JPWO2019152743A5 - - Google Patents

Description

In some embodiments of any one of the kits provided herein, the anti-PD-L1 antibody or antigen binding fragment is suitable for parenteral, optionally intravenous administration.
[Invention 1001]
(A) A step of administering T cell therapy to a subject with a B cell malignant tumor, wherein the cell therapy comprises a dose of genetically engineered T cells expressing a chimeric antigen receptor and comprises a chimeric antigen. Receptors specifically bind to target antigens expressed by B-cell malignant tumors;
(B) Subsequently, in the step of administering to the subject a checkpoint inhibitor which is an antibody capable of blocking an immune checkpoint pathway protein or an antigen-binding fragment thereof, the total dosage of the checkpoint inhibitor is determined. The total dose of the checkpoint inhibitor in the first of at least two dosing cycles, administered in each of at least two dosing cycles,
Same or less than the total dosage given in the second and / or subsequent dosing cycle; and
Administered in the form of multiple individual doses during the first dosing cycle, the number of individual doses is greater than the number of individual doses administered in the second and / or subsequent dosing cycle.
Process
Treatment methods, including.
[Invention 1002]
A treatment method comprising the step of administering to a subject having a B cell malignant tumor a checkpoint inhibitor which is an antibody capable of blocking an immune checkpoint pathway protein or an antigen-binding fragment thereof.
The subject is receiving T cell therapy comprising a dose of genetically engineered T cells expressing a chimeric antigen receptor that specifically binds to a target antigen expressed by a B cell malignant tumor, a checkpoint. The total dosage of the inhibitor is administered in each of at least two dosing cycles, and the total dose of the checkpoint inhibitor in the first of at least two dosing cycles is
Same or less than the total dosage given in the second and / or subsequent dosing cycle; and
Administered in the form of multiple individual doses during the first dosing cycle, the number of individual doses is greater than the number of individual doses administered in the second and / or subsequent dosing cycle.
Method.
[Invention 1003]
The method of the present invention 1001 or 1002, wherein the dosing cycle is a 21-day cycle.
[Invention 1004]
The method of the present invention 1001 or 1002, wherein the dosing cycle is a 28-day cycle.
[Invention 1005]
The method of any of 1001-1004 of the present invention, wherein the total dosage in the first of at least two dosing cycles is the same as the total dosage in the second of at least two dosing cycles.
[Invention 1006]
The method of any of 1001-1005 of the present invention, wherein the first of at least two dosing cycles comprises two, three, four or more individual doses.
[Invention 1007]
The dosing cycle is a 28-day cycle, with the first individual dose of at least two 28-day cycles being four doses each weekly (Q1W), two doses as Q1W doses for two consecutive weeks, or each. The method of the invention 1006, which is administered as two doses as a Q1W dose for two consecutive weeks followed by one dose once every two weeks (Q2W).
[Invention 1008]
The method of any of 1001-1007 of the present invention, wherein each of at least two dosing cycles independently administers a total dosage of 400 mg or about 400 mg to 2000 mg or about 2000 mg of the checkpoint inhibitor.
[Invention 1009]
The method of any of 1001-1008 of the present invention, wherein the checkpoint inhibitor blocks an immune checkpoint pathway protein selected from PD-L1, PD-L2, PD-1 and CTLA-4.
[Invention 1010]
The method of any of 1001 to 1009 of the present invention, wherein the checkpoint pathway is PD-1 / PD-L1 and the checkpoint inhibitor is an anti-PD-1 antibody.
[Invention 1011]
The method of the invention 1010, wherein the checkpoint inhibitor is nivolumab, pembrolizumab, or cemiplimab.
[Invention 1012]
Any of 1001-1011 of the present invention, wherein each of at least two dosing cycles independently administers a total dosage of 400 mg or about 400 mg to 600 mg or about 600 mg, optionally 480 mg or about 480 mg. Method.
[Invention 1013]
The method of any of 1001 to 1009 of the present invention, wherein the checkpoint pathway is PD-1 / PD-L1 and the checkpoint inhibitor is an anti-PD-L1 antibody.
[Invention 1014]
The method of any of 1001-1011 and 1013 of the present invention comprising administering a total dosage of 750 mg to 2000 mg, optionally 1500 mg or about 1500 mg, each of at least two dosing cycles independently.
[Invention 1015]
The administration of the checkpoint inhibitor and / or the beginning of the first dosing cycle,
(I) Peak or maximum levels of T cell therapy cells became detectable in the subject's blood;
(Ii) The number of T cell therapy cells detectable in the blood becomes undetectable or reduced after becoming detectable in the blood, optionally preceded by administration of T cell therapy. Reduced compared to time point;
(Iii) The number of T cell therapy cells detectable in the blood is 1.5 times the peak or maximum number of T cell therapy cells detectable in the blood of the subject after the start of T cell therapy administration, 2.0. Increased, 3.0 times, 4.0 times, 5.0 times, 10 times, or more, or more than 1.5 times, more than 2.0 times, more than 3.0 times, more than 4.0 times, more than 5.0 times, more than 10 times, or more;
(Iv) The number of cells detectable in the blood of the subject or derived from the cells after the peak or maximum level of cells of T cell therapy becomes detectable in the blood of the subject is the subject. Less than 10%, less than 5%, less than 1%, or less than 0.1% of total peripheral blood mononuclear cells (PBMC) in blood;
(V) Subjects showed disease progression after treatment with T cell therapy and / or relapsed following remission; and / or
(Iv) Subjects showed increased tumor volume compared to the tumor volume before or after cell administration and before the start of checkpoint inhibitor administration.
The method of any of 1001-1014 of the present invention, which is initiated at a time point, or optionally immediately thereafter or within 1-3 days thereof.
[Invention 1016]
Checkpoint inhibitor administration and / or the beginning of the first dosing cycle begins 29 days, 36 days, 43 days, or 50 days, or within 29 days, 36 days, 43 days after the start of T cell therapy administration. The method of the present invention 1001-1015, which is initiated within or within 50 days.
[Invention 1017]
Either 1001-1016 of the present invention, wherein the administration of the checkpoint inhibitor and / or the beginning of the first dosing cycle is initiated 22-36 days or approximately 22-36 days after the start of administration of T cell therapy. That way.
[Invention 1018]
The method of any of 1001-1017 of the present invention, wherein the administration of the checkpoint inhibitor and / or the beginning of the first dosing cycle is initiated 29 days or approximately 29 days after the initiation of administration of T cell therapy.
[Invention 1019]
The method of any of 1001-1018 of the present invention, wherein the administration of the checkpoint inhibitor and / or the beginning of the first dosing cycle is initiated 43 days or approximately 43 days after the initiation of administration of T cell therapy.
[Invention 1020]
The method of any of 1001-1019 of the present invention, wherein the subject has not shown significant toxicity following administration of T cell therapy at the beginning of the checkpoint inhibitor administration and / or first dosing cycle.
[Invention 1021]
Serious toxicity is severe cytokine release syndrome (CRS), optionally grade 3 or higher, long-term grade 3 or higher or grade 4 or 5 CRS; and / or
Serious toxicity is severe neurotoxicity, optionally grade 3 or higher, long-term grade 3 or higher or grade 4 or 5 neurotoxicity,
The method of the present invention 1020.
[Invention 1022]
(A) A step of administering T cell therapy to a subject with a B cell malignant tumor, wherein the T cell therapy comprises a dose of genetically engineered T cells expressing a chimeric antigen receptor and is chimeric. A step in which the antigen receptor specifically binds to a target antigen expressed by cells of a B-cell malignant tumor;
(B) Subsequent administration of an anti-PD-L1 antibody or antigen-binding fragment thereof to a subject comprising performing at least two 28-day cycles.
It is a treatment method including
The first 28-day cycle is an individual dose of 375 mg or about 375 mg of the anti-PD-L1 antibody or antigen-binding fragment thereof, respectively, as two separate doses of the 28-day cycle once a week (Q1W) for two consecutive weeks. The dose is followed by one dose of 750 mg or about 750 mg once every two weeks (Q2W) in a 28-day cycle; and
A second and / or subsequent 28-day cycle comprises administering the anti-PD-L1 antibody or antigen-binding fragment thereof in an amount of 1500 mg or approximately 1500 mg as one dose every 4 weeks (Q4W).
Method.
[Invention 1023]
A treatment method comprising the step of administering an anti-PD-L1 antibody or an antigen-binding fragment thereof to a subject having a B cell malignant tumor.
The subject has been administered T cell therapy comprising a dose of genetically engineered T cells expressing a chimeric antigen receptor that specifically binds to a target antigen expressed by a B cell malignant tumor and anti-PD. -Administration of the L1 antibody or antigen-binding fragment thereof comprises performing at least two 28-day cycles.
The first 28-day cycle is an individual dose of 375 mg or about 375 mg of the anti-PD-L1 antibody or antigen-binding fragment thereof, respectively, as two separate doses of the 28-day cycle once a week (Q1W) for two consecutive weeks. The dose is followed by one dose of 750 mg or about 750 mg once every two weeks (Q2W) in a 28-day cycle; and
A second and / or subsequent 28-day cycle comprises administering the anti-PD-L1 antibody or antigen-binding fragment thereof in an amount of 1500 mg or approximately 1500 mg as one dose every 4 weeks (Q4W).
Method.
[Invention 1024]
(A) A step of administering T cell therapy to a subject with a B cell malignant tumor, wherein the T cell therapy comprises a dose of genetically engineered T cells expressing a chimeric antigen receptor and is chimeric. A step in which the antigen receptor specifically binds to a target antigen expressed by a B cell malignant tumor;
(B) Subsequent administration of an anti-PD-L1 antibody or antigen-binding fragment thereof to a subject comprising performing at least two 28-day cycles.
It is a treatment method including
The first 28-day cycle comprises administering the anti-PD-L1 antibody or antigen-binding fragment thereof once a week (Q1W) for each of the 28-day cycles as four individual doses, each of which is independent. Includes two consecutive Q1W doses of 225 mg or about 225 mg, followed by two consecutive Q1W doses of 375 mg or about 375 mg, respectively;
The second and / or subsequent 28-day cycle comprises administering the anti-PD-L1 antibody or antigen-binding fragment thereof as two doses, each every two weeks (Q2W) of the 28-day cycle, with each Q2W administration. , Independently in an amount of 750 mg or about 750 mg, respectively
Method.
[Invention 1025]
A treatment method comprising the step of administering an anti-PD-L1 antibody or an antigen-binding fragment thereof to a subject having a B cell malignant tumor.
The subject has been administered T cell therapy comprising a dose of genetically engineered T cells expressing a chimeric antigen receptor that specifically binds to a target antigen expressed on B cell malignant tumors. The PD-L1 antibody or antigen-binding fragment thereof comprises performing at least two 28-day cycles.
The first 28-day cycle comprises administering the anti-PD-L1 antibody or antigen-binding fragment thereof once weekly (Q1W) for each of the 28-day cycles as four individual doses, each of which is independent. Includes two consecutive Q1W doses of 225 mg or about 225 mg, followed by two consecutive Q1W doses of 375 mg or about 375 mg, respectively;
The second and / or subsequent 28-day cycle administers the anti-PD-L1 antibody or antigen-binding fragment thereof as two separate doses every two weeks (Q2W) for the second and / or subsequent 28-day cycle. Including, each dose is independently an amount of 750 mg or about 750 mg,
Method.
[Invention 1026]
(A) A step of administering T cell therapy to a subject with a B cell malignant tumor, wherein the T cell therapy comprises a dose of genetically engineered T cells expressing a chimeric antigen receptor and is chimeric. A step in which the antigen receptor specifically binds to a target antigen expressed by a B cell malignant tumor;
(B) Subsequent administration of an anti-PD-L1 antibody or antigen-binding fragment thereof to a subject comprising performing at least two 28-day cycles.
It is a treatment method including
The first 28-day cycle comprises administering the anti-PD-L1 antibody or antigen-binding fragment thereof once a week (Q1W) as two separate doses, each of which is 375 mg independently. Or optionally, two doses are continuous Q1W doses, including an amount of about 375 mg, and optionally, two doses are administered on days 15 and 22 of the 28-day cycle; and
A second and / or subsequent 28-day cycle may administer the anti-PD-L1 antibody or antigen-binding fragment thereof in Q4W at a dose of 1500 mg or approximately 1500 mg per dose in the second and / or subsequent 28-day cycle. include,
Method.
[Invention 1027]
A treatment method comprising the step of administering an anti-PD-L1 antibody or an antigen-binding fragment thereof to a subject having a B cell malignant tumor.
The subject has been administered T cell therapy comprising a dose of genetically engineered T cells expressing a chimeric antigen receptor that specifically binds to a target antigen expressed on a B cell malignant tumor. Administration of PD-L1 antibody or antigen binding fragment comprises performing at least two 28-day cycles.
The first 28-day cycle comprises administering the anti-PD-L1 antibody or antigen-binding fragment thereof once a week (Q1W) as two separate doses, each of which is 375 mg independently. Or optionally, two doses are continuous Q1W doses, including an amount of about 375 mg, and optionally, two doses are administered on days 15 and 22 of the 28-day cycle; and
A second and / or subsequent 28-day cycle may administer the anti-PD-L1 antibody or antigen-binding fragment thereof in Q4W at a dose of 1500 mg or approximately 1500 mg per dose in the second and / or subsequent 28-day cycle. include,
Method.
[Invention 1028]
(A) A step of administering T cell therapy to a subject with a B cell malignant tumor, wherein the cell therapy comprises a dose of genetically engineered T cells expressing a chimeric antigen receptor and comprises a chimeric antigen. Receptors specifically bind to target antigens expressed by B-cell malignant tumors;
(B) Subsequently, the step of administering the anti-PD-L1 antibody or its antigen-binding fragment to the subject.
It is a treatment method including
Administration of the anti-PD-L1 antibody or antigen-binding fragment comprises performing at least two 28-day cycles, each of which has a total dosage of 750 mg to 2000 mg of the antibody or antigen-binding fragment. Including the administration of;
In at least one of the at least two 28-day cycles, administration of the total dosage of the anti-PD-L1 antibody or antigen-binding fragment administers multiple individual doses of the antibody or fragment during the at least one 28-day cycle. Implemented by
Method.
[Invention 1029]
A treatment method comprising the step of administering an anti-PD-L1 antibody or an antigen-binding fragment thereof to a subject having a B cell malignant tumor.
The subject has been administered T cell therapy comprising a dose of genetically engineered T cells expressing the chimeric antigen receptor, and the chimeric antigen receptor is specific for the target antigen expressed by the B cell malignant tumor. Combined
Administration of the anti-PD-L1 antibody or antigen-binding fragment comprises performing at least two 28-day cycles, each of which is independently 750 mg to 2000 mg of the antibody or antigen-binding fragment. Including administering the total dosage of;
In at least one of the at least two 28-day cycles, administration of the total dosage of the anti-PD-L1 antibody or antigen-binding fragment administers multiple individual doses of the antibody or fragment during the at least one 28-day cycle. Implemented by
Method.
[Invention 1030]
In the first of at least two 28-day cycles, administration of the total dosage of anti-PD-L1 antibody or antigen-binding fragment is more than the antibody or fragment compared to administration in the second and / or subsequent 28-day cycle. The method of the invention 1028 or 1029, performed by administering a large number of individual doses.
[Invention 1031]
The method of any of the inventions 1028-1030, wherein the total dosage of the anti-PD-L1 antibody or antigen-binding fragment in each 28-day cycle is independently between 750 mg or about 750 mg and 1500 mg or about 1500 mg.
[Invention 1032]
The method of any of 1028-1031 of the present invention, wherein the total dosage of the anti-PD-L1 antibody or antigen binding fragment in at least one of the 28-day cycles is 750 mg or about 750 mg.
[Invention 1033]
The method of any of the inventions 1028-1032, wherein the total dosage of the anti-PD-L1 antibody or antigen binding fragment in at least one of the 28-day cycles is 1200 mg or about 1200 mg.
[Invention 1034]
The method of any of 1028-1031 of the present invention, wherein the total dosage of the anti-PD-L1 antibody or antigen binding fragment in at least one of the 28-day cycles is 1500 mg or about 1500 mg.
[Invention 1035]
The method of any of 1028-1031 and 1034 of the present invention, wherein the total dosage of the anti-PD-L1 antibody or antigen-binding fragment in each 28-day cycle is independently 1500 mg or approximately 1500 mg.
[Invention 1036]
Any of the inventions 1028-1035, wherein the total dosage of the anti-PD-L1 antibody or antigen binding fragment in at least two of the at least two 28-day cycles, optionally in at least two 28-day cycles, is the same total dosage. That way.
[Invention 1037]
Any of the inventions 1028-1035, wherein the total dosage of the anti-PD-L1 antibody or antigen binding fragment is different in at least two of the at least two 28-day cycles, or different in each of the at least two 28-day cycles. Method.
[Invention 1038]
The total dosage of the anti-PD-L1 antibody or antigen-binding fragment in the first of at least two 28-day cycles is lower than in the second and / or subsequent of at least two 28-day cycles, according to the invention 1028-1035 and 1037. Either way.
[Invention 1039]
Administration of the total dosage in the first of at least two 28-day cycles comprises administering two, three or four individual doses of the anti-PD-L1 antibody or antigen-binding fragment thereof, according to the invention 1028-1038. Either way.
[Invention 1040]
Administration of the total dosage in the first of at least two 28-day cycles provides anti-PD-L1 antibody or antigen-binding fragment thereof.
(I) Two individual doses, once weekly (Q1W) each within the 28-day cycle, optionally on days 15 and 22 of the 28-day cycle;
(Ii) Weekly (Q1W) for each 28-day cycle, optionally 4 individual doses on days 1, 8, 15 and 22 of the 28-day cycle;
(Iii) Q1W for 2 consecutive weeks in a 28-day cycle, optionally following 2 individual doses on days 1 and 8 of the cycle, once every 2 weeks in a 28-day cycle (Q2W), optionally on day 15 of the cycle. One dose of; or
(Iv) Two individual doses every 2 weeks (Q2W) for each 28-day cycle, optionally on days 1 and 15 of the 28-day cycle
The method of any of 1028-1039 of the present invention comprising administering as an individual dose according to a more selected dosing regimen.
[Invention 1041]
Each Q1W dose administered in the first 28-day cycle is independently from 18% or about 18% to 32% or about 32% of the total dosage administered in the first 28-day cycle. Optionally 25% or about 25% of the total dosage administered in the first 28-day cycle; and / or
Each Q2W dose administered in the first 28-day cycle is independently from 40% or about 40% to 62.5% or about 62.5% of the total dosage in the first 28-day cycle, optionally the second. 50% or about 50% of the total dosage administered in one 28-day cycle,
The method of the present invention 1040.
[Invention 1042]
Administration of the total dosage in the first 28-day cycle comprises administration of the anti-PD-L1 antibody or its antigen-binding fragment according to dosing regimen (iii), with each of the two individual doses for Q1W consecutive 2 weeks. Independently, each is in an amount of 375 mg or about 375 mg, followed by one dose of Q2W in an amount of 750 mg or about 750 mg;
Administration of the total dosage in the first 28-day cycle comprises administration of the anti-PD-L1 antibody or antigen-binding fragment thereof according to the dosing regimen set forth in (ii), with four individual doses of Q1W being 225 mg or Includes two consecutive Q1W doses in an amount of about 225 mg followed by two consecutive Q1W doses in an amount of 375 mg or about 375 mg; or
Administration of the total dosage in the first 28-day cycle comprises administration of the anti-PD-L1 antibody or antigen-binding fragment thereof according to the dosing regimen set forth in (i), for two consecutive Q1W doses, 2 of Q1W. Each of the two individual doses is performed in an amount of 375 mg or about 375 mg,
The method of the present invention 1040 or 1041.
[Invention 1043]
Administration of the total dosage in the first of at least two 28-day cycles, individual doses,
(I) Two individual doses on the 15th or about 15th day and 22nd or about 22nd day of the 28-day cycle;
(Ii) 4 individual doses on 1 or about 1 day, 8 or about 8 days, 15 or about 15 days and 22 or about 22 days of the 28-day cycle;
(Iii) One dose on the 15th or about 15th day of the cycle, followed by two individual doses on the 1st or about 1st day and 8th or about 8th day of the 28-day cycle; or
(Iv) Two doses of 1 or about 1 day of the 28-day cycle and 15 or about 15 days of the 28-day cycle
The method of any of 1028-1040 of the present invention comprising administration according to a more selected dosing regimen.
[Invention 1044]
Administration of the total dosage in the first 28-day cycle involves administration of the anti-PD-L1 antibody or its antigen-binding fragment according to dosing regimen (iii), with each of the two individual doses being one of the 28-day cycles. Alternatively, it comprises an amount of 375 mg or about 375 mg on about 1 and 8 or about 8 days, followed by one dose of 750 mg or about 750 mg on 15 or about 15 days of the cycle;
Administration of the total dosage in the first 28-day cycle comprises administration of the anti-PD-L1 antibody or antigen-binding fragment thereof according to the dosing regimen set forth in (ii), with four individual doses of the 28-day cycle. 2 in an amount of 375 mg or about 375 mg on 15 or about 15 days and 22 or about 22 days, followed by 2 consecutive doses of 1 or about 1 and 8 or about 8 days 225 mg or about 225 mg Includes two consecutive doses; or
Administration of the total dosage in the first 28-day cycle comprises administration of the anti-PD-L1 antibody or antigen-binding fragment according to the dosing regimen set forth in (i), with each of the two individual doses being administered in the 28-day cycle. Including 2 consecutive doses of 375 mg or about 375 mg on 15 or about 15 days and 22 or about 22 days,
Any method of the present invention 1028-1043.
[Invention 1045]
Administration of the total dosage in the second and / or subsequent 28-day cycle comprises independently administering one or two doses of the anti-PD-L1 antibody or antigen-binding fragment thereof, according to the invention 1030-. One of the 1044 methods.
[Invention 1046]
Administration of total dosage in the second and / or subsequent 28-day cycle, independently
(I) Two individual doses every 2 weeks (Q2W) for the 2nd and / or subsequent 28-day cycle, respectively, optionally on days 1 and 15 of the 2nd and / or subsequent cycle; or
(Ii) Every 4 weeks (Q4W) of the 2nd and / or subsequent 28-day cycle, optionally one dose on the 1st day of the 2nd and / or subsequent cycle
The method of any of the present inventions 1030-1045, comprising a more selected dosing regimen.
[Invention 1047]
Each Q2W dose in the second and / or subsequent 28-day cycle is 50% or approximately 50% of the total dosage in the second and / or subsequent 28-day cycle; and / or
The Q4W dose in the second and / or subsequent 28-day cycle is or is approximately the total dosage in the second and / or subsequent 28-day cycle.
The method of the present invention 1046.
[Invention 1048]
A second and / or subsequent dose comprises administering Q2W of the anti-PD-L1 antibody or antigen-binding fragment thereof in an amount of 750 mg or about 750 mg for each of the two doses; or
A second and / or subsequent dose comprises administering Q4W of the anti-PD-L1 antibody or antigen-binding fragment thereof in an amount of 1500 mg or about 1500 mg per dose.
The method of the present invention 1046 or 1047.
[Invention 1049]
The method of any of 1004-1048 of the present invention, wherein at least two 28-day cycles further comprise a third 28-day cycle and / or a subsequent 28-day cycle is a third 28-day cycle.
[Invention 1050]
The method of the invention 1049, wherein the total dosage of the anti-PD-L1 antibody or antigen binding fragment in the third 28-day cycle is the same as the total dosage administered in the first and / or second 28-day cycle. ..
[Invention 1051]
The method of the invention 1049 or 1050, wherein the total dosage of the anti-PD-L1 antibody or antigen binding fragment in the third 28-day cycle is 1500 mg or about 1500 mg.
[Invention 1052]
(A) In the third 28-day cycle, administration of the total dosage of anti-PD-L1 antibody or antigen-binding fragment at a larger number of individual doses compared to the first and / or second 28-day cycle. , By administering an antibody or fragment; or
(B) In the third 28-day cycle, administration of the total dosage of anti-PD-L1 antibody or antigen-binding fragment administers the same number of doses of antibody or fragment compared to the second 28-day cycle. Implemented by,
Any method of the present invention 1049 to 1051.
[Invention 1053]
Administration of the total dosage in the 3rd 28-day cycle optionally comprises administration of one dose every 4 weeks (Q4W) in the 3rd 28-day cycle, on the 1st day of the 3rd 28-day cycle. Any method of the present invention 1049 to 1052.
[Invention 1054]
The first of at least two 28-day cycles,
(A) Time between 22nd and 36th day from the start of T cell therapy administration; or
(B) (i) Peak or maximum levels of T cell therapy cells became detectable in the subject's blood;
(Ii) The number of T cell therapy cells detectable in the blood becomes undetectable or reduced after becoming detectable in the blood, optionally preceded by administration of T cell therapy. Reduced compared to time point;
(Iii) The number of T cell therapy cells detectable in the blood is 1.5 times the peak or maximum number of T cell therapy cells detectable in the blood of the subject after the start of T cell therapy administration, 2.0. Increased, 3.0 times, 4.0 times, 5.0 times, 10 times or more, or more than 1.5 times, more than 2.0 times, more than 3.0 times, more than 4.0 times, more than 5.0 times, more than 10 times or more;
(Iv) The number of cells detectable in the blood of the subject or derived from the cells after the peak or maximum level of cells of T cell therapy becomes detectable in the blood of the subject is the subject. Less than 10%, less than 5%, less than 1% or less than 0.1% of total peripheral blood mononuclear cells (PBMC) in blood;
(V) Subjects showed disease progression after treatment with T cell therapy and / or relapsed following remission; and / or
(Iv) Subjects showed increased tumor volume compared to the tumor volume before or after cell administration and before the start of anti-PD-L1 antibody administration.
At that time or thereafter, optionally immediately after or within 1-3 days thereafter
The method of any of 1022 to 1053 of the present invention, which is initiated in.
[Invention 1055]
The method of any of 1022-1054 of the present invention, wherein the first of at least two 28-day cycles is initiated between days 22 and 36 from the start of administration of T cell therapy.
[Invention 1056]
At least two 28-day cycles include three or less 28-day cycles, and optionally the first of the at least two 28-day cycles is day 22 or about 22 to 36 or about 36 days. The method of any of 1022-1055 of the present invention, initiated during.
[Invention 1057]
The method of any of 1022-1056 of the present invention, wherein the first of at least two 28-day cycles is initiated 29 days or approximately 29 days after the start of administration of T cell therapy.
[Invention 1058]
The method of any of 1022-1057 of the present invention, wherein the first of at least two 28-day cycles is initiated 43 days or approximately 43 days after the start of administration of T cell therapy.
[Invention 1059]
(A) A step of administering T cell therapy to a subject with a B cell malignant tumor, wherein the T cell therapy comprises a dose of genetically engineered T cells expressing a chimeric antigen receptor and is chimeric. A step in which the antigen receptor specifically binds to a target antigen expressed by a B cell malignant tumor;
(B) Subsequent administration of the anti-PD-L1 antibody or antigen-binding fragment thereof to the subject, comprising administration of the antibody or antigen-binding fragment carrying out a 28-day cycle between 1 and 3. , Each cycle comprises administering a total dosage of 750 mg to 2000 mg of antibody or fragment, optionally the first of the 28-day cycles between the 1 to 3 is 22 days after the start of T cell therapy. Or between the 22nd and 36th days or the 36th day, optionally starting on the 29th day, the process
Treatment methods, including.
[Invention 1060]
A treatment method comprising the step of administering an anti-PD-L1 antibody or an antigen-binding fragment thereof to a subject having a B cell malignant tumor.
The subject has been administered T cell therapy comprising a dose of genetically engineered T cells expressing the chimeric antigen receptor, and the chimeric antigen receptor is specific for the target antigen expressed by the B-cell malignant tumor. Administration of the antibody or antigen-binding fragment comprises performing a 28-day cycle between one and three, each cycle administering a total dosage of 900 mg to 2000 mg of the antibody or fragment. And optionally, the first of the 28-day cycles between the 1 to 3 is optionally about 22 or about 22 to 36 or about 36 days after the start of T cell therapy. Beginning on the 29th day
Method.
[Invention 1061]
The method of the invention 1059 or 1060, wherein the total dosage of the anti-PD-L1 antibody or antigen binding fragment in each 28-day cycle is independently 1200 mg-1500 mg or approximately 1200 mg-1500 mg.
[Invention 1062]
The method of any of 1059-1061 of the present invention, wherein the total dosage of the anti-PD-L1 antibody or antigen binding fragment in at least one 28-day cycle is 1200 mg or about 1200 mg.
[Invention 1063]
The method of any of 1059-1061 of the present invention, wherein the total dosage of the anti-PD-L1 antibody or antigen binding fragment in at least one 28-day cycle is 1500 mg or about 1500 mg.
[Invention 1064]
The method of any of 1059-1061 and 1063 of the present invention, wherein the total dosage of the anti-PD-L1 antibody or antigen-binding fragment in each 28-day cycle is 1500 mg or approximately 1500 mg.
[Invention 1065]
The method of any of 1059-1064 of the invention, wherein the total dosage in each 28-day cycle comprises administering one, two, three or four doses of the anti-PD-L1 antibody or antigen-binding fragment thereof.
[Invention 1066]
Each 28-day cycle is independent,
(I) 4 doses once weekly (Q1W), optionally on days 1, 8, 15 and 22 of a 28-day cycle;
(Ii) Q1W respectively, optionally following two consecutive doses on days 1 and 8 of the 28-day cycle, once every two weeks for one dose (Q2W), optionally one dose on day 15;
(Iii) Two doses every 2 weeks (Q2W), optionally on days 1 and 15 of the 28-day cycle; or
(Iv) Every 4 weeks (Q4W), optionally one dose on day 1 of a 28-day cycle
The method of any of the present inventions 1059-1065, comprising a more selected dosing regimen.
[Invention 1067]
Anti-PD-L1 antibody or antigen-binding fragment is administered on days 1, 8 and 15 in the first 28-day cycle, day 1 in the second 28-day cycle, and day 1 in the third 28-day cycle. The method according to any one of the present inventions 1059 to 1066.
[Invention 1068]
Anti-PD-L1 antibody or antigen-binding fragment on days 1, 8, 15 and 22 in the first 28-day cycle, days 1 and 15 in the second 28-day cycle, and 1 day in the third 28-day cycle. The method of any of the present inventions 1059-1067 administered to the eye.
[Invention 1069]
The method of any of 1059-1068 of the present invention, wherein the anti-PD-L1 antibody or antigen binding fragment is administered on day 1 of each 28-day cycle.
[Invention 1070]
1 if the subject exhibits a partial response (PR) or less following treatment and / or PR or less at 3 months following initiation of T cell therapy and / or administration of anti-PD-L1 antibody or fragment. The method of any of 1059-1069 of the invention, further comprising administering the anti-PD-L1 antibody or antigen binding fragment in one or more additional 28-day cycles.
[Invention 1071]
The anti-PD-L1 antibody or antigen-binding fragment is administered at a total dosage of 900 mg to 2000 mg, optionally at a total dosage of 1500 mg or about 1500 mg, respectively, in one or more additional 28-day cycles, according to the invention 1070. the method of.
[Invention 1072]
The method of any of the present inventions 1013-1071, wherein the anti-PD-L1 antibody or antigen binding fragment is administered for a total duration of 12 months or less.
[Invention 1073]
Any of the present inventions 1013 to 1072, wherein administration of the anti-PD-L1 antibody or antigen binding fragment and / or initiation of the first 28-day cycle is initiated after 21 days after initiation of administration of T cell therapy. Method.
[Invention 1074]
Administration of anti-PD-L1 antibody or antigen-binding fragment and / or beginning of the first 28-day cycle,
(I) Peak or maximum levels of T cell therapy cells became detectable in the subject's blood;
(Ii) The number of T cell therapy cells detectable in the blood becomes undetectable or reduced after becoming detectable in the blood, optionally preceded by administration of T cell therapy. Reduced compared to time point;
(Iii) The number of T cell therapy cells detectable in the blood is 1.5 times the peak or maximum number of T cell therapy cells detectable in the blood of the subject after the start of T cell therapy administration, 2.0. Increased, 3.0 times, 4.0 times, 5.0 times, 10 times or more, or more than 1.5 times, more than 2.0 times, more than 3.0 times, more than 4.0 times, more than 5.0 times, more than 10 times or more;
(Iv) The number of cells detectable in the blood of the subject or derived from the cells after the peak or maximum level of cells of T cell therapy becomes detectable in the blood of the subject is the subject. Less than 10%, less than 5%, less than 1% or less than 0.1% of total peripheral blood mononuclear cells (PBMC) in blood;
(V) Subjects showed disease progression after treatment with T cell therapy and / or relapsed following remission; and / or
(Iv) Subjects showed increased tumor volume compared to the tumor volume before or after cell administration and before the start of anti-PD-L1 antibody administration.
The method of any of 1013-1073 of the present invention, which is initiated at the time point or thereafter, optionally immediately thereafter or within 1-3 days thereof.
[Invention 1075]
Administration of anti-PD-L1 antibody or antigen-binding fragment and / or the beginning of the first 28-day cycle is 29 days, 36 days, 43 days or 50 days, or within 29 days, 36 after the start of administration of T cell therapy. The method of the invention 1013-1074, which is initiated within days, 43 days, or 50 days.
[Invention 1076]
Administration of the anti-PD-L1 antibody or antigen-binding fragment and / or the beginning of the first 28-day cycle begins 22-36 days or approximately 22-36 days after the start of administration of T cell therapy. The method of any of the inventions 1013-1075.
[Invention 1077]
Administration of the anti-PD-L1 antibody or antigen-binding fragment and / or the beginning of the first 28-day cycle is initiated 29 or about 29 days after the start of T cell therapy administration, either 1013-1076 of the invention. the method of.
[Invention 1078]
The method of any of 1013-1077 of the invention, wherein the administration of the checkpoint inhibitor and / or the beginning of the first dosing cycle is initiated 43 days or approximately 43 days after the initiation of administration of T cell therapy.
[Invention 1079]
Administration of the anti-PD-L1 antibody or antigen-binding fragment and / or at the beginning of the first 28-day cycle, the subject showed no significant toxicity following administration of T cell therapy, according to the invention 1013-1078. Either way.
[Invention 1080]
Serious toxicity is severe cytokine release syndrome (CRS), optionally grade 3 or higher, long-term grade 3 or higher or grade 4 or 5 CRS; and / or
Serious toxicity is severe neurotoxicity, optionally grade 3 or higher, long-term grade 3 or higher or grade 4 or 5 neurotoxicity,
The method of the present invention 1079.
[Invention 1081]
The method of any of the present invention 1013-1080, wherein the anti-PD-L1 antibody or antigen-binding fragment thereof specifically binds to the extracellular domain of PD-L1.
[Invention 1082]
The anti-PD-L1 antibody or antigen-binding fragment thereof is MEDI4736 (durvalumab), MDPL3280A (atezolizumab), YW243.55.S70, MDX-1105 (BMS-936559), LY3300054, or MSB0010718C (avelumab), or said above. The method of any of 1013 to 1081 of the present invention, which is, or comprises, any of the antigen-binding fragments or regions thereof.
[Invention 1083]
The method of any of the present invention 1013-1082, wherein the anti-PD-L1 antibody or antigen-binding fragment thereof is MEDI4736 (durvalumab), or is an antigen-binding fragment or region thereof, or comprises.
[Invention 1084]
The method of any of the present invention 1013-1083, wherein the anti-PD-L1 antibody or antigen-binding fragment thereof is MEDI4736 (durvalumab).
[Invention 1085]
The method of any of 1001 to 1084 of the present invention, wherein the B-cell malignancies are non-Hodgkin's lymphoma (NHL).
[Invention 1086]
At or shortly before administration of T-cell therapy, the subject is treated with one or more prior therapies to NHL, optionally with one or two prior therapies other than another dose of cells expressing CAR. Whether the patient has relapsed following subsequent remissions or has become refractory to prior therapy and, optionally, one or more prior therapies are CD20-targeting agents or anthracyclines. Or the method of the present invention 1085 comprising it.
[Invention 1087]
NHL, invasive NHL, diffuse large B-cell lymphoma (DLBCL), DLBCL-NOS, optionally transformed indolent; EBV-positive DLBCL-NOS; T-cell / tissue-rich large-cell B-cell lymphoma; Primary mediasular large B-cell lymphoma (PMBCL); follicular lymphoma (FL), optionally follicular lymphoma grade 3B (FL3B); and / or having a rearrangement of MYC with BCL2 and / or BCL6, The method of the invention 1085 or 1086 comprising high-grade B-cell lymphoma (double / triple hit) with DLBCL histology.
[Invention 1088]
NHL has diffuse large B-cell lymphoma (DLBCL); DLBCL-NOS; DLBCL-NOS transformed indolent; follicular lymphoma grade 3B (FL3B); and / or reconstitution of MYC with BCL2 and / or BCL6 The method of any of 1085-1087 of the present invention comprising high-grade B-cell lymphoma (double / triple hit) with DLBCL histology.
[Invention 1089]
The method of any of 1001-1088 of the present invention, wherein the subject is identified or identified as having a status of Eastern Cooperative Oncology Group Performance Status (ECOG) less than or equal to 1.
[Invention 1090]
The method of any of 1001 to 1089 of the present invention, wherein the target antigen is a B cell antigen.
[Invention 1091]
The method of any of 1001 to 1090 of the present invention, wherein the target antigen is CD19.
[Invention 1092]
The method of the invention 1091 comprising an extracellular antigen recognition domain in which a chimeric antigen receptor (CAR) specifically binds to a target antigen and an intracellular signaling domain comprising ITAM.
[Invention 1093]
The method of the present invention 1092, wherein the intracellular signaling domain comprises the signaling domain of the CD3-zeta (CD3ζ) chain.
[Invention 1094]
The method of the invention 1092 or 1093, wherein the chimeric antigen receptor (CAR) further comprises a co-stimulation signaling region comprising the cytoplasmic signaling domain of the co-stimulating molecule.
[Invention 1095]
The method of the invention 1094, wherein the co-stimulation signaling region comprises the cytoplasmic signaling domain of CD28 or 4-1BB.
[Invention 1096]
The method of the invention 1094 or 1095, wherein the co-stimulation domain is or comprises the cytoplasmic signaling domain of 4-1BB.
[Invention 1097]
CAR,
CD19-specific scFv and
With the transmembrane domain,
A cytoplasmic signaling domain derived from a co-stimulating molecule, optionally with or containing a 4-1BB signaling domain,
Optionally with a cytoplasmic signaling domain derived from a major signaling ITAM-containing molecule that is or contains the CD3 zeta signaling domain.
Including
Optionally further include a spacer between the transmembrane domain and scFv,
Any method of the present invention 1001 to 1096.
[Invention 1098]
CAR, in order
CD19-specific scFv and
With the transmembrane domain,
A cytoplasmic signaling domain derived from a co-stimulating molecule, optionally with or containing a 4-1BB signaling domain,
With the cytoplasmic signaling domain derived from the major signaling ITAM-containing molecule, which is optionally the CD3 zeta signaling domain.
The method of any of 1001 to 1096 of the present invention, comprising.
[Invention 1099]
CAR, in order
CD19-specific scFv and
With spacers,
With the transmembrane domain,
A cytoplasmic signaling domain derived from a co-stimulating molecule, which is optionally a 4-1BB signaling domain,
With a cytoplasmic signaling domain derived from a major signaling ITAM-containing molecule, optionally with or containing a CD3 zeta signaling domain.
The method of any of 1001 to 1096 of the present invention, comprising.
[Invention 1100]
The spacer is
(A) Contains or consists of all or part of an immunoglobulin hinge or a modified version thereof, or contains about 15 or less amino acids, and does not contain the extracellular space of CD28 or CD8.
(B) Contains or consists of an immunoglobulin hinge, optionally an IgG4 hinge, or a modified version thereof, and / or contains about 15 or less amino acids, and the extracellular region of CD28 is also the extracellular region of CD8. Does not include, or
(C) 12 amino acid length or about 12 amino acid length and / or contains or consists of an immunoglobulin hinge, optionally IgG4, or all or part of a modified version thereof.
The method of the invention 1097 or 1099, which is a polypeptide spacer.
[Invention 1101]
The spacer comprises or consists of the formula X ₁ PPX ₂ P (SEQ ID NO: 58), wherein X ₁ is glycine, cysteine or arginine and X ₂ is cysteine or threonine, the present invention 1097, Either 1099 or 1100 method.
[Invention 1102]
The spacer is a sequence of SEQ ID NO: 1, a sequence encoded by SEQ ID NO: 2, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34 sequences, or at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, with them. The method of any of 1097 and 1099-1101 of the present invention comprising or comprising any of the above variants having 99% or more sequence identity.
[Invention 1103]
The method of any of 1097 and 1099-1102 of the present invention, wherein the spacer comprises a sequence of SEQ ID NO: 1.
[Invention 1104]
The cytoplasmic signaling domain of the co-stimulator is SEQ ID NO: 12 or at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%. , 96%, 97%, 98%, 99%, or any method of the present invention comprising a variant thereof having sequence identity of 994 to 1103.
[Invention 1105]
Cytoplasmic signaling domains derived from major signaling ITAM-containing molecules are at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, The method of any of 1092-1104 of the invention comprising SEQ ID NO: 13 or 14 or 15 having 96%, 97%, 98%, 99% or more sequence identity.
[Invention 1106]
The extracellular antigen recognition domain is scFv, where scFv is the CDRL1 sequence of RASQDISKYLN (SEQ ID NO: 35), the CDRL2 sequence of SRLHSGV (SEQ ID NO: 36), and / or the CDRL3 of GNTLPYTFG (SEQ ID NO: 37). The sequences of the present invention 1092-1105 comprising a sequence and a CDRH1 sequence of DYGVS (SEQ ID NO: 38), a CDRH2 sequence of VIWGSETTYYNSALKS (SEQ ID NO: 39), and / or a CDRH3 sequence of YAMDYWG (SEQ ID NO: 40). Either way.
[Invention 1107]
The present invention 1092 to the present invention, wherein the extracellular antigen recognition domain is scFv, and scFv contains the CDRL1 sequence of FMC63, the CDRL2 sequence of FMC63, the CDRL3 sequence of FMC63, the CDRH1 sequence of FMC63, the CDRH2 sequence of FMC63, and the CDRH3 sequence of FMC63. One of the 1106 methods.
[Invention 1108]
The method of any of 1092-1107 of the present invention, wherein the extracellular antigen recognition domain is scFv, wherein the scFv comprises a variable heavy chain region of FMC63 and a variable light chain region of FMC63.
[Invention 1109]
The method of any of 1092 to 1108 of the present invention, wherein the extracellular antigen recognition domain is scFv and the scFv comprises a _VH region comprising the amino acid sequence set forth in SEQ ID NO: 41.
[Invention 1110]
The method of any of 1092-1109 of the present invention, wherein the extracellular antigen recognition domain is scFv and the scFv comprises a _VL region comprising the amino acid sequence set forth in SEQ ID NO: 42.
[Invention 1111]
The extracellular antigen recognition domain is scFv,
scFv, in order
V _H , optionally containing the amino acid sequence shown in SEQ ID NO: 41 ,
With a linker, optionally including SEQ ID NO: 59,
Optionally contain the amino acid sequence set forth in SEQ ID NO: 42, with _VL
And / or
The scFv contains a flexible linker and / or contains the amino acid sequence shown as SEQ ID NO: 43.
The method of any of 1092 to 1110 of the present invention.
[Invention 1112]
The method of any of 1092-1111 of the present invention, wherein the extracellular antigen recognition domain is scFv and scFv comprises the amino acid sequence set forth in SEQ ID NO: 43.
[Invention 1113]
The doses of genetically engineered T cells are 1 x 10 ⁵ to 5 x 10 ⁸ total CAR-expressing T cells, 1 x 10 ⁶ to 2.5 x 10 ⁸ total CAR-expressing T cells, 5 x 10 ⁶ to 1. × 10 ⁸ total CAR-expressing T cells, 1 × 10 ⁷ to 2.5 × 10 ⁸ total CAR-expressing T cells, 5 × 10 ⁷ to 1 × 10 ⁸ total CAR-expressing T cells, or approximately 1 × 10 ^5-5 x 10 ⁸ total CAR-expressing T cells, about 1 x 10 ^6-2.5 x 10 ⁸ total CAR-expressing T cells, about 5 x 10 ^6-1 x 10 ⁸ total CAR-expressing T cells, Approximately 1 × 10 ⁷ to 2.5 × 10 ⁸ total CAR-expressing T cells, approximately 5 × 10 ⁷ to 1 × 10 ⁸ total CAR-expressing T cells (including values at both ends) of the present invention 1001 to 1001 to One of the 1112 methods.
[Invention 1114]
The dose of genetically engineered T cells is at least or at least about 1 × 10 ⁵ CAR-expressing cells, at least or at least about 2.5 × 10 ⁵ CAR-expressing cells, at least or at least about 5 × 10 ⁵ CAR expression. Cells, at least or at least about 1 × 10 ⁶ CAR-expressing cells, at least or at least about 2.5 × 10 ⁶ CAR-expressing cells, at least or at least about 5 × 10 ⁶ CAR-expressing cells, at least or at least about 1 × 10 ⁷ CAR-expressing cells, at least or at least about 2.5 × 10 ⁷ CAR-expressing cells, at least or at least about 5 × 10 ⁷ CAR-expressing cells, at least or at least about 1 × 10 ⁸ CAR-expressing cells, The method of any of 1001-1113 of the present invention comprising at least or at least about 2.5 × 10 ⁸ CAR-expressing cells, or at least or at least about 5 × 10 ⁸ CAR-expressing cells.
[Invention 1115]
The method of any of 1001-1114 of the present invention, wherein the dose of genetically engineered T cells comprises 5 × 10 ⁷ or approximately 5 × 10 ⁷ CAR-expressing cells.
[Invention 1116]
The method of any of 1001-1114 of the present invention, wherein the dose of genetically engineered T cells comprises 1 × 10 ⁸ or approximately 1 × 10 ⁸ CAR-expressing cells.
[Invention 1117]
The method of any of 1001-1114 of the present invention, wherein the dose of genetically engineered T cells comprises 1.5 × 10 ⁸ or approximately 1.5 × 10 ⁸ CAR-expressing cells.
[Invention 1118]
The method of any of 1001-1117 of the present invention, wherein the dose of genetically engineered T cells is administered parenterally, optionally intravenously.
[Invention 1119]
The method of 1118 of the present invention, wherein the T cells are primary T cells obtained from a subject.
[Invention 1120]
The method of any of the present inventions 1001-1119, wherein the T cells are self-derived with respect to the subject.
[Invention 1121]
The method of any of 1001-1119 of the present invention, wherein the T cells are allogeneic to the subject.
[Invention 1122]
The dose of genetically engineered T cells comprises CD4 + T cells expressing CAR and CD8 + T cells expressing CAR, and administration of the dose comprises administering multiple separate compositions. The invention 1001 comprises the plurality of separate compositions comprising a first composition comprising one of CD4 + T cells and CD8 + T cells and a second composition comprising the other of CD4 + T cells or CD8 + T cells. Any method of ~ 1121.
[Invention 1123]
The first and second compositions are administered at intervals of 0-12 hours, 0-6 hours, or 0-2 hours, or the first. Administration of the composition 1 and administration of the second composition were performed on the same day, with an interval of about 0 to about 12 hours and an interval of about 0 to about 6 hours. Or performed at intervals of about 0 to 2 hours; and / or
The start of administration of the first composition and the start of administration of the second composition are carried out at intervals of about 1 minute to about 1 hour, or at intervals of about 5 minutes to about 30 minutes. Be done,
The method of the present invention 1122.
[Invention 1124]
The first composition and the second composition are administered at intervals of 2 hours or less, 1 hour or less, 30 minutes or less, 15 minutes or less, 10 minutes or less, or 5 minutes or less, according to the present invention 1122 or 1123 method.
[Invention 1125]
The method of any of 1122-1124 of the present invention, wherein the first composition comprises CD4 + T cells.
[Invention 1126]
The method of any of 1122-1124 of the present invention, wherein the first composition comprises CD8 + T cells.
[Invention 1127]
The method of any of 1122 to 1126 of the present invention, wherein the first composition is administered prior to the second composition.
[Invention 1129]
The method of any of the present inventions 1001-1127, wherein the subject is preconditioned with lymphocyte depletion therapy comprising administration of fludarabine and / or cyclophosphamide prior to administration.
[Invention 1130]
The method of any of 1001-1129 of the present invention, further comprising the step of administering to the subject a lymphocyte depletion therapy comprising administration of fludarabine and / or cyclophosphamide immediately prior to administration.
[Invention 1131]
Lymphocyte depletion therapy is about 200 mg / m ² to 400 mg / m ² , optionally 300 mg / m ² or about 300 mg / m ² of cyclophosphamide (including its value), and / or about 20 mg / m ² to Includes daily administration of 40 mg / m ² , optionally 30 mg / m ² of fludarabine for 2-4 days, optionally 3 days, or
Lymphocyte depletion therapy involves administration of approximately 500 mg / m ² of cyclophosphamide,
The method of the present invention 1129 or 1130.
[Invention 1132]
Lymphocyte depletion therapy includes daily administration of 300 mg / m ² or about 300 mg / m ² of cyclophosphamide and about 30 mg / m ² of fludarabine for 3 days; and / or
Lymphocyte depletion therapy includes daily administration of 500 mg / m ² or about 500 mg / m ² of cyclophosphamide and about 30 mg / m ² of fludarabine for 3 days.
The method of any one of the present inventions 1129 to 1131.
[Invention 1133]
The method of any of 1001 to 1132 of the present invention, wherein the subject is a human.
[Invention 1134]
(A) A T cell therapy comprising a dose of genetically engineered T cells expressing a chimeric antigen receptor, wherein the chimeric antigen receptor specifically binds to a target antigen expressed by a B-cell malignant tumor. T cell therapy;
(B) Immune checkpoint pathway An antibody or checkpoint inhibitor that is an antigen-binding fragment thereof capable of blocking a protein, optionally formulated in the form of one or more individual doses. Checkpoint inhibitors; as well
(C) Instructions for administering T cell therapy and / or checkpoint inhibitors to subjects with B cell malignant tumors, T cell therapy and / or check by any of the methods 1001-1133 of the present invention. Instructions that specify the administration of point inhibitors
Kit including.
[Invention 1135]
(A) A T cell therapy comprising a dose of genetically engineered T cells expressing a chimeric antigen receptor, wherein the chimeric antigen receptor specifically binds to a target antigen expressed by a B-cell malignant tumor. T cell therapy;
(B) Instructions for administering T cell therapy to a subject with a B-cell malignant tumor, an antibody capable of blocking the immune checkpoint pathway protein after administration of the T cell therapy, or an antibody thereof. Instructions specifying that a checkpoint inhibitor, which is an antigen-binding fragment, be administered, and specifying T cell therapy and / or administration of a checkpoint inhibitor by any of the methods 1001-1133 of the present invention.
Kit including.
[Invention 1136]
(A) Immune checkpoint pathway An antibody or checkpoint inhibitor that is an antigen-binding fragment thereof capable of blocking a protein, optionally formulated in the form of one or more individual doses. Checkpoint inhibitor; and
(B) Instructions for administering a checkpoint inhibitor to a subject with a B-cell malignant tumor, wherein the checkpoint inhibitor is administered after the start of administration of T cell therapy. T cell therapy comprises a dose of genetically engineered T cells expressing a chimeric antigen receptor, and the chimeric antigen receptor specifically binds to a target antigen expressed by a B cell malignant tumor. However, the instructions specify the administration of T cell therapy and / or checkpoint inhibitors by any of the methods 1001-1133 of the present invention.
Kit including.

Claims (60)

A drug for treating B-cell malignancies in a subject, including T cell therapy and checkpoint inhibitors, which is followed by T cell therapy with a checkpoint inhibitor.
(A ) The T cell therapy comprises a dose of genetically engineered T cells expressing a chimeric antigen receptor, the chimeric antigen receptor specifically binding to a target antigen expressed by a B-cell malignant tumor. And (b) the checkpoint inhibitor is an antibody or antigen-binding fragment thereof capable of blocking the immune checkpoint pathway protein, and the total dose of the checkpoint inhibitor is at least two dosing cycles, respectively. The total dose of the checkpoint inhibitor in the first of at least two dosing cycles, administered in
Is equal to or less than the total dosage given in the second and / or subsequent dosing cycle; and is given in the form of multiple individual doses during the first dosing cycle, the number of individual doses being the second. 2 and / or more than the number of individual doses administered in subsequent dosing cycles,
Medicine . A drug for treating B cell malignancies in a subject , including a checkpoint inhibitor, which is an antibody or antigen-binding fragment thereof capable of blocking an immune checkpoint pathway protein. ,
The subject is receiving T cell therapy comprising a dose of genetically engineered T cells expressing a chimeric antigen receptor that specifically binds to a target antigen expressed by a B cell malignant tumor, a checkpoint. The total dosage of the inhibitor is administered in each of at least two dosing cycles, and the total dose of the checkpoint inhibitor in the first of at least two dosing cycles is
Is equal to or less than the total dosage given in the second and / or subsequent dosing cycle; and is given in the form of multiple individual doses during the first dosing cycle, the number of individual doses being the second. 2 and / or more than the number of individual doses administered in subsequent dosing cycles,
Medicine . The pharmaceutical according to claim 1 or 2, wherein the dosing cycle is a 21-day cycle or a 28 -day cycle. The dosing cycle is a 28-day cycle, with the first individual dose of at least two 28-day cycles being four doses each weekly (Q1W), two doses as Q1W doses for two consecutive weeks, or each. The drug according to any one of claims 1 to 3, which is administered as two doses as a Q1W dose for two consecutive weeks followed by one dose once every two weeks (Q2W). 13 . Dosing . The drug according to any one of claims 1 to 5 , wherein the checkpoint inhibitor blocks an immune checkpoint pathway protein selected from PD-L1, PD-L2, PD-1 and CTLA-4. The drug according to any one of claims 1 to 6 , wherein the checkpoint pathway is PD-1 / PD-L1 and the checkpoint inhibitor is an anti-PD-1 antibody . The pharmaceutical according to claim 7 , wherein the checkpoint inhibitor is nivolumab, pembrolizumab, or cemiplimab. Each of at least two dosing cycles comprises or independently administering a total dosage of 400 mg or about 400 mg to 600 mg or about 600 mg, optionally 480 mg or about 480 mg, or each of at least two dosing cycles. The pharmaceutical according to any one of claims 1 to 8 , wherein the total dosage of 750 mg to 2000 mg, optionally 1500 mg or about 1500 mg is administered independently . The drug according to any one of claims 1 to 9, wherein the checkpoint pathway is PD-1 / PD-L1 and the checkpoint inhibitor is an anti-PD-L1 antibody or an antigen-binding fragment thereof . Treatment involves performing at least two 28-day cycles, including
(A) In the first 28-day cycle, the anti-PD-L1 antibody or antigen-binding fragment thereof was administered at 375 mg or about 375 mg, respectively, as two individual doses of the anti-PD-L1 antibody or its antigen-binding fragment once a week (Q1W) for two consecutive weeks in the 28-day cycle, respectively. The individual dose of the dose is followed by one dose of 750 mg or about 750 mg once every two weeks (Q2W) in a 28-day cycle; and
A second and / or subsequent 28-day cycle comprises administering the anti-PD-L1 antibody or antigen-binding fragment thereof in an amount of 1500 mg or approximately 1500 mg as one dose every 4 weeks (Q4W), or
(B) The first 28-day cycle comprises administering the anti-PD-L1 antibody or antigen-binding fragment thereof once a week (Q1W) for each 28-day cycle as four individual doses, the four doses. Includes two consecutive Q1W doses of 225 mg or about 225 mg independently, followed by two consecutive Q1W doses of 375 mg or about 375 mg, respectively; and
The second and / or subsequent 28-day cycle comprises administering the anti-PD-L1 antibody or antigen-binding fragment thereof as two doses, each every two weeks (Q2W) of the 28-day cycle, with each Q2W administration. , Independently in an amount of 750 mg or about 750 mg, or
(c) The first 28-day cycle comprises administering the anti-PD-L1 antibody or antigen-binding fragment thereof once a week (Q1W) as two separate doses, each of which is independent. And optionally, two doses are continuous Q1W doses, including an amount of 375 mg or about 375 mg, and optionally, two doses are administered on days 15 and 22 of the 28-day cycle; and
A second and / or subsequent 28-day cycle may administer the anti-PD-L1 antibody or antigen-binding fragment thereof in Q4W at a dose of 1500 mg or approximately 1500 mg per dose in the second and / or subsequent 28-day cycle. include,
The medicine according to claim 10. The administration of the checkpoint inhibitor and / or the beginning of the first dosing cycle,
(I) Peak or maximum levels of T cell therapy cells became detectable in the subject's blood;
(Ii) The number of T cell therapy cells detectable in the blood becomes undetectable or reduced after becoming detectable in the blood, optionally preceded by administration of T cell therapy. Reduced compared to time point;
(Iii) The number of T cell therapy cells detectable in the blood is 1.5 times the peak or maximum number of T cell therapy cells detectable in the blood of the subject after the start of T cell therapy administration, 2.0. Increased, 3.0 times, 4.0 times, 5.0 times, 10 times, or more, or more than 1.5 times, more than 2.0 times, more than 3.0 times, more than 4.0 times, more than 5.0 times, more than 10 times, or more;
(Iv) The number of cells detectable in the blood of the subject or derived from the cells after the peak or maximum level of cells of T cell therapy becomes detectable in the blood of the subject is the subject. Less than 10%, less than 5%, less than 1%, or less than 0.1% of total peripheral blood mononuclear cells (PBMC) in blood;
(V) Subjects showed disease progression after treatment with T cell therapy and / or relapsed following remission; and / or (iv) Subjects received pre- or post-administration of cells and administration of checkpoint inhibitors. 13 . Medicine . Checkpoint inhibitor administration and / or the beginning of the first dosing cycle begins 29 days, 36 days, 43 days, or 50 days, or within 29 days, 36 days, 43 days after the start of T cell therapy administration. Within, or within 50 days , optionally, the start of the checkpoint inhibitor administration and / or the first dosing cycle begins 22 to 36 days or approximately 22 days after the start of T cell therapy administration. The drug according to any one of claims 1 to 12 , which is started on the 36th . 13 . Medicine . Severe toxicity is severe cytokine release syndrome (CRS), optionally grade 3 or higher, long-term grade 3 or higher or grade 4 or 5 CRS; and / or severe toxicity is severe neurology. Toxicity, optionally grade 3 or higher, long-term grade 3 or higher or grade 4 or 5 neurotoxicity,
The medicine according to claim 14 . A drug for treating B-cell malignant tumors in a subject, including T cell therapy and an anti-PD-L1 antibody or antigen-binding fragment thereof, wherein the anti-PD-L1 antibody or antigen-binding fragment thereof follows T cell therapy. Administered
The T -cell therapy comprises a dose of genetically engineered T cells expressing the chimeric antigen receptor, which specifically binds to the target antigen expressed by the B-cell malignant tumor; and Administration of the anti-PD-L1 antibody or antigen-binding fragment comprises performing at least two 28-day cycles, each of which has a total dosage of 750 mg to 2000 mg of the antibody or antigen-binding fragment. And administration of the total dosage of the anti-PD-L1 antibody or antigen-binding fragment in at least one of the at least two 28-day cycles comprises at least one individual dose of the antibody or fragment. Performed by administration during a 28-day cycle,
Medicine . A drug for treating B cell malignancies in a subject , including an anti- PD-L1 antibody or an antigen-binding fragment thereof.
The subject has been administered T cell therapy comprising a dose of genetically engineered T cells expressing the chimeric antigen receptor, and the chimeric antigen receptor is specific for the target antigen expressed by the B cell malignant tumor. Combined
Administration of the anti-PD-L1 antibody or antigen-binding fragment comprises performing at least two 28-day cycles, each of which is independently 750 mg to 2000 mg of the antibody or antigen-binding fragment. Containing administration of the total dosage of the antibody or fragment; and in at least one of the at least two 28-day cycles, administration of the total dosage of the anti-PD-L1 antibody or antigen-binding fragment is multiple individual doses of the antibody or fragment. Is performed by administering during at least one 28-day cycle,
Medicine . In the first of at least two 28-day cycles, administration of the total dosage of anti-PD-L1 antibody or antigen-binding fragment is more than the antibody or fragment compared to administration in the second and / or subsequent 28-day cycle. The pharmaceutical according to claim 16 or 17 , which is carried out by administering a large number of individual doses. The pharmaceutical according to any one of claims 16 to 18 , wherein the total dosage of the anti-PD-L1 antibody or antigen-binding fragment in each 28-day cycle is independently between 750 mg or about 750 mg and 1500 mg or about 1500 mg. .. The drug according to any one of claims 16 to 19 , wherein the total dosage of the anti-PD-L1 antibody or antigen-binding fragment in at least one of the 28-day cycles is 750 mg or about 750 mg. Administration of the total dosage in the first of at least two 28-day cycles provides anti-PD-L1 antibody or antigen-binding fragment thereof.
(I) Two individual doses, once weekly (Q1W) each within the 28-day cycle, optionally on days 15 and 22 of the 28-day cycle;
(Ii) Weekly (Q1W) for each 28-day cycle, optionally 4 individual doses on days 1, 8, 15 and 22 of the 28-day cycle;
(Iii) Q1W for 2 consecutive weeks in a 28-day cycle, optionally following 2 individual doses on days 1 and 8 of the cycle, once every 2 weeks in a 28-day cycle (Q2W), optionally on day 15 of the cycle. 1 dose; or (iv) every 2 weeks (Q2W) for a 28-day cycle, optionally as an individual dose according to a dosing regimen selected from 2 individual doses on days 1 and 15 of the 28-day cycle. The medicine according to any one of claims 16 to 20 , including. Administration of the total dosage in the first 28-day cycle comprises administration of the anti-PD-L1 antibody or its antigen-binding fragment according to dosing regimen (iii), with each of the two individual doses for Q1W consecutive 2 weeks. Independently, each is in an amount of 375 mg or about 375 mg, followed by one dose of Q2W in an amount of 750 mg or about 750 mg;
Administration of the total dosage in the first 28-day cycle comprises administration of the anti-PD-L1 antibody or antigen-binding fragment thereof according to the dosing regimen set forth in (ii), with four individual doses of Q1W being 225 mg or Includes two consecutive Q1W doses in an amount of about 225 mg followed by two consecutive Q1W doses in an amount of 375 mg or about 375 mg; or administration of the total dose in the first 28-day cycle is the anti-PD-L1 antibody or its. For two consecutive Q1W doses, each of the two individual doses of Q1W is performed in an amount of 375 mg or about 375 mg, comprising administering the antigen-binding fragment according to the dosing regimen shown in (i).
The medicine according to claim 21 . Administration of the total dosage in the first of at least two 28-day cycles, individual doses,
(I) Two individual doses on the 15th or about 15th day and 22nd or about 22nd day of the 28-day cycle;
(Ii) 4 individual doses on 1 or about 1 day, 8 or about 8 days, 15 or about 15 days and 22 or about 22 days of the 28-day cycle;
(Iii) 1 or about 1 day of the 28-day cycle and 2 individual doses of 8 or about 8 days, followed by 1 dose of 15 or about 15 days of the cycle; or (iv) 1 of the 28-day cycle The pharmaceutical according to any one of claims 16 to 21 , comprising administering according to a dosing regimen selected from two doses of 15 or about 15 days in a cycle of about 1 day and 28 days. Administration of the total dosage in the first 28-day cycle involves administration of the anti-PD-L1 antibody or its antigen-binding fragment according to dosing regimen (iii), with each of the two individual doses being one of the 28-day cycles. Alternatively, it comprises an amount of 375 mg or about 375 mg on about 1 and 8 or about 8 days, followed by one dose of 750 mg or about 750 mg on 15 or about 15 days of the cycle;
Administration of the total dosage in the first 28-day cycle comprises administration of the anti-PD-L1 antibody or antigen-binding fragment thereof according to the dosing regimen set forth in (ii), with four individual doses of the 28-day cycle. 2 in an amount of 375 mg or about 375 mg on 15 or about 15 days and 22 or about 22 days, followed by 2 consecutive doses of 1 or about 1 and 8 or about 8 days 225 mg or about 225 mg Includes two consecutive doses; or administration of the total dosage in the first 28-day cycle comprises administration of the anti-PD-L1 antibody or antigen-binding fragment according to the dosing regimen set forth in (i), two individual doses. Each contains two consecutive doses of 375 mg or about 375 mg on 15 or about 15 days and 22 or about 22 days of a 28-day cycle.
The medicine according to any one of claims 16 to 23 . Administration of total dosage in the second and / or subsequent 28-day cycle, independently
(I) 2 individual doses every 2 weeks (Q2W) for the 2nd and / or subsequent 28-day cycle, respectively, optionally on days 1 and 15 of the 2nd and / or subsequent cycle; or (ii) 2nd Any of claims 18-24 , comprising a dosing regimen selected from one dose on day 1 of the second and / or subsequent cycle, and / or every 4 weeks (Q4W) of the subsequent 28-day cycle. The medicine described in item 1. Claim 1 to claim 1 , wherein the dosing cycle is a 28-day cycle, at least two 28-day cycles further include a third 28-day cycle, and / or a subsequent 28-day cycle is a third 28-day cycle. The drug according to any one of 25 (A) In the third 28-day cycle, administration of the total dosage of anti-PD-L1 antibody or antigen-binding fragment at a larger number of individual doses compared to the first and / or second 28-day cycle. , By administering the antibody or fragment; or (b) in the third 28-day cycle, administration of the total dosage of the anti-PD-L1 antibody or antigen-binding fragment is compared to the second 28-day cycle. And by administering the same number of doses of antibody or fragment,
The medicine according to any one of claims 26 . The first of at least two 28-day cycles begins between (i) days 22 and 36 from the start of T cell therapy, or (ii) after the start of T cell therapy. The drug according to any one of claims 16 to 27 , which is started on the 29th day or about 29th day or 43rd day or about 43rd day . The drug according to any one of claims 10 to 28 , wherein the anti-PD-L1 antibody or antigen-binding fragment is administered for a total duration of 12 months or less. Administration of anti-PD-L1 antibody or antigen-binding fragment and / or the beginning of the first 28-day cycle is 29 days, 36 days, 43 days or 50 days, or within 29 days, 36 after the start of administration of T cell therapy. The drug according to any one of claims 10 to 29 , which is started within days, 43 days or 50 days. Administration of the anti-PD-L1 antibody or antigen-binding fragment and / or the beginning of the first 28-day cycle begins 22-36 days or approximately 22-36 days after the start of (i) administration of T cell therapy. Or (ii) the drug according to any one of claims 10 to 30 , which is started 29 days or about 29 days or 43 days or about 43 days after the start of T cell therapy administration . Claims 10-31 , claim 10-31 , in which the subject did not show significant toxicity following administration of T cell therapy at the beginning of the first 28-day cycle and / or administration of the anti-PD-L1 antibody or antigen binding fragment. The drug according to any one of the above. Serious toxicity is severe cytokine release syndrome (CRS), optionally grade 3 or higher, long-term grade 3 or higher or grade 4 or 5 CRS; and / or severe toxicity is severe neurological Toxicity, optionally grade 3 or higher, long-term grade 3 or higher or grade 4 or 5 neurotoxicity,
The medicine according to claim 32 . The drug according to any one of claims 10 to 33 , wherein the anti-PD-L1 antibody or an antigen-binding fragment thereof specifically binds to the extracellular domain of PD-L1. The anti-PD-L1 antibody or antigen-binding fragment thereof is MEDI4736 (durvalumab), MDPL3280A (atezolizumab), YW243.55.S70, MDX-1105 (BMS-936559), LY3300054, or MSB0010718C (avelumab), or said above. The drug according to any one of claims 10 to 34 , which is or contains any of the antigen-binding fragments or regions thereof. The drug according to any one of claims 1 to 35 , wherein the B cell malignant tumor is non-Hodgkin's lymphoma (NHL). At or shortly before administration of T-cell therapy, the subject is treated with one or more prior therapies to NHL, optionally with one or two prior therapies other than another dose of cells expressing CAR. Whether the patient has relapsed following subsequent remissions or has become refractory to prior therapy and, optionally, one or more prior therapies are CD20-targeting agents or anthracyclines. 30. The pharmaceutical agent according to claim 36 , which comprises it. NHL, invasive NHL, diffuse large B-cell lymphoma (DLBCL), DLBCL-NOS, optionally transformed indolent; EBV-positive DLBCL-NOS; T-cell / tissue-rich large-cell B-cell lymphoma; Primary mediasular large B-cell lymphoma (PMBCL); follicular lymphoma (FL), optionally follicular lymphoma grade 3B (FL3B); and / or having a rearrangement of MYC with BCL2 and / or BCL6, The pharmaceutical according to claim 36 or 37 , comprising high-grade B-cell lymphoma (double / triple hit) with DLBCL histology. The pharmaceutical according to any one of claims 1-38 , wherein the subject is identified or identified as having a status of Eastern Cooperative Oncology Group Performance Status (ECOG) less than or equal to 1. .. The drug according to any one of claims 1 to 39 , wherein the target antigen is a B cell antigen. The drug according to any one of claims 1 to 40 , wherein the target antigen is CD19. An intracellular signaling domain, optionally including an extracellular antigen recognition domain to which a chimeric antigen receptor (CAR) specifically binds to a target antigen, and an intracellular signaling domain including ITAM, is a CD3-zeta (CD3-Zeta). CD3ζ) The pharmaceutical according to claim 41 , which comprises a signaling domain of a chain . The chimeric antigen receptor (CAR) further comprises a co-stimulation signaling region containing the cytoplasmic signaling domain of the co-stimulating molecule, optionally the co-stimulating signaling region comprises the cytoplasmic signaling domain of CD28 or 4-1BB. , The pharmaceutical according to claim 42 . CAR,
CD19-specific scFv and
With the transmembrane domain,
Cytoplasmic signaling domains derived from costimulatory molecules, optionally with or containing 4-1BB signaling domains,
Includes and optionally contains a cytoplasmic signaling domain derived from a major signaling ITAM-containing molecule, which is or comprises the CD3 zeta signaling domain.
Optionally further include a spacer between the transmembrane domain and scFv,
The medicine according to any one of claims 1-43 . CAR, in order
CD19-specific scFv and
With the transmembrane domain,
A cytoplasmic signaling domain derived from a co-stimulatory molecule, optionally a 4-1BB signaling domain or containing it,
Includes, or optionally contains, a cytoplasmic signaling domain derived from a major signaling ITAM-containing molecule, which is a CD3 zeta signaling domain, or
CAR, in order
CD19-specific scFv and
With spacers,
With the transmembrane domain,
A cytoplasmic signaling domain derived from a co-stimulating molecule, which is optionally a 4-1BB signaling domain,
Optionally with a cytoplasmic signaling domain derived from a major signaling ITAM-containing molecule that is or contains the CD3 zeta signaling domain.
including,
The medicine according to any one of claims 1-43 . The extracellular antigen recognition domain is scFv, where scFv is the CDRL1 sequence of RASQDISKYLN (SEQ ID NO: 35), the CDRL2 sequence of SRLHSGV (SEQ ID NO: 36), and / or the CDRL3 of GNTLPYTFG (SEQ ID NO: 37). 45 . The drug described in any one of the above. The extracellular antigen recognition domain is scFv, and scFv contains a V _H region containing the amino acid sequence shown in SEQ ID NO: 41 and / or a V _L region containing the amino acid sequence shown in SEQ ID NO: 42 . The pharmaceutical agent according to any one of claims 42 to 46 , including . The drug according to any one of claims 42 to 47 , wherein the extracellular antigen recognition domain is scFv, and scFv comprises the amino acid sequence shown in SEQ ID NO: 43. The doses of genetically engineered T cells are 1 x 10 ^5-5 x 10 ⁸ total CAR-expressing T cells, 1 x 10 ^6-2.5 x 10 ⁸ total CAR-expressing T cells, 5 x 10 ^6-1 × 10 ⁸ total CAR-expressing T cells, 1 × 10 ⁷ to 2.5 × 10 ⁸ total CAR-expressing T cells, 5 × 10 ⁷ to 1 × 10 ⁸ total CAR-expressing T cells, or approximately 1 × 10 ⁵ to 5 x 10 ⁸ total CAR-expressing T cells, about 1 x 10 ⁶ to 2.5 x 10 ⁸ total CAR-expressing T cells, about 5 x 10 ⁶ to 1 x 10 ⁸ total CAR-expressing T cells, Approximately 1 × 10 ⁷ to 2.5 × 10 ⁸ total CAR-expressing T cells, approximately 5 × 10 ⁷ to 1 × 10 ⁸ total CAR-expressing T cells (including values at both ends), optionally genes The dose of engineered T cells is 5 × 10 ⁷ or about 5 × 10 ⁷ CAR-expressing T cells, 1 × 10 ⁸ or about 1 × 10 ⁸ CAR-expressing T cells, or 1.5 × 10 ⁸ The pharmaceutical according to any one of claims 1 to 48 , which comprises cells or about 1.5 × 10 ⁸ CAR-expressing cells . The drug according to any one of claims 1 to 49 , wherein the T cell is a primary T cell obtained from a subject. The drug according to any one of claims 1 to 50 , wherein the T cells are self-derived with respect to the subject. The drug according to any one of claims 1 to 50 , wherein the T cells are allogeneic to the subject. The dose of genetically engineered T cells comprises CD4 + T cells expressing CAR and CD8 + T cells expressing CAR, and administration of the dose comprises administering multiple separate compositions. The plurality of separate compositions include a first composition comprising one of CD4 + T cells and CD8 + T cells and a second composition comprising the other of CD4 + T cells or CD8 + T cells. The drug according to any one of ~ 52 . The pharmaceutical according to any one of claims 1 to 53 , wherein the subject is preconditioned with lymphocyte depletion therapy including administration of fludarabine and / or cyclophosphamide prior to administration. The pharmaceutical according to any one of claims 1 to 54 , further comprising the step of administering to the subject a lymphocyte depletion therapy comprising administration of fludarabine and / or cyclophosphamide immediately before administration. Lymphocyte depletion therapy is about 200 mg / m ² to 400 mg / m ² , optionally 300 mg / m ² or about 300 mg / m ² of cyclophosphamide (including its value), and / or about 20 mg / m ² to Includes daily administration of 40 mg / m ² , optionally 30 mg / m ² of fludalabine for 2-4 days, optionally for 3 days, or lymphocyte depletion therapy with approximately 500 mg / m ² of cyclophosphamide. include,
The medicine according to claim 54 or 55 . The drug according to any one of claims 1 to 56 , wherein the subject is a human. (A) A T cell therapy comprising a dose of genetically engineered T cells expressing a chimeric antigen receptor, wherein the chimeric antigen receptor specifically binds to a target antigen expressed by a B-cell malignant tumor. T cell therapy;
(B) Immune checkpoint pathway An antibody or checkpoint inhibitor that is an antigen-binding fragment thereof capable of blocking a protein, optionally formulated in one or more individual doses. Checkpoint Inhibitors; and (c) Instructions for administering T cell therapy and / or checkpoint inhibitors to subjects with B-cell malignant tumors, according to any one of claims 1-57 . A kit containing instructions that specifies the administration of T cell therapy and / or checkpoint inhibitors by drug . (A) T cell therapy comprising a dose of genetically engineered T cells expressing a chimeric antigen receptor, in which the chimeric antigen receptor specifically binds to a target antigen expressed by a B-cell malignant tumor. T cell therapy; and (b) instructions for administering T cell therapy to subjects with B-cell malignant tumors, in which the subject blocks immune checkpoint pathway proteins after administration of T cell therapy. A T cell therapy and / or a checkpoint inhibitor according to any one of claims 1 to 57 , which specifies that a checkpoint inhibitor, which is an antibody or an antigen-binding fragment thereof , can be administered. A kit containing instructions to specify administration. (A) Immune checkpoint pathway An antibody or checkpoint inhibitor that is an antigen-binding fragment thereof capable of blocking a protein, optionally formulated in one or more individual doses. Checkpoint Inhibitors; and (b) Instructions for Administering Checkpoint Inhibitors to Subjects with B-Cell Malignant Tumors, wherein the Checkpoint Inhibitors Administer T Cell Therapy. Specifying to be administered after initiation, T cell therapy comprises a dose of genetically engineered T cells expressing a chimeric antigen receptor, and the chimeric antigen receptor is a target expressed by a B-cell malignant tumor. A kit comprising instructions that specifically binds to an antigen and the instructions specify administration of T cell therapy and / or checkpoint inhibitors by the pharmaceutical according to any one of claims 1-57 .