T CELLS MODIFIED FOR USE IN THE TREATMENT OF B CELL NEOPLASMS BY ADOPTIVE CELL THERAPY.

Abstract

The present invention relates to a first composition comprising one of CD4+ T cells and CD8+ T cells for use with a second composition comprising the other of CD4+ T cells and CD8+ T cells in a method for treating a subject having chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), wherein the method comprises administering to the subject a dose of modified T cells comprising CD4+ and CD8+ T cells comprising a chimeric antigen receptor (CAR) that binds specifically to CD19, wherein: (i) the subject has relapsed following remission after treatment with, has become refractory to or has failed treatment with and / or has been intolerant to ibrutinib and venetoclax;(ii) administration comprises administering a plurality of separate compositions, wherein the plurality of separate compositions comprises the first composition comprising one of the CD4+ T cells and CD8+ T cells and the second composition comprising the other of the CD4+ T cells and CD8+ T cells, and (iii) the modified T cell dose comprises a defined ratio of CAR-expressing CD4+ cells to CAR-expressing CD8+ cells, optionally wherein the ratio is between approximately 1:3 and approximately 3:1;

Claims

1. A method for treating a subject having chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), wherein the method comprises administering to the subject a dose of modified T cells comprising CD4+ and CD8+ T cells, CD44· and CD8+ T cells comprising a chimeric antigen receptor (CAR) specifically binding to CD19, wherein the modified T cell dose (i) is enriched for primary human CD4+ and CD8+ T cells; (ii) comprises a defined ratio of CAR-expressing CD4+ cells to CAR-expressing CD8+ cells, optionally wherein the ratio is between approximately 1:3 and approximately 3:1, and (ii) comprises either approximately 2.5 x 10⁷ total CAR-expressing cells to either approximately 1.5 x 10⁸ total CAR-expressing cells.

2. A method for treating a subject having chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), wherein the method comprises administering to the subject a dose of modified T cells comprising CD4+ and CD8+ T cells, CD4+ and CD8+ T cells comprising a chimeric antigen receptor (CAR) specifically binding to CD19, wherein the subject has relapsed after remission following treatment with, has become refractory to failed treatment with and / or is intolerant to a Bruton's tyrosine kinase inhibitor (BTKi) and venetoclax.

3. The method of claim 2, wherein BTKi is ibrutinib.

4. A method for treating a subject having chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), wherein the method comprises administering to the subject a dose of modified T cells comprising CD4+ and CD8+ T cells, CD4+ and CD8+ T cells comprising a chimeric antigen receptor (CAR) specifically binding to CD19, wherein the subject has relapsed after remission following treatment with, has become refractory to failed treatment with and / or is intolerant to ibrutinib and venetoclax.

5. The method of any of claims 2-4, wherein the modified T cell dose is enriched for primary human CD4+ and CD8+ T cells.

6. The method of any of claims 2-5, wherein the modified T cell dose comprises a defined ratio of CAR-expressing CD4+ cells to CAR-expressing CD8+ cells, optionally wherein the ratio is between approximately 1:3 and approximately 3:

1.

7. The method of any of claims 1-6, wherein the administration comprises administering a plurality of separate compositions, wherein the plurality of separate compositions comprises a first composition comprising one of the CD4+ T cells and the CD8+ T cells and a second composition comprising the other of the CD4+ T cells and the CD8+ T cells.

8. A method for treating a subject who has or is suspected of having chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), wherein the method comprises administering to the subject a dose of modified T cells comprising CD4+ and CD8+ T cells, the CD4+ and CD8+ T cells comprising a CAR specifically binding to CD19, wherein the administration comprises administering a plurality of separate compositions, wherein the plurality of separate compositions comprises a first composition comprising one of the CD4+ T cells RQR / Cn / L7ñ7 / 3 / YILI 191 and CD8+ T cells and a second composition comprising the other of the CD4+ T cells and the CD8+ T cells.

9. The method of any of claims 1-8, wherein the modified T cell dose comprises a defined ratio of CAR-expressing CD4+ cells to CAR-expressing CD8+ cells is between approximately 1:3 and approximately 3:

1.

10. The method of any of claims 2-9, wherein the modified T cell dose comprises from or approximately 2.5 x 107 total cells expressing CAR to from or approximately 1.5 x 108 total cells expressing CAR.

11. The method of any of claims 8-10, wherein the modified T cell dose is enriched for primary human CD4+ and CD8+ T cells.

12. The method of any of claims 1-11, wherein the modified T cell dose enriched in primary human CD4+ and CD8+ T cells comprises more than or more than approximately 70%, more than or more than approximately 75%, more than or more than approximately 80%, more than or more than approximately 85%, more than or more than approximately 90%, more than or more than approximately 95% or more than or more than or more than approximately 98% of primary human CD4+ and CD8+ T cells.

13. The method of any of claims 1-12, wherein the modified T cell dose comprises a defined ratio of CAR-expressing CD4+ cells to CAR-expressing CD8+ cells that is or is approximately 1:

1.

14. The method of any of claims 1-13, wherein the modified T cell dose comprises from or approximately 2.5 x 10⁷ total cells expressing CAR to from or approximately 1.0 x 10⁸ total cells expressing CAR.

15. The method of any of claims 1-14, wherein the modified T cell dose comprises or approximately 2.5 × 10⁷ total CAR-expressing cells.

16. The method of any of claims 1-14, wherein the modified T cell dose comprises either approximately 5 x 107 total cells or total cells expressing CAR.

17. The method of any of claims 1-14, wherein the modified T cell dose comprises either approximately 1 x 108 total cells or total cells expressing CAR.

18. The method of any of claims 1-17, wherein the CAR comprising CD4+ T cells or the CAR comprising CD8+ T cells comprises a CAR that is the same and / or wherein the CD4+ T cells or the CD8+ T cells are genetically modified to express a CAR that is the same.

19. The method of any of claims 7-18, wherein the first composition comprises CD8+ T cells and the second composition comprises CD4+ T cells.

20. The method of claim 19, wherein the start of the administration of the first composition is carried out before the start of the administration of the second composition.

21. The method of any of claims 7-20, wherein the administration of the first composition RPR I Cn / L7ñ7 / 3 / YILI 192 and the administration of the second composition are carried out no more than 48 hours apart.

22. The method of any of claims 7-21, wherein the administration of the first composition and the administration of the second composition are carried out no more than 36 hours apart, no more than 24 hours apart, no more than 12 hours apart, no more than 6 hours apart, no more than 4 hours apart, no more than 2 hours apart, no more than 1 hour apart, or no more than 30 minutes apart.

23. The method of any of claims 7-22, wherein: the administration of the first composition and the administration of the second composition are carried out on the same day, are carried out between approximately 0 and approximately 12 hours apart, between approximately 0 and approximately 6 hours apart, or between approximately 0 and approximately 2 hours apart; or the start of the administration of the first composition and the start of the administration of the second composition are carried out between approximately 1 minute and approximately 1 hour apart, or between approximately 5 minutes and approximately 30 minutes apart.

24. The method of any of claims 7-23, wherein the first composition and the second composition are administered no more than 2 hours, no more than 1 hour, no more than 30 minutes, no more than 15 minutes, no more than 10 minutes, or no more than 5 minutes apart.

25. The method of any of claims 1-24, wherein: the subject has CLL or is suspected of having CLL; or the subject is identified or selected as having CLL.

26. The method of any of claims 1-25, wherein the CLL is a relapsed or refractory CLL.

27. The method of any of claims 1-26, wherein: the subject has SLL or is suspected of having SLL; or the subject is identified or selected as having SLL.

28. The method of any of claims 1-24 and 27, wherein the SLL is a relapsed or refractory SLL.

29. The method of claims 1-28, wherein, prior to the administration of the modified T-cell dose, the subject has been treated with one or more prior therapies for CLL or SLL, other than another CAR-expressing cell dose or a lymphopenia-producing therapy.

30. The method of claim 29, wherein the one or more prior therapies comprise at least two prior therapies, optionally 3, 4, 5, 6, 7, 8, 9 or more prior therapies.

31. The method of any of claims 1-30, wherein, at or immediately prior to the time of administration of the modified T-cell dose, the subject has relapsed after remission following treatment with, or has become refractory to, has failed and / or was intolerant to treatment with one or more of the above therapies for CLL or SLL.

32. The method of any of claims 1-31, wherein, at or immediately prior to the time of administration of the modified T-cell dose, the subject has relapsed after remission following treatment with, or has become refractory to, has failed and / or was intolerant to, treatment with two or more prior therapies.

33. The method of any of claims 1-32, wherein, at or immediately prior to the time of administration of the modified T-cell dose, the subject has relapsed after remission following treatment with, or has become refractory to, has failed and / or was intolerant to treatment with three or more prior therapies.

34. The method of any of claims 1-33, wherein one or more of the above therapies are selected from a kinase inhibitor, optionally a Bruton's tyrosine kinase (BTK) inhibitor, optionally ibrutinib; venetoclax; a combination therapy comprising fludarabine and rituximab; radiation therapy; and hematopoietic stem cell transplantation (HSCT).

35. The method of any of claims 1-35, wherein one or more of the above therapies comprise a Bruton's tyrosine kinase (BTK) inhibitor and / or venetoclax.

36. The method of any of claims 1-35, wherein one or more of the above therapies comprise ibrutinib and / or venetoclax.

37. The method of any of claims 1-36, wherein one or more of the above therapies comprise ibrutinib and venetoclax.

38. The method of any of claims 1-37, wherein the subject has relapsed after remission following treatment with, has become refractory to failed treatment with and / or is intolerant to a Bruton's tyrosine kinase (BTK) inhibitor and / or venetoclax.

39. The method of any of claims 1-38, wherein the subject has relapsed after remission following treatment with, has become refractory to treatment with, has failed treatment with and / or is intolerant to ibrutinib and venetoclax.

40. The method of any of claims 1-39, wherein at or prior to administration of the cell dose: the subject is or has been identified as having one or more cytogenetic abnormalities, optionally associated with high-risk CLL or SLL, optionally selected from: complex karyotype or cytogenetic abnormalities, 17p, unmutated IGVH gene, and TP53 mutation; and / or the subject is or has been identified as having high-risk CLL or SLL.

41. The method of any of claims 1-40, wherein at or prior to administration of the cell dose: the subject is or has been identified as having one or more cytogenetic abnormalities, optionally associated with high-risk CLL, optionally selected from: complex karyotype or cytogenetic abnormalities, 17p, unmutated IGVH gene, and TP53 mutation; and / or the subject is or has been identified as having high-risk CLL.

42. The method of claim 41, at or immediately before the time of administration of the cell dose, the subject has relapsed after remission following treatment with, or has become refractory to, has failed and / or was intolerant to treatment with two or more previous therapies.

43. The method of any of claims 1-40, wherein at or prior to the administration of the cell dose, the subject is or has been identified as having a standard risk CLL or SLL.

44. The method of claim 43, at or immediately before the time of administration of the cell dose, the subject has relapsed after remission following treatment with, or has become refractory to, has failed and / or was intolerant to treatment with three or more previous therapies.

45. The method of any of claims 1-44, wherein at or prior to administration of the cell dose, the subject is or has been identified as being intolerant to a Bruton's tyrosine kinase (BTK) inhibitor and has received a BTK inhibitor for a duration of less than or approximately 6 months, and / or is not eligible for treatment with a BTK inhibitor.

46. ​​The method of claim 45, wherein: (i) the subject is or has been identified as having high-risk CLL or SLL, and on or immediately prior to the time of cell dose administration, the subject has relapsed after remission following treatment with, or has become refractory to, has failed and / or was intolerant of treatment with one or more prior therapies other than the BTK inhibitor; or (ii) the subject is or has been identified as having standard-risk CLL or SLL, and on or immediately prior to the time of cell dose administration, the subject has relapsed after remission following treatment with, or has become refractory to, has failed and / or was intolerant of treatment with two or more prior therapies other than the BTK inhibitor.

47. The method of any of claims 1-46, wherein: the subject is or has been identified as having an ECOG state of 0 or 1; and / or the subject does not have an ECOG state of >1.

48. The method of any of claims 1-47, wherein at or immediately prior to the administration of the modified cell dose or lymphopenia-producing therapy, the subject does not have a Richter transformation of the CLL or SLL.

49. The method of any of claims 1-48, wherein the subject is an adult and / or is over or approximately 50, 60, or 70 years of age.

50. The method of any of claims 1-49, wherein the modified T cells are primary T cells obtained from a subject.

51. The method of any of claims 1-50, wherein the modified T cells are autologous to the subject.

52. The method of any of claims 1-51, wherein the modified cell dose consists of viable cells.

53. The method of any of claims 1-52, further comprising, prior to the administration of the modified T-cell dose, administering a lymphopenia-producing therapy to the subject.

54. The method of any of claims 1-53, wherein the method further comprises the subject being preconditioned with lymphopenia-producing therapy.

55. The method of claim 53 or claim 54, wherein the lymphopenia-producing therapy comprises the administration of fludarabine and / or cyclophosphamide.

56. The method of any of claims 53-55, wherein the lymphopenia-producing therapy comprises the administration of cyclophosphamide at approximately 200-400 mg / m2, optionally or approximately 300 mg / m2, inclusive, and / or fludarabine at approximately 20-40 mg / m2, optionally 30 mg / m2, daily for 24 days, optionally for 3 days.

57. The method of any of claims 53-56, wherein the lymphopenia-producing therapy comprises the administration of cyclophosphamide at approximately 300 mg / m2 and fludarabine at approximately 30 mg / m2 daily for 3 days, optionally, wherein the cell dose is administered at least or approximately 2-7 days after the lymphopenia-producing therapy or at least or approximately 2-7 days after the initiation of the lymphopenia-producing therapy.

58. The method of any of claims 1-57, wherein the administration of the modified T-cell dose and / or the lymphopenia-producing therapy is carried out by outpatient administration.

59. The method of any of claims 1-58, wherein the modified T-cell dose is administered parenterally, optionally intravenously.

60. The method of any of claims 1-59, wherein, from a plurality of subjects treated according to the method, the response in at least 50%, at least 60%, at least 60%, at least 70%, at least 80%, at least 90% of the treated subjects is an objective response rate.

61. The method of any of claims 1-60, wherein, out of a plurality of subjects treated according to the method, the response in at least 35%, at least 40%, at least 50%, at least 60% or at least 70% of the treated subjects is complete remission (CR).

62. The method of claim 60 or claim 61, wherein the duration of the response until progression is lasting for more than 3 months or more than 6 months.

63. The method of any of claims 1-62, wherein, of a plurality of subjects treated according to the method, more than 50%, more than 60%, or more than 70% had undetectable minimal residual disease (MRD) for at least one month, at least two months, at least three months, or at least six months after administering the modified T-cell dose.

64. The method of any of claims 1-63, wherein, from a plurality of subjects treated according to the method, no more than 10% of the subjects exhibit a cytokine release syndrome (CRS) higher than grade 2.

65. The method of any of claims 1-64, wherein, from a plurality of subjects treated with RCR ! in / LZñZ / q / YILI 196 in accordance with the method, no more than 10%, no more than 20%, no more than 30% or no more than 40% of the subjects exhibit neurotoxicity higher than grade 2.

66. The method of any of claims 60-64, wherein the plurality of subjects treated according to the method comprises a plurality of subjects who have relapsed after remission following treatment with, have become refractory to, have failed treatment with and / or are intolerant to ibrutinib and venetoclax.

67. A treatment method, comprising: evaluating a biological sample for the level, quantity, or concentration of TNF-alpha, wherein the biological sample is from a subject who is a candidate for treatment, optionally with cell therapy, the cell therapy comprising a dose of modified cells comprising CAR-expressing T cells to treat a disease or condition, wherein the biological sample is obtained from the subject prior to administration of the cell therapy and / or the biological sample does not comprise the CAR and / or the modified cells; and comparing the level, quantity, or concentration of TNF-alpha to a threshold level, wherein: (1) if the level, quantity, or concentration of TNF-alpha is at or above a threshold level, identifying the subject as being at risk of developing Grade 3 or higher neurotoxicity following administration of the cell therapy;and (2) if the level, amount or concentration of TNF-alpha is below the threshold level, identify the subject as not at risk of developing grade 3 or higher neurotoxicity after administration of cell therapy.; 68. The method of claim 67, wherein if the subject is identified as being at risk of developing grade 3 or higher neurotoxicity, the method further comprises: (i) administering the cell therapy to the subject, optionally at a reduced dose, optionally wherein (a) the method further comprises administering to the subject an agent or other treatment capable of treating, preventing, delaying, reducing, or attenuating the development or risk of developing neurotoxicity; and / or (b) the administration of the cell therapy to the subject is carried out or is specified to be carried out in a hospital setting and / or with hospital admission for one or more days; or (i) administering to the subject an alternative treatment other than cell therapy to treat the disease or condition.

69. The method of claim 67, wherein if the subject is identified as not at risk of developing grade 3 or higher neurotoxicity after administration of cell therapy: (i) the subject is not administered an agent or other treatment capable of treating, preventing, delaying, reducing or attenuating the development or risk of development of toxicity except or until the subjects exhibit a sign or symptom of toxicity, optionally at or after the subject exhibits a sustained fever or a fever that is or has not been reduced by more than 1°C after treatment with an antipyretic;and / or (i) administration and any follow-up is carried out on an outpatient basis and / or without admitting the subject to a hospital and / or without an overnight stay in a hospital and / or without requiring admission or an overnight stay in a hospital, optionally unless or until the subject exhibits a sustained fever or a fever that is or RQR I Cn / L7ñ7 / 3 / YILI 197 has not been reduced or has not been reduced by more than 1°C following treatment with an antipyretic.; 70. The method of any of claims 67-69, wherein the evaluation comprises: (a) contacting a biological sample with one or more reagents capable of detecting or specific for TNF-alpha, optionally wherein the one or more reagents comprise an antibody that specifically recognizes TNF-alpha; and (b) detecting the presence or absence of a complex comprising the one or more reagents and TNF-alpha.

71. A treatment method, wherein the method comprises administering to a subject a cell therapy to treat a disease or condition, the cell therapy comprising a dose of modified cells comprising CAR-expressing T cells, wherein: (1) if the subject has a level, amount, or concentration of TNF-alpha in a biological sample from the subject that is at or above a threshold level, the subject is identified as being at risk of developing grade 3 or higher neurotoxicity following administration of the cell therapy: (i) administering the cell therapy to the subject at a reduced dose, (ii) further administering to the subject an agent or other treatment capable of treating, preventing, delaying, reducing, or attenuating the development or risk of developing a toxicity;and / or (iii) the administration of cell therapy to the subject is carried out or is specified to be carried out in a hospital setting and / or with hospital admission for one or more days; or (2) if the subject is selected or identified as having a level, amount, or concentration of TNF-alpha in a biological sample from the subject that is below a threshold level, the subject is identified as not at risk of developing grade 3 or higher neurotoxicity following administration of cell therapy: (i) do not administer to the subject an agent or other treatment capable of treating, preventing, delaying, reducing, or attenuating the development or risk of developing toxicity except or until the subjects exhibit a sign or symptom of toxicity, optionally on or after the subject exhibits a sustained fever or a fever that is or has not been reduced by more than 1°C following treatment with an antipyretic;and / or (i) the administration and any follow-up is carried out on an outpatient basis and / or without admitting the subject to a hospital and / or without an overnight stay in a hospital and / or without requiring admission to or an overnight stay in a hospital, optionally except that or until the subject exhibits a sustained fever or a fever that is or has not been reduced or has not been reduced by more than 1°C after treatment with an antipyretic, where the subject is a candidate for treatment with cell therapy, the biological sample obtained from the subject prior to administering the cell therapy and / or the biological sample does not comprise the CAR and / or the modified cells.; 72. The method of any of claims 68, 70, and 71, wherein if the subject is identified as being at risk of developing grade 3 or higher neurotoxicity following administration of cell therapy, administer the agent or other treatment capable of treating, preventing, delaying, reducing, or attenuating the development or risk of developing such toxicity, wherein the agent is administered to the subject concurrently with cell therapy or within three days of the administration of cell therapy to the subject. RQR / Cn / L7ñ7 / 3 / YILI 198 73. The method of any of claims 67-72, wherein: the threshold level is within 25%, within 20%, within 15%, within 10% or within 5% and / or is within one standard deviation above the median or mean level, amount or concentration, or is at or approximately at the median or mean level, amount or concentration, of TNF-alpha in a biological sample obtained from a group of subjects prior to receiving cell therapy, wherein each of the subjects in the group did not exhibit any degree of neurotoxicity, following administration of a dose of modified cells expressing CAR to treat the same disease or condition; the threshold level is at or greater than 1.25 times higher than the median or mean level, amount or concentration, of TNF-alpha in a biological sample obtained from a group of subjects prior to receiving cell therapy, wherein each of the subjects in the group did not exhibit any degree of neurotoxicity, after administration of a dose of modified cells expressing CAR to treat the same disease or condition; the threshold level is at or greater than 1.25 times higher than the level, amount or concentration, of TNF-alpha in a biological sample obtained from a group of normal or healthy subjects who are not candidates for treatment with cell therapy.

74. A treatment method, wherein the method comprises: (a) evaluating a biological sample from a subject for the level, quantity, or concentration of IL-16, the subject having received administration of a cell therapy comprising a dose of modified cells comprising CAR-expressing T cells to treat a disease or condition, wherein the biological sample is obtained from the subject within one, two, or three days after the start of administration of the cell therapy; and (b) comparing the level, quantity, or concentration of IL-16 to a threshold level, wherein: (1) if the level, quantity, or concentration of IL-16 is at or above a threshold level, identifying the subject as being at risk of developing grade 3 or higher neurotoxicity; and (2) if the level, quantity, or concentration of IL-16 is below the threshold level, identifying the subject as not being at risk of developing grade 3 or higher neurotoxicity.

75. The method of claim 74, wherein if the subject is identified as being at risk of developing grade 3 or higher neurotoxicity, administer an agent or other treatment capable of treating, preventing, delaying, reducing or mitigating the development or risk of developing toxicity.

76. The method of claim 74 or claim 75, wherein the evaluation comprises: (a) contacting a biological sample with one or more reagents capable of detecting or specific for IL-16, optionally wherein the one or more reagents comprise an antibody that specifically recognizes IL-16; and (b) detecting the presence or absence of a complex comprising the one or more reagents and IL-16.

77. The method of any of claims 74-76, further comprising, prior to evaluation, administering cell therapy to the subject.

78. A treatment method, wherein the method comprises administering to a subject, identified as being at risk of developing grade 3 or higher neurotoxicity, an agent or other treatment capable of treating, preventing, delaying, reducing, or attenuating the development or risk of developing toxicity, the subject having previously received administration of cell therapy to treat a disease or condition, wherein, on or immediately prior to the administration of the agent, the subject is selected or identified as being at risk of developing grade 3 or higher neurotoxicity if the level or quantity or concentration of IL-16 in a biological sample, obtained from the subject within one, two, or three days of the start of administration of cell therapy, is above a threshold level.

79. The method of any of claims 75-78, wherein the administration of the agent is carried out at a time when the subject exhibits a sustained fever or a fever that is or has not been reduced or has not been reduced by more than 1°C after treatment with an antipyretic.

80. The method of any of claims 75-79, wherein the administration of the cell therapy to the subject was carried out on an outpatient basis and, if the level, quantity or concentration of IL-16 is above a threshold level, the method comprises admitting the patient to the hospital for one or more days.

81. The method of any of claims 74-80, wherein the threshold level is within 25% and / or is within one standard deviation above the median or mean level, amount, or concentration, or is or approximately the median or mean level, amount, or concentration, of IL-16 in a biological sample obtained from a group of subjects within one, two, or three days after receiving cell therapy comprising the administration of a dose of modified cells expressing CAR to treat the same disease or condition, wherein each of the subjects in the group did not exhibit any degree of neurotoxicity after administration of the cell therapy.

82. The method of any of claims 74-80, wherein the threshold level is at or greater than 1.3 times higher than the median or mean level, amount, or concentration of IL-16 in a biological sample obtained from a group of subjects prior to receiving cell therapy, wherein each of the subjects in the group did not exhibit any degree of neurotoxicity after administration of a dose of modified cells expressing CAR to treat the same disease or condition.

83. The method of any of claims 74-80, wherein the threshold level is at or greater than 1.3 times higher than the level, amount, or concentration of IL-16 in a biological sample obtained from a group of normal or healthy subjects who are not candidates for cell therapy treatment.

84. The method of any of claims 67-83, wherein the biological sample is or is obtained from a blood, plasma, or serum sample.

85. The method of any of claims 67-84, wherein the evaluation comprises an immunoassay.

86. The method of any of claims 67-85, wherein the disease or condition is a cancer.

87. The method of any of claims 67-86, wherein the disease or condition is a myeloma, leukemia, or lymphoma.

88. The method of any of claims 67-87, wherein the biological sample comprises an ROR antigen! en / L7ñ7 / 3 / YILI 200 which is ROR1, B cell maturation antigen (BCMA), carbonic anhydrase 9 (CAIX), tEGFR, Her2 / neu (erbB2 tyrosine kinase receptor), L1-CAM, CD19, CD20, CD22, mesothelin, CEA, and hepatitis B surface antigen, anti-folate receptor, CD23, CD24, CD30, CD33, CD38, CD44, EGFR, epithelial glycoprotein 2 (EPG-2), epithelial glycoprotein 40 (EPG-40), EPHa2, erb-B2, erb-B3, erb-B4, erbB dimers, EGFR VIII, folate-binding protein (FBP), FCRL5, FCRH5, fetal acetylcholine receptor, GD2, GD3, HMW-MAA, IL-22R-alpha, IL-13R-alpha2, kinase insertion domain receptor (kdr), kappa light chain, Lewis Y, L1 cell adhesion molecule (L1-CAM), melanoma-associated antigen (MAGE)-A1, MAGE-A3, MAGE-A6, preferentially expressed melanoma antigen (PRAME), survivin, TAG72, B7H6, IL-13 alpha 2 receptor (IL-13Ra2), CA9, GD3,HMW-MAA, CD171, G250 / CAIX, HLA-AI MAGE A1, HLA-A2 NY-ESO1, PSCA, folate receptor-α, CD44v6, CD44v7 / 8, avb6 integrin, 8H9, NCAM, VEGF receptors, 5T4, fetal AChR, NKG2D ligands, CD44v6, dual antigen, cancer-testis antigen, mesothelin, murine CMV, mucin 1 (MUC1), MUC16, PSCA, NKG2D, NY-ESO-1, MART-1, gp100, oncofetal antigen, ROR1, TAG72, VEGF-R2, carcinoembryonic antigen (CEA), Her2 / neu, estrogen receptor, progesterone receptor, ephrin B2, CD123, c-Met, GD-2, GD2 O-acetylated (OGD2), CE7, Wilms tumor 1 (WT-1), a cyclin, cyclin A2, CCL-1, CD138, G protein-coupled receptor 5D (GPCR5D), or a pathogen-specific antigen.

89. The method of any of claims 67-88, wherein the biological sample comprises an antigen that is CD19.

90. The method of any of claims 67-89, wherein the disease or condition is a B-cell cancer and / or is acute lymphoblastic leukemia (ALL), adult ALL, chronic lymphoblastic leukemia (CLL), small lymphocytic lymphoma (SLL), non-Hodgkin lymphoma (NHL), and diffuse large B-cell lymphoma (DLBCL).

91. The method of any of claims 67-90, wherein the disease or condition is CLL or SLL.

92. The method of any of claims 68-73 and 75-91, wherein the agent or other treatment is or comprises an anti-IL-6 antibody, anti-IL-6R antibody, or a steroid.

93. The method of any of claims 68-73 and 75-92, wherein the agent is or comprises tocilizumab, siltuximab, or dexamethasone.

94. The method of any of claims 1-93, wherein: the CAR comprises a CD19-specific extracellular antigen-binding domain, a transmembrane domain, a cytoplasmic signaling domain derived from a costimulatory molecule, which is optionally a 4-1 BB, and a cytoplasmic signaling domain derived from a molecule containing a primary signaling ITAM, which is optionally a CD3zeta; the CAR comprises, in order, a CD19-specific extracellular antigen-binding domain, a transmembrane domain, a cytoplasmic signaling domain derived from a costimulatory molecule, and a cytoplasmic signaling domain derived from a molecule containing a primary signaling ITAM.

95. The method according to claim 94, wherein the antigen-binding domain is an scFv.

96. The method of claim 95, wherein: RCR I Cn / L7ñ7 / 3 / YILI 201 the scFv comprises a CDRL1 sequence from RASQDISKYLN (SEQ ID NO: 35), a CDRL2 sequence from SRLHSGV (SEQ ID NO: 36), and / or a CDRL3 sequence from GNTLPYTFG (SEQ ID NO: 37) and / or a CDRH1 sequence from DYGVS (SEQ ID NO: 38), a CDRH2 sequence from VIWGSETTYYNSALKS (SEQ ID NO: 39), and / or a CDRH3 sequence from YAMDYWG (SEQ ID NO: 40); The scFv comprises an FMC63 variable heavy chain region and an FMC63 variable light chain region and / or an FMC63 CDRL1 sequence, an FMC63 CDRL2 sequence, an FMC63 CDRL3 sequence, an FMC63 CDRH1 sequence, an FMC63 CDRH2 sequence, and an FMC63 CDRH3 sequence or binds to the same epitope or competes for binding with any of the above;the scFv comprises a VH exposed in SEQ ID NO:41 and a VL exposed in SEQ ID NO: 42, optionally wherein the VH and VL are separated by a flexible linker, optionally wherein the flexible linker is or comprises the sequence exposed in SEQ ID NO:24; and / or the scFv is or comprises the sequence exposed in SEQ ID NO:43.; 97. The method of any of claims 94-96, wherein the costimulatory signaling region is a CD28 or 4-1BB signaling domain.

98. The method of any of claims 94-97, wherein the costimulatory signaling region is a 4-1 BB signaling domain.

99. The method of any of claims 94-98, wherein the costimulatory domain comprises SEQ ID NO: 12 or a variant thereof having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity to the same.

100. The method of any of claims 94-99, wherein the primary signaling domain is a CD3zeta signaling domain.

101. The method of any of claims 94-100, wherein the primary signaling domain comprises SEQ ID NO: 13 or 14 or 15 having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity to the same.

102. The method of any of claims 94-101, wherein the CAR further comprises a spacer between the transmembrane domain and the scFv.

103. The method of claim 102, wherein the spacers are a polypeptide spacer comprising or consisting of all or a portion of an immunoglobulin hinge or a modified version thereof, optionally an lgG4 hinge, or a modified version thereof.

104. The method of claim 102 or claim 103, wherein the spacer is approximately 15 amino acids or less, and does not comprise an extracellular CD28 region or an extracellular CD8 region.

105. The method of any of claims 102-104, wherein the spacer is of or approximately 12 amino acids in length.

106. The method of any of claims 102-105, wherein: RCR / en / LZñZ / q / YILI 202 the spacer has or consists of the sequence SEQ ID NO: 1, a sequence encoded by SEO ID NO: 2, SEO ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, or a variant of any of the foregoing having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity thereto; and / or comprises or consists of the formula X1PPX2P, where X1 is glycine, cysteine ​​or arginine and X2 is cysteine ​​or threonine.

107. The method of any of claims 1-106, wherein the subject is a human subject.

108. A manufactured article comprising a cell therapy composition, or one of a plurality of cell therapy compositions, comprising T cells expressing an anti-CD19 chimeric antigen receptor (CAR), and instructions for administering the cell therapy, wherein the instructions specify administering the T cell composition according to the methods of any of claims 1-106.