD38 monoclonal antibody Includes information for treating adult patients with relapsed or refractory multiple myeloma who have received four or more prior treatments. ,method. (Example 98) Siltacaptagenautoleucyl Includes suspension Pharmaceuticals Sales To make a request It is a method, The aforementioned pharmaceutical Sales To make a request Including, here, Drug label of the reference product of the aforementioned drug These are proteasome inhibitors and Immunomodulatory drugs and an anti-CD38 monoclonal antibody Includes information for treating adult patients with relapsed or refractory multiple myeloma who have received four or more prior treatments. ,method. example

[0253] The following examples are provided to further illustrate some of the embodiments disclosed herein. The examples are intended to illustrate, not to limit, the embodiments disclosed. Example 1: Siltacaptagenautoleucyl

[0254] B cell maturation antigen (BCMA, also known as CD269 and TNFRSF17) is a 20-kilodalton type III membrane protein that is part of the tumor necrosis receptor superfamily. BCMA is a cell surface antigen that is highly expressed primarily in B lineage cells. Figure 1 shows BCMA expression in various immune-derived cells. Comparative studies have shown that BCMA is deficient in most normal tissues and is not expressed in CD34-positive hematopoietic stem cells. BCMA binds to two ligands that induce B cell proliferation and plays a crucial role in B cell maturation and subsequent differentiation into plasma cells. Due to its selective expression and biological importance for myeloma cell proliferation and survival, BCMA is used in CAR-T-based immunotherapy. Siltacaptagenautoleucyl ) became a promising target.

[0255] Siltacaptagenautoleucyl This is an autologous chimeric antigen receptor T cell (CAR-T) therapy that targets BCMA. Siltakabutagenautoleucelchimera The antigen receptor (CAR) is designed to confer avidity and contains two VHH domains that target B cell maturation antigens (BCMAs). A diagram of the construct is shown in Figure 2. Siltacaptagenautoleucyl This includes a VHH domain containing the amino acid sequence described in SEQ ID NO: 2 and a VHH domain containing the amino acid sequence described in SEQ ID NO: 4. Example 2: Siltacaptagenautoleucyl Treatment methods

[0256] Here, a Stage 1b-2, open-label, multicenter study is described, and this study is... Adults with relapsed or refractory multiple myeloma in Siltacaptagenautoleucyl The purpose was to evaluate the safety and effectiveness of [the drug]. In Stage 1b of the study, Siltacaptagenautoleucyl The recommended Stage 2 dose (RP2D) was confirmed. In Stage 2, the RP2D established in Stage 1b was used. subject The treatment was performed. The objective of the Stage 2 portion of the study was Siltacaptagenautoleucyl The goal is to further establish its safety and effectiveness. Figure 3 shows a schematic overview of the research flowchart, which is as follows: Siltacaptazine autoleucel infusion Lymph ball Includes removal regimens.

[0257] The first analysis is the last subject The initial dose Siltacaptagenautoleucyl This was conducted approximately six months after the procedure. This report was generated by the first analysis specified by the regimen. Table 1 shows the participants in the study. subject A summary is listed, where the percentage represents all of the participants in the analysis population. subject The number was used as the denominator in the calculation. In the United States, a total of 113 people subject (Stage 1b: 35 people, Stage 2: 78 people) participated in the test (apheresis), and here, 101 people subject (Stage 1b: 30 people, Stage 2: 71 people) underwent conditioning regimens, and 97 people subject (Stage 1b: 29 people, Stage 2: 68 people) Siltacabutagene autoleucel infusion In response, under the target RP2D, Import These 97 people received a note. subject This constituted all treatment analysis groups, and it formed the basis for all efficacy and safety analyses presented below. At the clinical cutoff, according to the marginal estimate of the Kaplan-Meier product, the median follow-up period for all treatment analysis groups was 12.4 months. Table 2 lists a summary of the follow-up periods for this study, which is as follows: Siltacaptagenautoleucyl The first Import The tracking period for the note date (Day 1) is listed.

[0258] Relapsed or refractory To include patients with multiple myeloma, the patient population was screened, and these patients Do you have a history of 3 prior lines of treatment? , or both PI / IMiD It is difficult to treat. , and previously PI, IMiD, anti-CD38 exposure Here, PI is a proteasome inhibitor, and IMiD is, Immunomodulatory drugsIt was a substance. Another possible drug was an alkylating agent (ALKY). Patients who met the criteria were age ≥ 18 years, diagnosed with MM based on the International Myeloma Working Group (IMWG) diagnostic criteria, had measurable disease at baseline, and were in the East Coast Cancer Group (ECOG). Performance Status The score was 0, 1, or 2. The demographic and disease characteristics of the patient population in stage 1b of the study are shown in Figure 8.

[0259] To collect peripheral blood mononuclear cells (PBMCs), the following conditions must be met. subject Apheresis was performed on the subject. Participation in the trial was defined as the day of the apheresis. Siltacaptagen Autoleucel Pharmaceuticals (DP) was produced by T cells selected from apheresis. Apheresis or production failures subject This allows apheresis to be attempted again.

[0260] When there is a clinical instruction (i.e., Siltacaptagenautoleucyl (While waiting for the manufacturing to be completed, in order to maintain the stability of the disease), Bridging therapy (Antiplasmocyte-targeted therapy between apheresis and the first dose conditioning regimen) was acceptable. subject Based on the clinical condition and the available time for the CAR-T product, additional cycles Bridging therapy This was taken into consideration. Bridging therapy Previously, subject It was defined as a short-term treatment that resulted in at least disease stabilization.

[0261] After meeting the safety standards for treatment, subject Lymph by ball To assist in achieving removal and promote the amplification of CAR-T cells, subject A conditioning regimen implementation Lymph ball The elimination regimen is cyclophosphamide 300 mg / m². 2 and fludarabine 30 mg / m² 2 This includes administering it intravenously (IV) daily for three days. Before infusion of siltacabutagen autoleucelCyclophosphamide 300 mg / m² 2 and fludarabine 30 mg / m² 2 This is the lymphatic treatment used in commercially available CAR-T products Kymriah and Yescarta ball It matched the removal regimen.

[0262] Five to seven days after the start of the conditioning regimen, as shown in Figure 4. virus Manufactured from apheresis material by transduction Siltacaptagenautoleucyl It was administered on the day defined as day one. Siltacabutagene autoleucel infusion About an hour before that, subject He received premedication. Corticosteroids were, Import Note: Not used during the period before the note. Table 5 is: Pre-infusion medication I listed them. Pre-infusion medication After treatment, 0.75 × 10 6 CAR-positive live T cells / kg (range: 0.5~1.0 × 10) 6 A single dose of the total target dose (number of CAR-positive live T cells / kg) Import Note Siltacaptagenautoleucyl The drug is administered, with a maximum total dose of 1.0 × 10⁻⁶. 8 These were CAR-positive live T cells.

[0263] One or two patient-specific IV bags that have been frozen contain: A certain dose of Siltacaptagenautoleucyl It contained [something]. Melting time of siltacaptagene autoleucel teeth Import It was timed to coincide with the injection time. When the patient was ready. Siltacabutagene autoleucel for infusion In order to obtain Import Check the pouring time in advance. melting The start time was adjusted. One or more bags were received therapeutically. Import When placing an order, please take one bag at a time. melting Yes. Once it is confirmed that the previous bag has been administered safely, the next bag... Thawing / infusion do.

[0264] In the later stages of infusion, siltacabutagene autoleucel is administered. It began on day 1, when the first treatment was completed, and continued until day 100. The later stage of treatment began on day 101, when the study was completed (the last subjectThe initial dose Siltacaptagenautoleucyl This continued until two years after the examination (defined as two years after the examination). Figure 14 shows the results measured by blood concentration. Siltacaptagenautoleucyl This summarizes the amplification and persistence of [the phenomenon]. Example 3: Siltacaptagenautoleucyl Evaluation of the effectiveness of treatment methods

[0265] Using the response criteria based on the IMWG, summarized in Table 6, the study classified responses from best to worst as follows: strict complete response (sCR), complete response (CR), best partial response (VGPR), partial response (PR), minimal response (MR), disease stabilization, or disease progression. Disease progression was consistently documented throughout the clinical study. The trials conducted to evaluate the IMWG response criteria are as follows: • Measurement of myeloma protein in serum and urine: Myeloma protein (M protein) was measured using the following tests from blood and 24-hour urine samples: serum quantitative Ig, serum protein electrophoresis (SPEP), serum immunofixation electrophoresis, and serum FLC assay (CR / sCR suspected). Target They suffer only from serum FLC disease. subject Disease assessment was performed at each stage of the illness, 24-hour urinary M-protein electrophoresis (UPEP), urinary immunofixation electrophoresis, and serum β2-microglobulin. Disease progression based on only one laboratory test was demonstrated by at least one repeated study. After relapse from CR, disease assessment was continued until disease progression was confirmed. Serum and urinary immunofixation and serum free light chain (FLC) assays were performed at screening and thereafter when CR was suspected (serum or 24-hour urinary M-protein electrophoresis [by SPEP or UPEP] was 0 or unquantifiable). Patients with light chain multiple myeloma subject Generally, serum and urine immunofixation tests were performed. • Serum calcium corrected for albumin: Until proven disease progression progresses, blood samples should be collected and analyzed to calculate serum calcium corrected for albumin. In the absence of any other cause, progression of hypercalcemia (corrected serum calcium > 11.5 mg / dL [> 2.9 mmol / L]) may indicate disease progression or relapse. Calcium is biologically active only when bound to albumin, and only unbound (free) calcium is biologically active; therefore, serum calcium levels must be adjusted for abnormal albumin levels ("corrected serum calcium"). • Bone marrow examination: Bone marrow aspiration or biopsy was performed for clinical assessment. Bone marrow aspiration was performed for biomarker evaluation. Clinical classification (morphology, cytogenetics, immunohistochemistry or immunofluorescence or flow cytometry) was performed. Immunophenotyping was performed on a portion of the bone marrow aspirate to monitor checkpoint ligand expression in BCMA and CD138-positive multiple myeloma cells and checkpoint expression in T cells. Where possible, bone marrow aspiration was performed to confirm CR, sCR and disease progression. Since minimal residual disease (MRD) negativity is considered a potential substitute for PFS and OS in multiple myeloma treatment, next-generation sequencing (NGS) was performed on bone marrow aspirate DNA. subject MRD was monitored in the following cases. Myeloma clones were defined using baseline bone marrow aspirates, and MRD negativity was assessed using post-treatment samples. Fresh bone marrow aspirates were collected (≤7 days) before the first dose conditioning regimen. • Bone Survey: During the screening phase, a bone survey (including the skull, entire spine, pelvis, chest, humerus, femur, and any other bones suspected by the researcher to be disease-related) was performed and evaluated by radiographic imaging ("X-ray") or low-dose computed tomography (CT) scans without the use of IV contrast. When CT scans were used, they had diagnostic quality. After siltacabutagene autoleucel infusionFurthermore, before confirming disease progression, localized X-ray or CT scans were performed to record response or progression, regardless of whether there were clinical instructions based on symptoms. Magnetic resonance imaging (MRI) is an acceptable method for evaluating bone disease and was incorporated as needed; however, it did not replace bone examination. Disease status was recorded in two ways, by using radionuclide bone scans at screening in addition to a complete bone examination. These tests were performed simultaneously. Radionuclide bone scans may not replace a complete bone examination. subject If the disease progression is manifested by pain symptoms due to bone changes, subject Depending on the symptoms experienced, disease progression was recorded by bone examination or other radiographic imaging. If radiographic examination provided a clear diagnosis of disease progression, repeated confirmatory radiographs were not considered necessary. If changes were not clear, repeated radiographs were performed within 1 to 3 weeks. • Documentation of extramedullary plasmacytoma: The known location of the extramedullary plasmacytoma was recorded ≤ 14 days prior to the first dose conditioning regimen. The extramedullary location of the disease was recorded using clinical examination or MRI. CT scan evaluation was considered an acceptable alternative regimen if there were no contraindications to IV contrast use. Positron emission tomography scans or ultrasound examinations to record the size of the extramedullary plasmacytoma were not permitted. However, PET / CT fusion scans were optional for recording extramedullary plasmacytoma if the CT portion of the PET / CT fusion scan had sufficient diagnostic quality. All patients with a history of plasmacytoma subject For patients with a history of plasmacytoma, or if there was a clinical instruction within 14 days prior to the first dose conditioning regimen, extramedullary plasmacytoma was assessed by clinical examination or radiographic imaging. Target or Others who received clinical instructions during treatment subjectFor patients with extramedullary disease, local assessment, measurement, or evaluation of measurable sites was performed every four weeks (for physical examination) until a confirmed complete response (CR) or confirmed disease progression occurred. Where only radiological assessment was possible, extramedullary plasmacytoma was evaluated every 12 weeks. Lesions that had been irradiated or resected were considered unmeasurable, and only disease progression was monitored. To qualify for a VGPR or PR / minimal response (MR), the sum of the vertical diameter products of the original extramedullary plasmacytoma had to decrease by more than 90% or at least 50%, and no new plasmacytoma had to develop. To qualify for disease progression, the sum of the vertical diameter products of the original extramedullary plasmacytoma had to increase by at least 50%, or the longest diameter of previous lesions >1 cm on the short axis had to increase by at least 50%, or a new plasmacytoma had to have developed. Not all extramedullary plasmacytomas are reported, but a disease progression criterion was met if the sum of the products of the vertical diameters of reported plasmacytomas increased by at least 50%.

[0266] If it was confirmed that the research treatment interfered with the immunofixation assay, CR was defined as the disappearance of the original M protein associated with multiple myeloma at immunofixation, and the assay for CR was not affected by unrelated M proteins secondary to the research treatment. The endpoints of the study were as follows (as assessed by the Independent Review Committee (IRC): • Using next-generation sequencing (clonoSEQ version 2.0) (Adaptive Biotechnologies, Seattle, WA, USA), MRD was assessed at baseline, at day 28, and at follow-up at 6, 12, 18, and 24 months in patients suspected of complete response, and then every 12 months until disease progression in patients remaining in the study. MRD negativity was assessed in the following samples, and these samples were calibrated or quality-controlled and 10 -5The study included a sufficient number of cells to evaluate the test threshold. The persistence of MRD negativity was assessed by estimating the MRD negativity rate at 6 and 12 months of follow-up. • The clinical benefit rate (CBR) was determined based on IMWG criteria, resulting in a reduced response (MR) or a better response (sCR+CR+VGPR+PR+MR). subject It was defined as the proportion of • Overall response rate (ORR) was determined based on IMWG criteria, indicating a partial response (PR) or a better response (sCR+CR+VGPR+PR). subject It was defined as the proportion of • The response rate for VGPR or better response is defined as achieving VGPR or better response (sCR+CR+VGPR) based on IMWG criteria. subject It was defined as the proportion of • Duration of response (DOR) was calculated for responders (with partial response or better response) from the date of the first recorded response (PR or better response) to the date of the first recorded evidence of disease progression (as defined by the IMWG criteria). Relapse from complete response (CR) due to positive immunofixation or trace amounts of M protein was not considered disease progression. After relapse from CR, disease assessment was continued until disease progression was confirmed. • The duration of response (TTR) is: Siltacaptagenautoleucyl But first Infusion From the day it was done, subject This was defined as the time to the first efficacy evaluation that met all the criteria for a partial response (PR) or a better response. • Progression-free survival (PFS) is, Siltacaptagenautoleucyl But first Infusion It was defined as the time from the date of diagnosis until the date on which disease progression (as defined by the IMWG criteria) was first recorded, or death from any cause (as prior to the date of death). • Overall survival time (OS) is Siltacaptagenautoleucyl But first Infusion From the day it was done, subject Measurements were taken up to the day of death.

[0267] For ORR, the response rate and its 95% accurate confidence interval (CI) were calculated based on a binomial distribution, and the null hypothesis was rejected if the lower limit of the confidence interval exceeded 30%. Analysis of VGPR or better response rates, DOR, PFS, and OS was performed using the same cutoff values ​​as ORR. The Kaplan-Meier method was used to estimate the event time efficacy endpoints (DOR, PFS, and OS). The distribution of DOR (median and Kaplan-Meier curve) was provided using Kaplan-Meier estimates. Similar analyses were performed for OS, PFS, and TTR. Example 4: Siltacaptagenautoleucyl Safety evaluation of treatment methods

[0268] Adverse events, excluding CRS and CAR-T cell-related neurotoxicities (e.g., ICANS), were tracked, reported, and classified according to the National Cancer Institute Common Terminology Standard for Adverse Events (NCI-CTCAE version 5.0). CRS was assessed based on the ASTCT Consensus Classification and summarized in Table 7. If the first CRS sign (e.g., fever) was present, subject The patient was immediately hospitalized and evaluated. If other causes of fever are ruled out, tocilizumab intervention may be used to address fever symptoms as needed. subject It was used to treat CRS. Tocilizumab is used in patients with a high risk of CRS severity. subject It was used as needed for the early treatment of CRS (e.g., high baseline tumor burden, fever initiated early, or persistent fever 24 hours after symptomatic treatment). In particular, if CRS did not respond to tocilizumab, other cytokine-targeting monoclonal antibodies (e.g., anti-IL1 and / or anti-TNFα) were used on an optional basis.

[0269] CAR-T cell-associated neurotoxicities (e.g., ICANS) were classified according to the ASTCT consensus classification and summarized in Table 8. Note that CRS (e.g., fever, hypotension) and ICANS (e.g., level of consciousness) are classified separately. of decline, seizureAll individual symptoms were obtained as individual adverse events and classified according to the CTCAE criteria. Neurotoxicities not transiently related to CRS, or any other neurological adverse events not conforming to ICANS, were classified according to the CTCAE criteria. Any adverse or serious adverse events not risked under NCI CTCAE version 5.0 were classified according to the following criteria grades based on the researcher's clinical judgment. • Grade 1: Mild ; Asymptomatic or mild symptoms ; Clinical or diagnostic observation only ; No intervention has been ordered. Grade 2: Moderate ; Directing minimal, local, or non-invasive interventions ; Restrict age-appropriate instrumental activities in daily life. • Grade 3: Serious or medically significant, but not immediately It is not life-threatening; We will instruct the patient to be hospitalized or to have their hospitalization period extended. ; hindrance ; Limit self-care daily living activities. Grade 4: life of threaten result ; Order emergency intervention. • Grade 5: Death related to an adverse event.

[0270] Based on assessments by the Independent Review Committee (IRC), with a median follow-up period of 12.4 months, the response and duration of response in all treatment analysis populations are as shown in Figure 5. Table 9 shows the response and duration of response in all treatment analysis populations. subject The overall best response was summarized. In all treatment analysis groups, based on IRC ratings, 94 patients were included. subject (96.9%) achieved a partial response or a better response, with 65 patients. subject (67.0%) achieved complete response (CR) or a better response, and the CBR was 96.9%. Below, Siltacaptagenautoleucyl It shows a deep and sustained response induced by VGPR or a better response. ratio The success rate was 92.8%, with complete response (CR) or a better response. ratioThe rate was 67.0%, and the median follow-up period for the clinical cutoff time was 12.4 months, which did not reach the median DOR. The following is a summary of the findings: Siltacaptagenautoleucyl Indicators for evaluating its effectiveness have been compiled. • Reduced tumor burden: 100% subject The tumor burden decreased. Figure 10 shows a graph of the reduction in tumor burden in patients in the Stage 1b-2 study. • Overall response rate (ORR): 96.9% subject It has a total response rate and a 95% accurate CI (91.2%). %, It has a 99.4% success rate. Figure 11 shows a summary of patient ORRs in the Stage 1b-2 study. • VGPR or better response: 90 patients subject (92.8% subject ) achieved VGPR (best partial response) or better response. • Duration of response (DOR): 95% CI (15.9 , NE) In months, the median DOR has not been reached, and the probability of a responder maintaining a response at 9 months and 12 months is 80.2% (95% CI: 70.4%), respectively. %, 87.0% and 68.2% (95% CI: 54.4%) %, The figure was 78.6%. Figure 6 shows the Kaplan-Meier plot of DOR for all responders in all treatment analysis populations, and Table 10 summarizes the DOR for all responders in all treatment analysis populations. Figure 13 shows a graph of patient DOR in stage 1b-2 studies. • Duration of response (TTR): The median duration of the first response (PR or better response) and the best response. up to The median durations were 0.95 and 2.56 months, respectively. • Progression-free survival (PFS): 95% CI (16.79) , NE) In months, the median PFS had not been reached, and the PFS rates (95% CI) at 9 months and 12 months were 80.3% (70.9%). %, 87.0% and 76.6% (66.0 %,The figure was 84.3%. Table 11 shows a summary of PFS for all treatment analysis groups. • Overall survival (OS): At the clinical cutoff time, 14 patients subject (14.4%) had already died. The overall survival rates (95% CI) at 9 months and 12 months were 90.7% (82.8%), respectively. %, 95.0% and 88.5% (80.2%) %, The figure was 93.5%. Figure 7 shows the Kaplan-Meier plot of OS based on all treatment analysis populations, and Table 12 summarizes the OS based on all treatment analysis populations. · Average residual disease (MRD) negative rate (10 -5 At the sensitivity level): The MRD negative rate was 54.6% (95% CI: 44.2%). %, 64.8% and 33 people (34.0%) subject All MRD-negative CR / sCR were achieved. Table 13 shows all treatment analysis groups. subject 10 in the bone marrow -5 A summary of the total MDR-negative rates is shown, and Table 14 shows the 10% across all treatment analysis groups. -5 It has a sample that can be evaluated. subject A summary of the total MDR negative rate is shown. Evaluable samples are calibrated and quality-controlled samples and have sufficient cells to be evaluated under each test threshold. Figures 12 and 15 show a summary of patient MRD in stage 1b-2 studies.

[0271] Siltacaptagenautoleucyl It was confirmed that it possesses safety characteristics consistent with the mechanism of action of CAR-T therapy. Figure 9 shows a summary of adverse events in the Stage 1b-2 trial. • CRS: CAR-T cell-related adverse events in CRS were common (94.8%), but most were low-grade. According to the ASTCT consensus classification system, CRS of all grades accounted for 92 patients. subject (94.8%) reported this. The duration of the CRS was 97 days. subjectWith the exception of one fatal event (1.1%), all CRS events resolved. Table 15 and Figure 16 summarize the CRS events that occurred during treatment in all treatment analysis populations. Figures 17–19 show graphs and summaries of various CRS protein markers observed from all patients. • Immunoeffector cell-associated neurotoxicity (ICANS): According to the ASTCT consensus classification system, 16 patients (16.5%) had ICANs of any grade. subject It was reported that all events resolved. Table 16 shows the results for all treatment groups. Siltacabutagene autoleucel infusion A summary of ICANS cases that developed afterward is presented. • Cytopenia: Grade 3 or Grade 4 cytopenia is, Import Note: These are commonly seen in the later stages and include lymphopenia, neutropenia, and thrombocytopenia, but the vast majority of these events resolve by day 60. Infusion of siltacabutagene autoleucel Within 100 days thereafter, 96 people (99.0%), 95 people (97.9%), and 60 people (61.9%) subject These patients suffered from grade 3 or grade 4 lymphopenia, neutropenia, and thrombocytopenia, respectively. By day 60, 88 patients (90.7%), 85 patients (87.6%), and 41 patients (42.3%) had developed lymphopenia, neutropenia, and thrombocytopenia, respectively. subject This reduced initial grade 3 or grade 4 events of lymphopenia, neutropenia, and thrombocytopenia to grade 2 or lower. Table 17 shows the results for all treatment analysis groups. Siltacaptagenautoleucyl A summary of cytopenia after treatment is shown.

[0272] In short, a single drug and Single-dose infusion of siltacabutagene autoleucel In a large number of previously treated patients, it demonstrated unprecedented clinical activity, including an ORR of 96.9% and rapid response initiated within one month. Example 5: Median follow-up period of 18 months Siltacaptagenautoleucyl Evaluation results of treatment methods

[0273] By the time of this analysis, 97 patients had been identified. Siltacabutagene autoleucel infusion (The median dose is 0.71 × 10 6The range is 0.51 × 10 6 ~0.95 × 10 6 The study received CAR-positive live T cells (1 / kg). In 91 patients with baseline cytogenetic data, 23 patients (23.7%) had cytogenetic features based on high risk, including del17p (19.6%), t(4;14) (3.1%), and / or t(14;16) (2.1%). In 96 patients with evaluable bone marrow biopsy and / or aspiration samples, more than half (60.4%) had a low disease burden (≤30 plasma cells), 21.9% had a high disease burden (≥60 plasma cells), and 17.7% had a moderate disease burden (30–60 plasma cells). Plasma cell tumors were detected in 19.6% of patients at screening.

[0274] Tables 18-26 and Figures 20-23 describe in detail various safety / efficacy parameters when the median follow-up period is 18 months, and these parameters are summarized below. effect • For a median follow-up of 18 months, the ORR was 97.9% (95% CI). , The sCR rate was 80.4%, the VGPR rate was 14.4%, and the PR rate was 3.1% (Table 1). • First response up to The median duration was 1 month (range, 0.9-10.7), and the best response rate was 1 month. up to The median duration was 2.6 months (range, 0.9–15.2), indicating complete response (CR) or a better response. up to The median duration was 2.6 months (range, 0.9–15.2). • The median DOR for the population is 21.8 months (95% CI). , (21.8 - Undeterminable) and was not achieved in sCR patients. • The median PFS for all patients was 22.8 months (95% CI). , The 18-month PFS rate was 22.8% (22.8% - not estimable) and was not reached in sCR patients (Figure 20). The 18-month PFS rate in all patients and sCR patients was 66.0% (95% CI), respectively., 54.9-75.0) and 75.9% (95% CI) , The range was 63.6-84.5. • The 18-month overall survival rate for all patients was 80.9% (95% CI). , The values ​​were 71.4-87.6 (Figure 20). • Among 61 patients for whom MRD assessment was possible, 91.8% of patients were 10 -5 The MRD negativity status was reached at the threshold. MRD negativity persisted for ≥6 months in 44.3% (27 / 61) of patients, and for ≥12 months in 18% (11 / 61) patients. o The 18-month PFS rates in patients with MRD lasting ≥6 months and ≥12 months were 96.3% (95% CI), respectively. , 76.5 ~ The percentages were 99.5% and 100%. • ORR across all subgroups is consistently high (range , 95.1%~100%, 3 lines of prior treatment history Patients treated with (100% [95% CI) , Patients with high cytogenetic risk features (80.5-100) (100% [95% CI]) , [85.2-100]), patients with high disease burden (≧60% myeloid plasma cells, 95.2% [95% CI] , [76.2~99.9] and plasmacytoma patients (100.0% [95% CI] , Table 2 includes [82.4~100]). MRD negativity rates across all subgroups of patients for whom MRD is rated (threshold, 10 -5 The percentage was between 80% and 100%. • Negative benefits for ORR and MRD were consistent, but did not maintain other efficacy outcomes in specific subgroups. • Stage ISS III patients had a lower median DOR (13.8 months [95% CI]). , 5.1~Unestimable), 18-month PFS rate (34.3% [95% CI]) , 9.4~61.6) and 18-month OS rate (48.2% [95% CI] ,Patients with a median dose of 20.8–71.2 (20.8–71.2) but with plasmacytoma present at baseline had a lower median dose-response ratio (6.8 months [4.0–unestimable]) and an 18-month progression-free survival rate (46.8% [95% CI]). , [23.7-67.0] and 18-month OS rate (64.5% [95% CI]) , It had [35.6~83.0]. Patients with high tumor burden (≥60% myeloid plasma cells) had a lower 18-month PFS rate (50.6% [95% CI]). , [27.5-69.9] and 18-month OS rate (71.4% [95% CI] , It had [47.2~86.0]. safety · Siltacaptagenautoleucyl In patients treated with this drug, no new safety signals were observed during the long follow-up period. The most common (≧25%) grade 3 / 4 adverse events (TEAEs) that occurred during treatment were neutropenia (94.8%), anemia (68.0%), leukopenia (60.8%), thrombocytopenia (59.8%), and lymphopenia (49.5%) (Table 3). The most common grade 3 / 4 non-hematological TEAEs were hypophosphatemia (7.2%), fatigue (5.2%), and elevated aspartate aminotransferase (AST) (5.2%) (Table 3). CRS was reported in 94.8% (n=92) of patients (94.6% with grade 1 / 2), with a median time to onset of 7 days (range: 1–12) and a median duration of 4 days (range: 1–97). Of the 92 patients, 91 experienced remission of CRS within 14 days and had grade 5 CRS and hemophagocytic lymphohistiocytosis. 1 person The patient died on day 99 after complications from prolonged grade 4 CRS. Compared to the initial analysis, no new neurotoxic events were reported in the extended follow-up, and no new neurocognitive TEAE cases were identified. • One patient whose disease is progressing, Siltacaptagenautoleucyl The patient was retreated, and their condition remained stable after retreatment (according to a computer algorithm), and no treatment-related neurotoxicity occurred.

[0275] Described in this specification Siltacaptagenautoleucyl Such extended follow-up of the trial, Siltacaptagenautoleucyl However, the median of 6 Pre-treatment In RRMM patients who received the treatment, clinical benefit was maintained for 18 months, and these patients experienced manageable side effect characteristics and no new safety signals were observed. A high ORR (97.9%) was maintained during an additional 6-month follow-up period. Deep and sustained responses were observed, with 80.4% of patients achieving sCR. MRD negativity was also maintained in 91.8% of evaluable patients, lasting for 6–12 months. Prior medical history to exposure Given the evidence demonstrating the prognostic value of MRD negativity for improved long-term survival outcomes across multiple disease backgrounds, including patients who have undergone MRD testing, assessing the persistence of MRD negativity is of particular interest.

[0276] Siltacaptagenautoleucyl After 18 months of follow-up, no new safety signals were identified. The most frequently reported TEAEs were those reported in the initial analysis. Siltacaptagenautoleucyl The side effect characteristics were consistent with those of the previous drug. No new neurotoxic events were reported, and no new motor or neurocognitive TEAE cases were observed.

[0277] In short, having a longer tracking period as described herein Siltacaptagenautoleucyl The test data is, This is a triple-class exposé. In RRMM patients Siltacaptagenautoleucyl This demonstrated a significant clinical benefit. Example 6: In patient subgroups Siltacaptagenautoleucyl Evaluation results of treatment methods

[0278] Next, Stage 1b-2 Siltacaptagenautoleucyl In clinical trials, in different patient subgroups Siltacaptagenautoleucyl The efficacy and safety of the drug were evaluated. Patients who met the criteria had multiple myeloma (MM) and had received at least three prior regimens or proteasome inhibitors (PIs). Immunomodulatory drugs Both of the objects (IMiD) It is difficult to treat.I received PI, IMiD, and anti-CD38 antibody. After apheresis, Bridging therapy This made it possible to do so. The patient's lymph ball Removal (300mg / m 2 Cyclophosphamide, 30 mg / m² 2 Fludarabine, daily for a total of 3 days, followed by a single dose 5-7 days later. Siltacabutagene autoleucel infusion (Target dose: 0.75×10 6 Individual CAR+ active T cells / kg, range 0.5~1.0 × 10⁻⁶ 6 ) was taken. The main purpose was, Siltacaptagenautoleucyl The objectives are to characterize safety and efficacy, confirm the recommended stage 2 dose (stage 1b), and evaluate efficacy (stage 2). Lee et al. (Blood 2014) classified cytokine release syndrome (CRS) and neurotoxicity based on the Common Terminology Standard for Adverse Events (CTCAE) v5.0 (stage 1b). CRS and immunoeffector cell-associated neurotoxicity (ICANS) were classified based on the American Society for Transplantation and Cell Therapy (ASTCT) criteria (stage 2). In this specification, Lee et al. and CTCAE v5.0 are mapped to ASTCT for CRS and ICANS, respectively. Efficacy and safety were evaluated in the following subgroups based on baseline (BL) characteristics: age ≥ 65 years, Black / African American, 3 lines of prior treatment history (LOT), ≥ 4 previous LOTs, It is triple-class refractory, and is refractory to five different drugs. , cytogenetic standard and high risk, international classification stage III, myeloid plasma cells (≤30%, >30 to <60%, and ≥60%), BCMA tumor expression (<median, ≥median), and presence of plasmacytoma (bone-based and extramedullary).

[0279] Tables 28-32 and Figures 24-27 detail the various safety / efficacy parameters of different subgroups analyzed when the median follow-up period was 18 months. These parameters are summarized as follows:

[0280] By the time of this subgroup analysis, with a median follow-up period of 18 months, 97 patients in the population (58.8% male, median age 61 years [range 43–78], median time from diagnosis to participation in the study 5.9 years [1.6–18.2]) had participated. Siltacaptagenautoleucyl The study was conducted. Efficacy results were consistent with the population, with consistently high ORR across all evaluated subgroups (ranging from 95.1% to 100%, see table), including subgroups with high cytogenetic risk, ISS stage IIIMM, and ≥60% BL myeloid and BL plasmacytoma. Median DOR and median PFS were consistent with the population or not achieved in the majority of subgroups, but were even lower in patients with high-risk diseases such as ISS stage III and BL plasmacytoma (see table). In all subgroups, 10 -5 Below the threshold, the vast majority of patients (80%–100%) who were eligible for MRD assessment achieved MRD negativity. 18-month PFS and OS rates were consistent with the population in most subgroups. These improvements were also observed in patients with low-incidence but high-risk diseases (Table). In different subgroups, the incidence of CRS, ICANs, and other CAR T-cell neurotoxicities (events not reported as ICANs [i.e., those occurring some time after recovery from CRS and ICANs]) was consistent with the population, and there were no new safety signals.

[0281] At a median follow-up of 18 months, a single Import poured Siltacaptagenautoleucyl This drug elicited deep and sustained responses in all evaluated high-risk patient subgroups with poor prognosis described herein. Across different subgroups, 90%–100% of patients achieved ORR and were cytogenetically high-risk, ISS stage IIIMM This includes patients with BL myeloid cells ≥60% and BL plasmacytoma, across subgroups. Siltacaptagenautoleucyl The safety characteristics were consistent with the population, and no new safety signals were identified. Example 7: Siltacaptagenautoleucyl Comparison of treatment methods and physician-selected treatments

[0282] As described in Examples 2-4 (same as above), Siltacabutagene autoleucel is used for relapsed or refractory conditions. In patients with multiple myeloma ("RRMM"), it is effective and safe, and these patients This is a triple-class exposé. ( Immunomodulatory drugs The substances include proteasome inhibitors and anti-CD38 monoclonal antibodies. exposure (It was done.) There are no clear care standards for the indication, and Siltacaptagenautoleucyl And because there are no direct face-to-face trials to evaluate other related treatments, Siltacaptagenautoleucyl An indirect treatment comparison (ITC) was conducted between the treatments currently used in clinical practice (i.e., physicians' treatment choices ("PCT")) and the treatments currently used in clinical practice. In short, a meta-analysis was performed and the ITCs were integrated. This is a triple-class exposé. In RRMM patients Siltacaptagenautoleucyl We evaluated PCT and obtained estimates of a single ensemble effect on overall survival ("OS") and progression-free survival ("PFS").

[0283] For OS and PFS Siltacaptagenautoleucyl and ITCs to investigate the relative effectiveness of PCT. Figure 28 summarizes the selection of comparison groups for ITC analysis. Data on PCT are derived from the following sources: (i) the Flatiron database based primarily on multiple myeloma registries in the US community, (ii) long-term follow-up results from three global RRMM daratum mab randomized clinical trials (POLLUX [NCT02076009], CASTOR [NCT02136134] and EQUULEUS [NCT01998971]), (iii) the US-based retrospective MAMMOTH study, (iv) representative German patient registries maintained by Oncology Information Service (OIs), and (v) the LocoMMotion study [NCT04035226]. At least 3 lines of prior treatment history (at least 1 type A pre-emptive, non-interventional, multinational study on the efficacy and safety of actual life care standards in patients with RRMM who have received PI, IMiD, and anti-CD38 antibodies. In each ITC, the PCT group is described in Examples 2-4. Siltacaptagenautoleucyl Stage 1b-2 clinical trial (" SiltacaptagenautoleucylThe study consisted of patients who met the crucial eligibility criteria for the "trial," and used inverse probability weighting to determine them. Siltacaptagenautoleucyl The test was made equivalent to the actual test. Therefore, ITC is considered suitable for meta-analysis. The meta-analysis uses a robust variance estimator to analyze each pair of ITCs. Siltacaptagenautoleucyl I interpreted the use of the test.

[0284] A meta-analysis was conducted on two groups. (1) Siltacaptagenautoleucyl The "ITT" (intent to treat) population includes all participants in the study (apheresis) and all patients in the PCT group who meet the criteria, and (2) Siltacaptagene autoleucel infusion study The "mITT" (modified treatment intention) population includes all participants and all patients in the PCT group who meet the condition of no progression or death within 47 days of treatment initiation (52 days for OIs and LocoMMotion). Siltacaptagenautoleucyl From apheresis in research Infusion The median (mean) time until [a certain point]. The meta-analysis was performed in two forms. 1. The main meta-analyses considered all index dates for populations using modified treatment intentions ("mITT") and treatment intentions ("ITT"), compared to PCT. Siltacaptagenautoleucyl In the exam, Siltacaptagenautoleucyl All participants in the treatment were included. For these meta-analyses, the start date of each eligible LOT was used as the index date. Patients who received multiple subsequent therapies and met the criteria for the PCT group contributed multiple LOTs to the analysis (as independent observations) if they also met the criteria at LOT start. ITCs with all index dates could not be used for MAMMOTH and LocoMMotion. 2. Additional analyses were performed for ITC using the first index date of the mITT and ITT populations. For these meta-analyses, the start of the first LOT that met the criteria was used as the index date, and each patient in the PCT group contributed only the first LOT that met the criteria to the analysis.

[0285] Sensitivity analysis is, SiltacaptagenautoleucylThe ITC effect estimates based on all participants in the trial were considered. The ensemble combined effect estimates were presented as hazard ratios (HR) and corresponding 95% confidence intervals (CI).

[0286] Based on data availability, the main meta-analysis includes four ITCs for OS and three ITCs for PFS. A sensitivity analysis including all participants in the trial validated the results of the main meta-analysis. Figures 29-32 use all index dates or the first index date. Siltacaptagenautoleucyl The report presents a meta-analysis comparing overall survival (OS) or progression-free survival (PFS) between patients who participated in / were treated in the trial and those who received treatment at the physician's discretion.

[0287] In the OS, PFS, and TTNT ORRs, Siltacaptagenautoleucyl It showed a significant advantage over PCT, This is a triple-class exposé. The potential of this as an effective therapy for RRMM patients was highlighted. The conclusions were consistent across populations (mITT and ITT) and available index dates.

[0288] In short, meta-analysis shows that Siltacaptagenautoleucyl However, it has been shown to have a significant advantage over PCT in OS and PFS. This is a triple-class exposé. The potential of this as an effective therapy for RRMM patients was highlighted. Siltacaptagenautoleucyl If a face-to-face comparison has not been made with the treatments used in actual clinical practice, this meta-analysis of ITCs will show that This is a triple-class exposé. For RRMM patients, Siltacaptagenautoleucyl The clinical benefits provided by this approach were shown to be far greater than those of the PCT. [Table 1] [Table 2] [Table 3] [Table 4] [Table 5] [Table 6] TIFF2023164695000007.tif144170 [Table 7] [Table 8] a: Based on the toxicity classification by Lee et al. 2019 b: The ICANS grade is determined by the most serious event that cannot be attributed to any other cause (ICE score, level of consciousness, seizures, motor findings, elevated ICP / cerebral edema). Note: During the two studies, all other neurological adverse events (unrelated to ICANS) should continue to be classified using CTCAE version 5.0. [Table 9] [Table 10] [Table 11] [Table 12] [Table 13] [Table 14] [Table 15] [Table 16] [Table 17] [Table 18] [Table 19] [Table 20] [Table 21] [Table 22] [Table 23] [Table 24] [Table 25] [Table 26] [Table 27] [Table 28] [Table 29] [Table 30] [Table 31] [Table 32] [Table 33] [Table 34] Example 8: Approved Pharmaceuticals label

[0289] Approved Pharmaceuticals label: [Table 35] TIFF2023164695000037.tif243170 [Table 36] 1. Indications and Method of Use CARVYKTI is a gene-modified autologous T-cell immunotherapy targeting B-cell maturation antigens (BCMAs), and is a proteasome inhibitor. Immunomodulatory drugs and an anti-CD38 monoclonal antibody This is applicable to the treatment of adult patients with relapsed or refractory multiple myeloma who have received four or more prior treatments. . 2. Dosage and Administration For personal use only. For intravenous use only. 2.1 Dosage CARVYKTI is a single-dose medication. Import Provided as a note, each infusion bag contains a suspension of chimeric antigen receptor (CAR)-positive live T cells. The recommended dosage range is 0.5 to 1.0 × 10 6 The number of CAR-positive live T cells / kg body weight is one Infusion The maximum dose is 1 × 10 8 These are individual CAR-positive live T cells. 2.2 Administration CARVYKTI is for personal use only. The patient's identity must match the patient identifier on the CARVYKTI case and IV bag. Do not administer CARVYKTI if the information on the patient label does not match the expected patient. CARVYKTI for patients Infusion Prepare Lymphocyte depletion chemotherapy regimen Before starting, check the availability of CARVYKTI. Pre-treatment Lymphocyte depletion chemotherapy regimen Dosage: Cyclophosphamide 300 mg / m² per day 2 Intravenous (IV) and fludarabine 30 mg / m² 2 I continued with IV for three days. For information on dose adjustments for renal impairment, please refer to the prescribing information for cyclophosphamide and fludarabine. The patient's past Bridging therapy (Including clinically significant active infection, cardiotoxicity and pulmonary toxicity) or if a serious adverse reaction occurs due to anti-host disease of an active graft from a previous allogeneic stem cell transplant patient, lymph ball The removal regimen must be delayed. If the CARVYKTI administration is delayed for more than 14 days, the patient will have their first lymph node dissection. ball If the lymphatic system recovers from the toxicity of the removal regimen, ball We will consider repeating the removal regimen. Lymphocyte depletion chemotherapy regimen CARVYKTI will be available 2-4 days after completion. Infusion Administer the drug. If the patient is in any of the following situations, CARVYKTI Import Note: This must be delayed. • Clinically significant active infection or inflammatory disorder. • Non-hematological toxicity of ≥ Grade 3, excluding Grade 3 nausea, vomiting, diarrhea, or constipation, conditioned with cyclophosphamide and fludarabine. CARVYKTI Infusion These events should be delayed until they have resolved to a Grade 1 or lower level. Premedication CARVYKTI Infusion 30-60 minutes prior, all patients should be given the following: Pre-infusion medication of implementation do. · Antipyretic (Administer 650 to 1000 mg of acetaminophen orally or intravenously). · antihistamines (Administer 25 to 50 mg of diphenhydramine or an equivalent substance orally or intravenously.) The prophylactic use of systemic corticosteroids should be avoided because it may inhibit the activity of CARVYKTI. Acceptance o...

Claims

1. A pharmaceutical composition for use in a method of treating a subject, wherein the method is: The subject is subjected to a single infusion of a certain dose of a composition containing T cells that contain a chimeric antigen receptor (CAR). Here, the CAR contains the amino acid sequence of SEQ ID NO: 17, and the dose is 0.5 × 10⁻¹⁶ per kg of body weight of the subject. ６ from 1.0 x 10 ６ Including a number of T cells, The pharmaceutical composition comprising completing the administration of the dose of T cells to the subject within approximately 2.5 hours at a temperature of approximately 20°C to 25°C.

2. The pharmaceutical composition according to claim 1, wherein the subject is suffering from relapsed or refractory multiple myeloma, has a history of multiple prior treatments, and optionally has a history of three or more prior treatments.

3. The subject is a pharmaceutical composition according to claim 2, having a history of four or more prior treatments.

4. The pharmaceutical composition according to claim 2, wherein the prior treatment history includes a proteasome inhibitor, an immunomodulator, and an anti-CD38 monoclonal antibody.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the T cells are autologous T cells.

6. The method described above is: (1) Before administering the T cells to the subject, the subject is subjected to a lymphocyte apheresis chemotherapy regimen, which is optional, (a) The lymphocyte-depleting chemotherapy regimen comprises administering cyclophosphamide and fludarabine to the subject, (b) The lymphocyte-depleting chemotherapy regimen comprises intravenous administration of cyclophosphamide and fludarabine to the subject, (c) The lymphocyte apheresis chemotherapy regimen comprises administering cyclophosphamide at a dose of approximately 300 mg / m² and fludarabine at a dose of 30 mg / m² intravenously to the subject daily. (d) The lymphocyte apheresis chemotherapy regimen is approximately 3 days long, or (e) The method includes administering the lymphocyte apheresis chemotherapy regimen to the subject for at least two to four days prior to administering the T cells to the subject, or, (2) Premedication to the subject within 60 minutes prior to administration of the T cells to the subject, wherein the premedication includes an antipyretic and an antihistamine, and is optional, (a) The method includes administering the premedication to the subject approximately 30 to 60 minutes before administering the T cells to the subject, (b) The antipyretic contains paracetamol or acetaminophen, (c) The antipyretic contains acetaminophen in a dose of approximately 650 mg to 1000 mg. (d) The antihistamine contains diphenhydramine, (e) The dose of diphenhydramine is approximately 25 mg to 50 mg or an equivalent dose. (f) The premedication is administered orally or intravenously, (g) The premedication does not contain systemic corticosteroids, and the above procedure is carried out. A pharmaceutical composition according to any one of claims 1 to 4, further comprising:

7. The pharmaceutical composition according to any one of claims 1 to 4, wherein the method comprises thawing the dose of T cells before administration, wherein the thawing is completed within about 15 minutes, and optionally, the dose of T cells is thawed at a temperature of about 37°C ± 2°C.

8. The method further comprises administering the aforementioned dose of T cells and then treating the subject's cytokine release syndrome (CRS), optionally comprising administering an anti-cytokine agent or a corticosteroid to the subject, optionally, (1) The anti-cytokine agent comprises a monoclonal antibody targeting a cytokine, optionally, the monoclonal antibody targeting the cytokine is an IL-6R inhibitor, optionally, the IL-6R inhibitor is tocilizumab, optionally, the method comprises intravenous administration of tocilizumab at a dose of approximately 8 mg / kg within approximately 1 hour, optionally, the dose of tocilizumab does not exceed approximately 800 mg, optionally, the dose of tocilizumab is no more than three or no more than four doses within 24 hours, optionally, the anti-cytokine agent further comprises an anti-cytokine agent other than tocilizumab, optionally, the anti-cytokine agent further comprises a monoclonal antibody targeting a cytokine other than tocilizumab. (2) The corticosteroid comprises dexamethasone or methylprednisolone, and optionally the corticosteroid is dexamethasone, and optionally the method comprises administering approximately 10 mg of dexamethasone intravenously to the subject approximately every 12 to 24 hours, optionally the method comprises administering approximately 10 mg of dexamethasone intravenously to the subject approximately every 12 hours, and optionally the method comprises administering approximately 20 mg of dexamethasone to the subject approximately every 6 to 12 hours The method includes administering intravenously each time, and optionally further includes administering approximately 20 mg of dexamethasone intravenously to the subject approximately every 6 hours, optionally the corticosteroid being methylprednisolone, and optionally further includes administering approximately 2 mg / kg of methylprednisolone intravenously to the subject approximately every 12 hours, and optionally further includes administering approximately 1-2 g of methylprednisolone intravenously to the subject approximately every 24 hours, or (3) The method includes administering an immunosuppressant to the subject, A pharmaceutical composition according to any one of claims 1 to 4.

9. CRS is characterized by fever, high fever, hypotension, elevated aspartate aminotransferase, chills, elevated alanine aminotransferase, sinus tachycardia, hyperbilirubinemia, hypoxia, respiratory failure, acute kidney injury, disseminated intravascular coagulation and bleeding (e.g., retroperitoneal hemorrhage, intracerebral hemorrhage, or gastrointestinal bleeding), hemophagocytic lymphohistiocytosis (HLH), macrophage activation syndrome (MAS), angina pectoris, supraventricular tachycardia and ventricular tachycardia, malaise, muscle pain, elevated C-reactive protein, elevated ferritin, elevated serum alkaline phosphatase, and gamma-glutamyl The pharmaceutical composition according to claim 8, comprising transferase elevation, organ toxicity, or any combination thereof, optionally comprising hemophagocytic lymphohistiocytosis (HLH) or macrophage activation syndrome (MAS), optionally comprising symptoms of HLH or MAS comprising hypotension, hypoxia with diffuse alveolar damage, coagulation disorders, cytopenia, multi-organ dysfunction including renal dysfunction, or any combination thereof, and further optionally comprising the method providing treatment to the subject to alleviate HLH or MAS.

10. The pharmaceutical composition according to any one of claims 1 to 4, further comprising administering the dose of T cells and then treating the neurotoxicity of the subject.

11. The pharmaceutical composition according to claim 10, wherein the neurotoxicity includes immunoeffector cell-associated neurotoxic syndrome (ICANS), parkinsonism, Guillain-Barré syndrome, immune-mediated myelitis, peripheral neuropathy, cranial nerve palsy, or any combination thereof.

12. The neurotoxicity includes ICANS, which include encephalopathy, aphasia, headache, decreased level of consciousness, seizures, motor system findings, increased intracranial pressure (ICP), cerebral edema, or any combination thereof, and optionally includes focal or generalized seizures, nonconvulsive seizures on electroencephalography (EEG), life-threatening prolonged seizures, recurrent clinical or electrical seizures, deep focal motor dysfunction, hemiplegia, paraplegia, focal / focal edema on neuroimaging, stupor, coma, diffuse cerebral edema on neuroimaging, decerebrate or deckorticite rigidity, cranial nerve palsy (VII), optic disc edema, Cushing's triad, or any combination thereof, and optionally includes (1) The method includes administering approximately 10 mg of dexamethasone intravenously to the subject at intervals of approximately 12 to 24 hours for approximately 2 to 3 days. (2) The method includes intravenously administering approximately 10 mg of dexamethasone to the subject approximately every 12 hours for approximately 2 to 3 days or more. (3) The method includes administering approximately 10 to 20 mg of dexamethasone intravenously to the subject approximately every 6 hours, or (4) The method includes administering methylprednisolone to the subject at a dose of approximately 1 to 2 g / day every 24 hours. The pharmaceutical composition according to claim 11, wherein the ICANs further optionally comprises cerebral edema, the method further optionally comprises administering hyperventilation and hyperosmolar therapy to the subject, the method further optionally comprises administering a non-sedating antiseizure agent to the subject, and the non-sedating antiseizure agent is levetiracetam.

13. (1) The neurotoxicity includes parkinsonism, optionally, the parkinsonism includes parkinsonian symptoms or non-parkinsonian symptoms, optionally, the parkinsonian symptoms or non-parkinsonian symptoms include tremor, bradykinesia, involuntary movements, stereotypic syndrome, loss of spontaneous movement, masked facies, apathy, flattening of emotions, fatigue, muscle rigidity, psychomotor retardation, micrographia, dysgraphia, apraxia, lethargy, confusion, somnolence, loss of consciousness, delayed reflexes, hyperreflexia, amnesia, dysphagia, fecal incontinence, falls, flexion posture, shuffling gait, muscle weakness and atrophy, motor dysfunction, loss of movement and sensation, akinetic mutism, frontal lobe release signs, or any combination thereof, optionally, the method includes administering treatment to the subject to alleviate the parkinsonism. (2) The neurotoxicity includes Guillain-Barré syndrome, and optionally, Guillain-Barré syndrome includes symptoms consistent with the Miller-Fischer subtype of Guillain-Barré syndrome, encephalopathy, motor dysfunction, speech disorders, polyradiculitis, or any combination thereof, and optionally, the method includes providing treatment to the subject to alleviate Guillain-Barré syndrome. (3) The neurotoxicity includes immune-mediated myelitis, and optionally, the symptoms of immune-mediated myelitis include decreased sensation in the lower extremities or lower abdomen accompanied by sphincter dysregulation, and optionally, the method includes providing treatment to the subject to alleviate immune-mediated myelitis, and optionally, the treatment includes corticosteroids or immunoglobulins, and optionally, the method includes intravenous administration of the immunoglobulins. (4) The neurotoxicity includes peripheral neuropathy, which optionally includes sensory neuropathy, motor neuropathy, sensorimotor neuropathy, or any combination thereof, and the method optionally includes administering treatment to the subject to alleviate the peripheral neuropathy. (5) The neurotoxicity includes cranial nerve palsy, and optionally the cranial nerve palsy includes cranial nerve palsy of the third cranial nerve, cranial nerve palsy of the sixth cranial nerve, cranial nerve palsy of the sixth cranial nerve, or bilateral cranial nerve palsy of the sixth cranial nerve, and optionally the method includes administering treatment to the subject to alleviate the cranial nerve palsy. The pharmaceutical composition according to claim 11.

14. The method further comprises treating the subject's prolonged or recurrent cytopenia after administering a lymphocyte-depleting chemotherapy regimen to the subject before administering the T cells containing the CAR, or after administering the dose of T cells containing the CAR, wherein the prolonged or recurrent cytopenia optionally includes prolonged neutropenia, prolonged thrombocytopenia, recurrent neutropenia, thrombocytopenia, lymphopenia, anemia, or any combination thereof, according to any one of claims 1 to 4.

15. The pharmaceutical composition according to any one of claims 1 to 4, wherein the method further comprises treating an infection in the subject, optionally, the infection being caused by a viral, bacterial, fungal, or unspecified pathogen, optionally, the infection including a lung abscess, sepsis, pneumonia, bronchopulmonary aspergillosis, Pneumocystis pneumonia, CMV colitis (with HSV-1 hepatitis), fungal aneurysm, cerebral aspergillosis, or COVID-19 infection, optionally, the infection causing febrile neutropenia or subarachnoid hemorrhage, optionally, the method comprising administering an antimicrobial agent to the subject, optionally, the antimicrobial agent being an antibiotic, optionally, the antibiotic being a broad-spectrum antibiotic, optionally, the infection being viral, and optionally, the method comprising administering antiviral therapy or a vaccine to the subject.

16. The aforementioned method, (1) The method further comprises treating the hypogammaglobulinemia of the subject, optionally including administering the dose of T cells containing CAR, after which the hypogammaglobulinemia includes laboratory IgG levels lower than about 500 mg / dL, and optionally including administering the dose of T cells containing CAR to the subject, after which the treatment comprises administering a certain dose of intravenous immunoglobulin (IVIG), or (2) Further comprising treating a hypersensitivity reaction of the subject, optionally including, the hypersensitivity reaction includes flushing, chest discomfort, tachycardia, wheezing, tremor, burning sensation, anaphylaxis, or any combination thereof, and optionally, the method comprises providing treatment to the subject to alleviate the hypersensitivity reaction, or (3) To treat secondary malignant tumors of the subject, A pharmaceutical composition according to any one of claims 1 to 4, further comprising:

17. The pharmaceutical composition according to any one of claims 1 to 4, further comprising an excipient selected from dimethyl sulfoxide or dextran 40, wherein optionally the excipient is dimethyl sulfoxide, optionally the excipient is about 1 to 10% dimethyl sulfoxide, and optionally the excipient is about 5% dimethyl sulfoxide.

18. A pharmaceutical product comprising a siltacapatene autoleucel suspension for intravenous infusion, wherein the pharmaceutical product is packaged, the packaging comprising a label, the label identifying the siltacapatene autoleucel suspension as an approved pharmaceutical product for the treatment of adult patients with relapsed or refractory multiple myeloma who have received four or more lines of prior treatment including proteasome inhibitors, immunomodulators, and anti-CD38 monoclonal antibodies.

19. A pharmaceutical composition for use in a method of treating relapsed or refractory multiple myeloma in a patient in need thereof, the method comprising administering an approved drug comprising a siltacaptagene autoleucel suspension in the amount and manner described on the drug label of the approved drug.

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