The Impact of Various Cellular Product Characteristics on the Efficacy of Anti-CD19 Therapy with T-Lymphocytes Modified with Chimeric Antigen Receptor

Introduction. The production cycle of CAR T-cell product includes several sequential stages, each of which may infl uence the efficiency of transgenic cells: obtaining the patient’s cellular material, isolating the target T-lymphocyte population, activation, transduction of the cells with a viral vector carrying the CAR construct, and expansion of the obtained CAR T-cells with further administration to the patient.

Aim: to review the impact of each of the production steps on the cell product performance in both in vitro and in vivo experiments, as well as clinical applications.

Main findings. The manufacturing characteristics of various CAR T-cell products were analyzed in this review, followed by a discussion on how different manufacturing characteristics and chimeric antigen receptor structures affect the antitumor efficacy and safety profi le of the cell product. The production of a CAR T-cell product is a multifactorial process that requires optimization of parameters and must take into account the characteristics of the initial raw material (T-lymphocytes).

1. Rodriguez-Abreu D., Bordoni A., Zucca E. Epidemiology of hematological malignancies. Ann Oncol. 2007;18 (Suppl 1):i3–8. DOI: 10.1093/annonc/mdl443.

2. Aleksandrova G.A., Akhmetzyanova R.R., Golubev N.A., et al. Zdravookhranenie v Rossii 2023. Moscow: Rosstat; 2023 (In Russian).

3. Kaprin A.D., Starinsky V.V., Shakhzadova A.O. Malignant neoplasms in Russia in 2023 (morbidity and mortality). P.A. Herzen Moscow Research Institute of Oncology — branch of FGBI ‘NMRC Radiology’, Ministry of Health of Russia, Moscow. 2024 (In Russian).

4. Mitra A., Barua A., Huang L., et al. From bench to bedside: the history and progress of CAR T cell therapy. Front Immunol. 2023;14:1188049. DOI: 10.3389/fimmu.2023.1188049.

5. Wei G., Hu Y., Pu C., et al. CD19 targeted CAR-T therapy versus chemotherapy in re-induction treatment of refractory/relapsed acute lymphoblastic leukemia: results of a case-controlled study. Ann Hematol. 2018;97(5):781–9. DOI: 10.1007/s00277-018-3246-4.

6. Sadelain M., Brentjens R., Rivière I. The Basic Principles of Chimeric Antigen Receptor Design. Cancer Discovery. 2013;3(4):388–98. DOI: 10.1158/21598290.CD-12-0548.

7. First-Ever CAR T-cell Therapy Approved in U.S. Cancer Discovery. 2017;7(10):OF1. DOI: 10.1158/2159-8290.CD-NB2017-126.

8. Rotte A., Frigault M.J., Ansari A., et al. Dose–response correlation for CAR-T cells: a systematic review of clinical studies. J Immunother Cancer. 2022;10(12):e005678. DOI: 10.1136/jitc-2022-005678.

9. FDA. Package Insert and Medication Guide — YESCARTA. 2017.

10. FDA. Package Insert and Medication Guide — KYMRIAH. 2017.

11. FDA. Package Insert and Medication Guide — TECARTUS. 2020.

12. FDA. Package Insert and Medication Guide — BREYANZI. 2021.

13. FDA. Package Insert and Medication Guide — ABECMA. 2021.

14. FDA. Package Insert and Medication Guide — CARVYKTI. 2022.

15. FDA. Package Insert — AUCATZYL. 2024.

16. Sterner R.C., Sterner R.M. CAR-T cell therapy: current limitations and potential strategies. Blood Cancer J. 2021;11(4):69. DOI: 10.1038/s41408-02100459-7.

17. Ayala Ceja M., Khericha M., Harris C.M., et al. CAR-T cell manufacturing: Major process parameters and next-generation strategies. J Exp Med. 2024;221(2):e20230903. DOI: 10.1084/jem.20230903.

18. Shelikhova L., Rakhteenko A., Molostova O., et al. Allogeneic Donor-Derived Myeloid Antigen Directed CAR-T Cells — for Relapsed/Refractory Acute Myeloid Leukemia in Children after Allogeneic Hematopoietic Stem Cell Transplantation: Report of Three Cases. Blood. 2022;140(Suppl 1):4600–1. DOI: 10.1182/blood-2022-168891.

19. Pulsipher M.A., Levine J.E., Hayashi R.J., et al. Safety and efficacy of allogeneic PBSC collection in normal pediatric donors: The Pediatric Blood and Marrow Transplant Consortium Experience (PBMTC) 1996–2003. Bone Marrow Transplant. 2005;35(4):361–7. DOI: 10.1038/sj.bmt.1704743.

20. Worel N., Peteres C., Gerhartl K., et al. Collection of peripheral blood stem cells (PBSC) after chemotherapy and administration of rhGM-CSF in children weighing less than 17 kg. Transfus Sci. 1996.;17(4):601–6.

21. Das R.K., Vernau L., Grupp S.A., et al. Naive T-cell Defi cits at Diagnosis and after Chemotherapy Impair Cell Therapy Potential in Pediatric Cancers. Cancer Discov. 2019;9(4):492–9. DOI: 10.1158/2159-8290.CD-18-1314.

22. Zhang D., Zhu Y., Jin Y., et al. Leukapheresis and Hyperleukocytosis, Past and Future. IJGM. 2021;14:3457–67. DOI: 10.2147/IJGM.S321787.

23. Künkele A., Brown C., Beebe A., et al. Manufacture of Chimeric Antigen Receptor T Cells from Mobilized Cyropreserved Peripheral Blood Stem Cell Units Depends on Monocyte Depletion. Biol Blood Marrow Transplant. 2019;25(2):223– 32. DOI: 10.1016/j.bbmt.2018.10.004.

24. Hayden P.J., Roddie C., Bader P., et al. Management of adults and children receiving CAR T-cell therapy: 2021 best practice recommendations of the European Society for Blood and Marrow Transplantation (EBMT) and the Joint Accreditation Committee of ISCT and EBMT (JACIE) and the European Haematology Association (EHA). Ann Oncol. 2022;33(3):259–75. DOI: 10.1016/j.annonc.2021.12.003.

25. Qayed M., McGuirk J.P., Myers G.D., et al. Leukapheresis guidance and best practices for optimal chimeric antigen receptor T-cell manufacturing. Cytotherapy. 2022;24(9):869–78. DOI: 10.1016/j.jcyt.2022.05.003.

26. Vormittag P., Gunn R., Ghorashian S., et al. A guide to manufacturing CAR T cell therapies. Curr Opin Biotechnol. 2018 г.;53:164–81. DOI: 10.1016/j.copbio.2018.01.025.

27. López-Cantillo G., Urueña C., Camacho B.A., et al. CAR-T Cell Performance: How to Improve Their Persistence? Front Immunol. 2022;13:878209. DOI: 10.3389/fimmu.2022.878209.

28. Wada F., Jo T., Arai Y., et al. T-cell counts in peripheral blood at leukapheresis predict responses to subsequent CAR-T cell therapy. Sci Rep. 2022;12(1):18696. DOI: 10.1038/s41598-022-23589-9.

29. Allen E.S., Stroncek D.F., Ren J., et al. Autologous lymphapheresis for the production of chimeric antigen receptor T cells. Transfusion. 2017;57(5):1133–41. DOI: 10.1111/trf.14003.

30. Anagnostou T., Riaz I.B., Hashmi S.K., et al. Anti-CD19 chimeric antigen receptor T-cell therapy in acute lymphocytic leukaemia: a systematic review and meta-analysis. Lancet Haematol. 2020;7(11):e816–26. DOI: 10.1016/S23523026(20)30277-5.

31. Hu Y., Wang J., Wei G., et al. A retrospective comparison of allogenic and autologous chimeric antigen receptor T cell therapy targeting CD19 in patients with relapsed/refractory acute lymphoblastic leukemia. Bone Marrow Transplant. 2019;54(8):1208–17. DOI: 10.1038/s41409-018-0403-2.

32. Park J.H., Rivière I., Gonen M., et al. Long-Term Follow-up of CD19 CAR Therapy in Acute Lymphoblastic Leukemia. N Engl J Med. 2018;378(5):449–59. DOI: 10.1056/NEJMoa1709919.

33. Smith M., Zakrzewski J., James S., et al. Posttransplant chimeric antigen receptor therapy. Blood. 2018;131(10):1045–52. DOI: 10.1182/blood-2017-08-752121.

34. Yang Y., Kohler M.E., Chien C.D., et al. TCR engagement negatively affects CD8 but not CD4 CAR T cell expansion and leukemic clearance. Sci Transl Med. 2017;9(417):eaag1209. DOI: 10.1126/scitranslmed.aag1209.

35. Bridgeman J.S., Ladell K., Sheard V.E., et al. CD3ζ-based chimeric antigen receptors mediate T cell activation via cis — and trans -signalling mechanisms: implications for optimization of receptor structure for adoptive cell therapy. Clin Exp Immunol. 2014;175(2):258–67. DOI: 10.1111/cei.12216.

36. Wang X., Rivière I. Clinical manufacturing of CAR T cells: foundation of a promising therapy. Mol Ther Oncolytics. 2016;3:16015. DOI: 10.1038/mto.2016.15.

37. Nazarpour R., Zabihi E., Alijanpour E., et al. Optimization of Human Peripheral Blood Mononuclear Cells (PBMCs) Cryopreservation. Int J Mol Cell Med. 2012;1(2):88–93.

38. Brezinger-Dayan K., Itzhaki O., Melnichenko J., et al. Impact of cryopreservation on CAR T production and clinical response. Front Oncol. 2022;12:1024362. DOI: 10.3389/fonc.2022.1024362.

39. Abraham-Miranda J., Menges M., Atkins R., et al. CAR-T manufactured from frozen PBMC yield efficient function with prolonged in vitro production. Front Immunol. 2022;13:1007042. DOI: 10.3389/fimmu.2022.1007042.

40. Su T., Ying Z., Lu X., et al. The clinical outcomes of fresh versus cryopreserved CD19-directed chimeric antigen receptor T cells in non-Hodgkin lymphoma patients. Cryobiology. 2020;96:106–13. DOI: 10.1016/j.cryobiol.2020.07.009.

41. Locke F.L., Rossi J.M., Neelapu S.S., et al. Tumor burden, infl ammation, and product attributes determine outcomes of axicabtagene ciloleucel in large B-cell lymphoma. Blood Adv. 2020.;4(19):4898–911. DOI: 10.1182/bloodadvances.2020002394.

42. Panch S.R., Srivastava S.K., Elavia N., et al. Effect of Cryopreservation on Autologous Chimeric Antigen Receptor T Cell Characteristics. Mol Ther. 2019;27(7):1275–85. DOI: 10.1016/j.ymthe.2019.05.015.

43. Tyagarajan S., Schmitt D., Acker C., et al. Autologous cryopreserved leukapheresis cellular material for chimeric antigen receptor–T cell manufacture. Cytotherapy. 2019;21(12):1198–205. DOI: 10.1016/j.jcyt.2019.10.005.

44. Okuma A. Generation of CAR-T Cells by Lentiviral Transduction. Methods Mol Biol. 2021; 2312:3–14. DOI: 10.1007/978-1-0716-1441-9_1.

45. Safety and Efficacy of Gene-Based Therapeutics for Inherited Disorders. Ed. Brunetti-Pierri N. Springer Int Pub; 2017. DOI: 10.1007/978-3-319-53457-2.

46. Labbé R.P., Vessillier S., Rafi q Q.A. Lentiviral Vectors for T Cell Engineering: Clinical Applications, Bioprocessing and Future Perspectives. Viruses. 2021;13(8):1528. DOI: 10.3390/v13081528.

47. Pedersen F.S., Mikkelsen J.G. Retroviruses in Human Gene Therapy. In: Encyclopedia of Life Sciences. Wiley; 2018:1–12. DOI: 10.1002/9780470015902.a0001002.pub4.

48. Cesana D., Volpin M., Serina Secanechia Y.N., et al. Safety and Efficacy of Retroviral and Lentiviral Vectors for Gene Therapy. In Safety and Efficacy of Gene Based Therapeutics for Inherited Disorders. Ed. Brunetti-Pierri N. Springer Int Publ; 2017:9–35. DOI: 10.1007/978-3-319-53457-2_2.

49. Xia Y., Zhang J., Li J., et al. Cytopenias following anti-CD19 chimeric antigen receptor (CAR) T cell therapy: a systematic analysis for contributing factors. Ann Med. 2022;54(1):2950–64. DOI: 10.1080/07853890.2022.2136748.

50. Poletti V., Mavilio F. Designing Lentiviral Vectors for Gene Therapy of Genetic Diseases. Viruses. 2021;13(8):1526. DOI: 10.3390/v13081526.

51. Wilson W. Bryan. Tisagenlecleucel Novartis Pharmaceuticals Corporation. Oncologic Drugs Advisory Committee Meeting; 2017.

52. Bushman F.D. Retroviral Insertional Mutagenesis in Humans: Evidence for Four Genetic Mechanisms Promoting Expansion of Cell Clones. Mol Ther. 2020;28(2):352–6. DOI: 10.1016/j.ymthe.2019.12.009.

53. Dulery R., Guiraud V., Choquet S., et al. T cell malignancies after CAR T cell therapy in the DESCAR-T registry. Nat Med., 2025; 31(4): 1130–1133. DOI: 10.1038/s41591-024-03458-w.

54. Jadlowsky J.K., Hexner E.O., Marshall A., et al. Long-term safety of lentiviral or gammaretroviral gene-modifi ed T cell therapies. Nat Med., 2025; 31(4) 1134–1144. DOI: 10.1038/s41591-024-03478-6.

55. Harrison S.J., Touzeau C., Kint N., et al. CAR+ T-Cell Lymphoma after Cilta-cel Therapy for Relapsed or Refractory Myeloma. N Engl J Med. 2025;392(7):677– 85. DOI: 10.1056/NEJMoa2309728.

56. Perica K., Jain N., Scordo M., et al. CD4+ T-Cell Lymphoma Harboring a Chimeric Antigen Receptor Integration in TP53. N Engl J Med. 2025;392(6):577– 83. DOI: 10.1056/NEJMoa2411507.

57. Lamers C.H.J., Willemsen R., Van Elzakker P., et al. Immune responses to transgene and retroviral vector in patients treated with ex vivo–engineered T cells. Blood. 2011;117(1):72–82. DOI: 10.1182/blood-2010-07-294520.

58. Hudecek M., Ivics Z. Non-viral therapeutic cell engineering with the Sleeping Beauty transposon system. Curr Opin Genet Dev. 2018;52:100–8. DOI: 10.1016/j.gde.2018.06.003.

59. Izsvák Z., Ivics Z. Sleeping Beauty Transposition: Biology and Applications for Molecular Therapy. Mol Ther. 2004;9(2):147–56. DOI: 10.1016/j.ymthe.2003.11.009.

60. Monjezi R., Miskey C., Gogishvili T., et al. Enhanced CAR T-cell engineering using non-viral Sleeping Beauty transposition from minicircle vectors. Leukemia. 2017;31(1):186–94. DOI: 10.1038/leu.2016.180.

61. Atsavapranee E.S., Billingsley M.M., Mitchell M.J. Delivery technologies for T cell gene editing: Applications in cancer immunotherapy. EBioMedicine. 2021;67:103354. DOI: 10.1016/j.ebiom.2021.103354.

62. Kebriaei P., Singh H., Huls M.H., et al. Phase I trials using Sleeping Beauty to generate CD19-specifi c CAR T cells. J Clin Invest. 2016;126(9):3363–76. DOI: 10.1172/JCI86721.

63. Yusa K. piggyBac Transposon. Chandler M, Craig N, редакторы. Microbiol Spectr. 2015;3(2):3.2.04. DOI: 10.1128/microbiolspec.MDNA3-0028-2014.

64. Zhang Y., Zhang Z., Ding Y., et al. Phase I clinical trial of EGFR-specifi c CAR-T cells generated by the piggyBac transposon system in advanced relapsed/refractory non-small cell lung cancer patients. J Cancer Res Clin Oncol. 2021;147(12):3725–34. DOI: 10.1007/s00432-021-03613-7.

65. Hu Y., Zhou Y., Zhang M., et al. CRISPR/Cas9-Engineered Universal CD19/ CD22 Dual-Targeted CAR-T Cell Therapy for Relapsed/Refractory B-cell Acute Lymphoblastic Leukemia. Clin Cancer Res. 2021;27(10):2764–72. DOI: 10.1158/1078-0432.CCR-20-3863.

66. Garner E., Kelly E., Namburi S., et al. CB-012, an allogeneic anti-CLL-1 CART cell therapy engineered with next-generation CRISPR technology to resist both the immunosuppressive tumor microenvironment and immune cell-mediated rejection, for patients with relapsed or refractory acute myeloid leukemia. Cancer Res. 2023;83 (7_Suppl):3201. DOI: 10.1158/1538-7445.AM2023-3201.

67. Rurik J.G., Tombácz I., Yadegari A., et al. CAR T cells produced in vivo to treat cardiac injury. Science. 2022;375(6576):91–6. DOI: 10.1126/science.abm0594.

68. Cheng Z., Wei R., Ma Q., et al. In Vivo Expansion and Antitumor Activity of Coinfused CD28and 4-1BB-Engineered CAR-T Cells in Patients with B Cell Leukemia. Mol Ther. 2018;26(4):976–85. DOI: 10.1016/j.ymthe.2018.01.022.

69. Sommermeyer D., Hudecek M., Kosasih P.L., et al. Chimeric antigen receptormodifi ed T cells derived from defi ned CD8+ and CD4+ subsets confer superior antitumor reactivity in vivo. Leukemia. 2016;30(2):492–500. DOI: 10.1038/leu.2015.247.

70. Turtle C.J., Hanafi L.-A., Berger C., et al. CD19 CAR–T cells of defi ned CD4+:CD8+ composition in adult B cell ALL patients. J Clin Invest. 2016;126(6):2123–38. DOI: 10.1172/JCI85309.

71. MacPherson S., Keyes S., Kilgour M.K., et al. Clinically relevant T cell expansion media activate distinct metabolic programs uncoupled from cellular function. Mol Ther Methods Clin Dev. 2022;24:380–93. DOI: 10.1016/j.omtm.2022.02.004.

72. Eberhardt F., Hückelhoven-Krauss A., Kunz A., et al. Impact of serum-free media on the expansion and functionality of CD19.CAR T-cells. Int J Mol Med. 2023;52(1):58. DOI: 10.3892/ijmm.2023.5261.

73. Sato K., Kondo M., Sakuta K., et al. Impact of culture medium on the expansion of T cells for immunotherapy. Cytotherapy. 2009;11(7):936–46. DOI: 10.3109/14653240903219114.

74. Ghassemi S., Martinez-Becerra F.J., Master A.M., et al. Enhancing Chimeric Antigen Receptor T Cell Anti-tumor Function through Advanced Media Design. Mol Ther Methods Clin Dev. 2020;18:595–606. DOI: 10.1016/j.omtm.2020.07.008.

75. Medvec A.R., Ecker C., Kong H., et al. Improved Expansion and In Vivo Function of Patient T Cells by a Serum-free Medium. Mol Ther Methods Clin Dev. 2018;8:65–74. DOI: 10.1016/j.omtm.2017.11.001.

76. Pawlik-Sobecka L., Sołkiewicz K., Kokot I., et al. The Infl uence of Serum Sample Storage Conditions on Selected Laboratory Parameters Related to Oxidative Stress: A Preliminary Study. Diagnostics. 2020;10(1):51. DOI: 10.3390/diagnostics10010051.

77. Xu H., Wang N., Cao W., et al. Infl uence of various medium environment to in vitro human T cell culture. In Vitro Cell Dev Biol Animal. 2018;54(8):559–66. DOI: 10.1007/s11626-018-0273-3.

78. Du L., Nai Y., Shen M., et al. IL-21 Optimizes the CAR-T Cell Preparation Through Improving Lentivirus Mediated Transfection Efficiency of T Cells and Enhancing CAR-T Cell Cytotoxic Activities. Front Mol Biosci. 2021;8:675179. DOI: 10.3389/fmolb.2021.675179.

79. Zeng R., Spolski R., Casas E., et al. The molecular basis of IL-21–mediated proliferation. Blood. 2007;109(10):4135–42. DOI: 10.1182/ blood-2006-10-054973.

80. Cui W., Liu Y., Weinstein J.S., et al. An Interleukin-21Interleukin-10-STAT3 Pathway Is Critical for Functional Maturation of Memory CD8+ T Cells. Immunity. 2011.;35(5):792–805. DOI: 10.1016/j.immuni.2011.09.017.

81. Adachi K., Kano Y., Nagai T., et al. IL-7 and CCL19 expression in CAR-T cells improves immune cell infi ltration and CAR-T cell survival in the tumor. Nat Biotechnol. 2018;36(4):346–51. DOI: 10.1038/nbt.4086.

82. Zhou J., Jin L., Wang F., et al. Chimeric antigen receptor T (CAR-T) cells expanded with IL-7/IL-15 mediate superior antitumor effects. Protein Cell. 2019;10(10):764–9. DOI: 10.1007/s13238-019-0643-y.

83. Talleur A.C., Qudeimat A., Métais J.-Y., et al. Preferential expansion of CD8+ CD19-CAR T cells postinfusion and the role of disease burden on outcome in pediatric B-ALL. Blood Adv. 2022;6(21):5737–49. DOI: 10.1182/bloodadvances.2021006293.

84. Zhang C., Liu J., Zhong J.F., et al. Engineering CAR-T cells. Biomark Res. 2017;5(1):22. DOI: 10.1186/s40364-017-0102-y.

85. Molostova O., Shelikhova L., Muzalevsky Y., et al. CD19 Car T Therapy In Children with R/R All: Adaptive Split Dosing Improves Safety and Maintains Efficacy of the Approach. Bone Marrow Transplant. 2021;56 (SUPPL 1):36.

86. Brentjens R.J., Davila M.L., Riviere I., et al. CD19-Targeted T Cells Rapidly Induce Molecular Remissions in Adults with Chemotherapy-Refractory Acute Lymphoblastic Leukemia. Sci Transl Med. 2013;5(177): 177ra38. DOI: 10.1126/scitranslmed.3005930.

87. Li C.-H., Sharma S., Heczey A.A., et al. Long-term outcomes of GD2-directed CAR-T cell therapy in patients with neuroblastoma. Nat Med. 2025; ;31(4):1125– 1129. DOI: 10.1038/s41591-025-03513-0.

88. Roselli E., Boucher J.C., Li G., et al. 4-1BB and optimized CD28 co-stimulation enhances function of human mono-specifi c and bi-specifi c third-generation CAR T cells. J Immunother Cancer. 2021;9(10):e003354. DOI: 10.1136/jitc-2021003354.

89. Chmielewski M., Abken H. TRUCKs: the fourth generation of CARs. Expert Opin Biol Ther. 2015;15(8):1145–54. DOI: 10.1517/14712598.2015.1046430.

90. Tang L., Pan S., Wei X., et al. Arming CAR-T cells with cytokines and more: Innovations in the fourth-generation CAR-T development. Mol Ther. 2023;31(11):3146–62. DOI: 10.1016/j.ymthe.2023.09.021.

91. FDA. BLA Clinical Review Memorandum — KYMRIAH.

92. FDA. BLA Clinical Review Memorandum — YESCARTA.

93. Research C. for B.E. and. TECARTUS. FDA. 2024 г.

94. FDA. Clinical Pharmacology BLA Review — BREYANZI.

95. FDA. Summary Basis for Regulatory Action — AUCATZYL.

96. FDA. BLA Clinical Review Memorandum — ABECMA.

97. FDA. Summary Basis for Regulatory Action — CARVYKTI.

98. Awasthi R., Waldron E., Grupp S., et al. Long Term Durable Responses in Relapsed/Refractory (r/r) ALL, DLBCL, and FL Patients Treated with Tisagenlecleucel and Its Association with Persistence of CAR T-Cells. Blood. 2023;142(Suppl 1):4872. DOI: 10.1182/blood-2023-181663.

99. Wittibschlager V., Bacher U., Seipel K., et al. CAR T-Cell Persistence Correlates with Improved Outcome in Patients with B-Cell Lymphoma. IJMS. 2023;24(6):5688. DOI: 10.3390/ijms24065688.

100. Roddie C., Sandhu K.S., Tholouli E., et al. Obecabtagene Autoleucel in Adults with B-Cell Acute Lymphoblastic Leukemia. N Engl J Med. 2024;391(23):2219– 30. DOI: 10.1056/NEJMoa2406526.

101. Shen X., Zhang R., Nie X., et al. 4-1BB Targeting Immunotherapy: Mechanism, Antibodies, and Chimeric Antigen Receptor T. Cancer Biother Radiopharm. 2023;38(7):431–44. DOI: 10.1089/cbr.2023.0022.

102. June C.H., Ledbetter J.A., Linsley P.S., et al. Role of the CD28 receptor in T-cell activation. Immunol Today. 1990 ;11:211–6. DOI: 10.1016/01675699(90)90085-N.

103. Tao Z., Chyra Z., Kotulová J., et al. Impact of T cell characteristics on CART cell therapy in hematological malignancies. Blood Cancer J. 2024;14(1):213. DOI: 10.1038/s41408-024-01193-6.

104. Frigault M.J., Lee J., Basil M.C., et al. Identifi cation of Chimeric Antigen Receptors That Mediate Constitutive or Inducible Proliferation of T Cells. Cancer Immunol Res. 2015;3(4):356–67. DOI: 10.1158/2326-6066.CIR-14-0186.

105. Muller Y.D., Nguyen D.P., Ferreira L.M.R., et al. The CD28-Transmembrane Domain Mediates Chimeric Antigen Receptor Heterodimerization With CD28. Front Immunol. 2021;12:639818. DOI: 10.3389/fimmu.2021.639818.

106. Neelapu S.S., Tummala S., Kebriaei P., et al. Chimeric antigen receptor Tcell therapy — assessment and management of toxicities. Nat Rev Clin Oncol. 2018;15(1):47–62. DOI: 10.1038/nrclinonc.2017.148.

107. Parker K.R., Migliorini D., Perkey E., et al. Single-Cell Analyses Identify Brain Mural Cells Expressing CD19 as Potential Off-Tumor Targets for CAR-T Immunotherapies. Cell. 2020;183(1):126–142.e17. DOI: 10.1016/j.cell.2020.08.022.

108. Zhang Y., Qin D., Shou A.C., et al. Exploring CAR-T Cell Therapy Side Effects: Mechanisms and Management Strategies. JCM. 2023;12(19):6124. DOI: 10.3390/jcm12196124.

109. The Lymphoma Academic Research Organisation. French Register Of Patients With Hemopathy Eligible For CAR-T Cell Treatment (DESCAR-T). clinicaltrials.gov. Report No.: NCT04328298.

110. Bachy E., Le Gouill S., Di Blasi R., et al. A real-world comparison of tisagenlecleucel and axicabtagene ciloleucel CAR T cells in relapsed or refractory diffuse large B cell lymphoma. Nat Med. 2022;28(10):2145–54. DOI: 10.1038/s41591-022-01969-y.

111. Schuster S.J., Bishop M.R., Tam C.S., et al. Tisagenlecleucel in Adult Relapsed or Refractory Diffuse Large B-Cell Lymphoma. N Engl J Med. 2019;380(1):45– 56. DOI: 10.1056/NEJMoa1804980.

112. Jacobson C.A., Chavez J.C., Sehgal A.R., et al. Axicabtagene ciloleucel in relapsed or refractory indolent non-Hodgkin lymphoma (ZUMA-5): a single-arm, multicentre, phase 2 trial. Lancet Oncol. 2022 ;23(1):91–103. DOI: 10.1016/s1470-2045(21)00591-X.

113. Munshi N.C., Anderson L.D., Shah N., и др. Idecabtagene Vicleucel in Relapsed and Refractory Multiple Myeloma. N Engl J Med. 2021;384(8):705–16. DOI: 10.1056/NEJMoa2024850.

114. Berdeja J.G., Madduri D., Usmani S.Z., et al. Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): a phase 1b/2 open-label study. Lancet. 2021;398(10297):314–24. DOI: 10.1016/S01406736(21)00933-8.

115. Jain T., Olson T.S., Locke F.L. How I Treat Cytopenias after CAR T-cell Therapy. Blood. 2023;blood.2022017415. DOI: 10.1182/blood.2022017415.

116. Fried S., Avigdor A., Bielorai B., et al. Early and late hematologic toxicity following CD19 CAR-T cells. Bone Marrow Transplant. 2019;54(10):1643–50. DOI: 10.1038/s41409-019-0487-3.

117. Wang L., Hong R., Zhou L., et al. New-Onset Severe Cytopenia After CAR-T Cell Therapy: Analysis of 76 Patients With Relapsed or Refractory Acute Lymphoblastic Leukemia. Front Oncol. 2021;11:702644. DOI: 10.3389/fonc.2021.702644.

118. Rejeski K., Perez A., Sesques P., et al. CAR-HEMATOTOX: a model for CAR T-cell–related hematologic toxicity in relapsed/refractory large B-cell lymphoma. Blood. 2021;138(24):2499–513. DOI: 10.1182/blood.2020010543.

119. Hill J.A., Li D., Hay K.A., et al. Infectious complications of CD19-targeted chimeric antigen receptor–modifi ed T-cell immunotherapy. Blood. 2018;131(1):121– 30. DOI: 10.1182/blood-2017-07-793760.

120. Vora S.B., Waghmare A., Englund J.A., et al. Infectious Complications Following CD19 Chimeric Antigen Receptor T-cell Therapy for Children, Adolescents, and Young Adults. Open Forum Infect Dis. 2020;7(5):ofaa121. DOI: 10.1093/ofi d/ofaa121.

121. Mikkilineni L., Yates B., Steinberg S.M., et al. Infectious complications of CAR T-cell therapy across novel antigen targets in the fi rst 30 days. Blood Adv. 2021;5(23):5312–22. DOI: 10.1182/bloodadvances.2021004896.

122. Jennifer M. Logue, Elisa Zucchetti, Christina A. Bachmeier, et al. Immune reconstitution and associated infections following axicabtagene ciloleucel in relapsed or refractory large B-cell lymphoma. Haematologica. 2020;106(4):978– 86. DOI: 10.3324/haematol.2019.238634.

123. Wudhikarn K., Palomba M.L., Pennisi M., et al. Infection during the fi rst year in patients treated with CD19 CAR T cells for diffuse large B cell lymphoma. Blood Cancer J. 2020;10(8):79. DOI: 10.1038/s41408-020-00346-7.

124. Beyar‐Katz O., Kikozashvili N., Bar On Y., et al. Characteristics and recognition of early infections in patients treated with commercial anti‐CD19 CAR‐T cells. Eur J Haematol. 2022;108(1):52–60. DOI: 10.1111/ejh.13712.

125. Kampouri E., Little J.S., Rejeski K., et al. Infections after chimeric antigen receptor (CAR)‐T‐cell therapy for hematologic malignancies. Transplant Infectious Dis. 2023;25(S1):e14157. DOI: 10.1111/tid.14157.

126. Chong E.A., Ruella M., Schuster S.J. Five-Year Outcomes for Refractory BCell Lymphomas with CAR T-Cell Therapy. N Engl J Med. 2021;384(7):673–4. DOI: 10.1056/NEJMc2030164.

127. Cappell K.M., Kochenderfer J.N. Long-term outcomes following CAR T cell therapy: what we know so far. Nat Rev Clin Oncol. 2023;20(6):359–71. DOI: 10.1038/s41571-023-00754-1.