Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment paradigms for hematological malignancies. However, more than half of these patients cannot achieve sustainable tumor control, partially due to the inadequate potency of CAR-T cells in eradicating tumor cells. T cells are crucial components of the anti-tumor immune response, and multiple intrinsic T-cell features significantly influence the outcomes of CAR-T cell therapy. Herein, we review progressing research on T-cell characteristics that impact the effectiveness of CAR-T cells, including T-cell exhaustion, memory subsets, senescence, regulatory T-cells, the CD4+ to CD8+ T-cell ratio, metabolism, and the T-cell receptor repertoire. With comprehensive insight into the biological processes underlying successful CAR-T cell therapy, we will further refine the applications of these novel therapeutic modalities, and enhance their efficacy and safety for patients.

Department of Haematooncology Faculty of Medicine University of Ostrava Ostrava Czech Republic

Department of Haematooncology University Hospital Ostrava Ostrava Czech Republic

Zobrazit více v PubMed

Maude SL, Frey N, Shaw PA, Aplenc R, Barrett DM, Bunin NJ, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N. Engl J Med. 2014;371:1507–17. PubMed PMC

Shah BD, Ghobadi A, Oluwole OO, Logan AC, Boissel N, Cassaday RD, et al. KTE-X19 for relapsed or refractory adult B-cell acute lymphoblastic leukaemia: phase 2 results of the single-arm, open-label, multicentre ZUMA-3 study. Lancet. 2021;398:491–502. PubMed PMC

Westin JR, Oluwole OO, Kersten MJ, Miklos DB, Perales MA, Ghobadi A, et al. Survival with Axicabtagene Ciloleucel in Large B-Cell Lymphoma. N. Engl J Med. 2023;389:148–57. PubMed

Fowler NH, Dickinson M, Dreyling M, Martinez-Lopez J, Kolstad A, Butler J, et al. Tisagenlecleucel in adult relapsed or refractory follicular lymphoma: the phase 2 ELARA trial. Nat Med. 2022;28:325–32. PubMed

Wang M, Munoz J, Goy A, Locke FL, Jacobson CA, Hill BT, et al. KTE-X19 CAR T-Cell Therapy in Relapsed or Refractory Mantle-Cell Lymphoma. N. Engl J Med. 2020;382:1331–42. PubMed PMC

Siddiqi T, Maloney DG, Kenderian SS, Brander DM, Dorritie K, Soumerai J, et al. Lisocabtagene maraleucel in chronic lymphocytic leukaemia and small lymphocytic lymphoma (TRANSCEND CLL 004): a multicentre, open-label, single-arm, phase 1-2 study. Lancet. 2023;402:641–54. PubMed PMC

Rodriguez-Otero P, Ailawadhi S, Arnulf B, Patel K, Cavo M, Nooka AK, et al. Ide-cel or Standard Regimens in Relapsed and Refractory Multiple Myeloma. N. Engl J Med. 2023;388:1002–14. PubMed

Schuster SJ, Tam CS, Borchmann P, Worel N, McGuirk JP, Holte H, et al. Long-term clinical outcomes of tisagenlecleucel in patients with relapsed or refractory aggressive B-cell lymphomas (JULIET): a multicentre, open-label, single-arm, phase 2 study. Lancet Oncol. 2021;22:1403–15. PubMed

Kamdar M, Solomon SR, Arnason J, Johnston PB, Glass B, Bachanova V, et al. Lisocabtagene maraleucel versus standard of care with salvage chemotherapy followed by autologous stem cell transplantation as second-line treatment in patients with relapsed or refractory large B-cell lymphoma (TRANSFORM): results from an interim analysis of an open-label, randomised, phase 3 trial. Lancet. 2022;399:2294–308. PubMed

Jacobson CA, Chavez JC, Sehgal AR, William BM, Munoz J, Salles G, et al. Axicabtagene ciloleucel in relapsed or refractory indolent non-Hodgkin lymphoma (ZUMA-5): a single-arm, multicentre, phase 2 trial. Lancet Oncol. 2022;23:91–103. PubMed

Morschhauser F, Dahiya S, Palomba ML, Martin Garcia-Sancho A, Reguera Ortega JL, Kuruvilla J, et al. Lisocabtagene maraleucel in follicular lymphoma: the phase 2 TRANSCEND FL study. Nat Med. 2024;30:2199–207. PubMed PMC

Wang Y, Jain P, Locke FL, Maurer MJ, Frank MJ, Munoz JL, et al. Brexucabtagene Autoleucel for Relapsed or Refractory Mantle Cell Lymphoma in Standard-of-Care Practice: Results From the US Lymphoma CAR T Consortium. J Clin Oncol. 2023;41:2594–606. PubMed PMC

San-Miguel J, Dhakal B, Yong K, Spencer A, Anguille S, Mateos MV, et al. Cilta-cel or Standard Care in Lenalidomide-Refractory Multiple Myeloma. N. Engl J Med. 2023;389:335–47. PubMed

Munshi NC, Anderson LD Jr, Shah N, Madduri D, Berdeja J, Lonial S, et al. Idecabtagene Vicleucel in Relapsed and Refractory Multiple Myeloma. N. Engl J Med. 2021;384:705–16. PubMed

Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bittencourt H, et al. Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia. N. Engl J Med. 2018;378:439–48. PubMed PMC

Amatya C, Weissler KA, Fellowes V, Lam N, Cutmore LC, Natrakul DA, et al. Optimization of anti-CD19 CAR T cell production for treatment of patients with chronic lymphocytic leukemia. Mol Ther Methods Clin Dev. 2024;32:101212. PubMed PMC

Xiao X, Huang S, Chen S, Wang Y, Sun Q, Xu X, et al. Mechanisms of cytokine release syndrome and neurotoxicity of CAR T-cell therapy and associated prevention and management strategies. J Exp Clin Cancer Res. 2021;40:367. PubMed PMC

Wang X, Borquez-Ojeda O, Stefanski J, Du F, Qu J, Chaudhari J, et al. Depletion of high-content CD14(+) cells from apheresis products is critical for successful transduction and expansion of CAR T cells during large-scale cGMP manufacturing. Mol Ther Methods Clin Dev. 2021;22:377–87. PubMed PMC

Waldman AD, Fritz JM, Lenardo MJ. A guide to cancer immunotherapy: from T cell basic science to clinical practice. Nat Rev Immunol. 2020;20:651–68. PubMed PMC

Wherry EJ, Kurachi M. Molecular and cellular insights into T cell exhaustion. Nat Rev Immunol. 2015;15:486–99. PubMed PMC

Baessler A, Vignali DAA. T Cell Exhaustion. Annu Rev Immunol. 2024;42:179–206. PubMed

Belk JA, Daniel B, Satpathy AT. Epigenetic regulation of T cell exhaustion. Nat Immunol. 2022;23:848–60. PubMed PMC

Fraietta JA, Lacey SF, Orlando EJ, Pruteanu-Malinici I, Gohil M, Lundh S, et al. Determinants of response and resistance to CD19 chimeric antigen receptor (CAR) T cell therapy of chronic lymphocytic leukemia. Nat Med. 2018;24:563–71. PubMed PMC

Deng Q, Han G, Puebla-Osorio N, Ma MCJ, Strati P, Chasen B, et al. Characteristics of anti-CD19 CAR T cell infusion products associated with efficacy and toxicity in patients with large B cell lymphomas. Nat Med. 2020;26:1878–87. PubMed PMC

Garcia-Calderon CB, Sierro-Martinez B, Garcia-Guerrero E, Sanoja-Flores L, Munoz-Garcia R, Ruiz-Maldonado V, et al. Monitoring of kinetics and exhaustion markers of circulating CAR-T cells as early predictive factors in patients with B-cell malignancies. Front Immunol. 2023;14:1152498. PubMed PMC

Finney OC, Brakke HM, Rawlings-Rhea S, Hicks R, Doolittle D, Lopez M, et al. CD19 CAR T cell product and disease attributes predict leukemia remission durability. J Clin Invest. 2019;129:2123–32. PubMed PMC

Schuster SJ, Bishop MR, Tam CS, Waller EK, Borchmann P, McGuirk JP, et al. Tisagenlecleucel in Adult Relapsed or Refractory Diffuse Large B-Cell Lymphoma. N. Engl J Med. 2019;380:45–56. PubMed

Leblay N, Maity R, Barakat E, McCulloch S, Duggan P, Jimenez-Zepeda V, et al. Cite-seq profiling of T cells in multiple myeloma patients undergoing BCMA targeting CAR-T or bites immunotherapy. Blood. 2020;136:11–2. PubMed

Huang Y, Shao M, Teng X, Si X, Wu L, Jiang P, et al. Inhibition of CD38 enzymatic activity enhances CAR-T cell immune-therapeutic efficacy by repressing glycolytic metabolism. Cell Rep. Med. 2024;5:101400. PubMed PMC

Long AH, Haso WM, Shern JF, Wanhainen KM, Murgai M, Ingaramo M, et al. 4-1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of chimeric antigen receptors. Nat Med. 2015;21:581–90. PubMed PMC

Prinzing B, Schreiner P, Bell M, Fan Y, Krenciute G, Gottschalk S. MyD88/CD40 signaling retains CAR T cells in a less differentiated state. JCI Insight. 2020;5:e136093. PubMed PMC

Calderon H, Mamonkin M, Guedan S. Analysis of CAR-Mediated Tonic Signaling. Methods Mol Biol. 2020;2086:223–36. PubMed

Watanabe N, Bajgain P, Sukumaran S, Ansari S, Heslop HE, Rooney CM, et al. Fine-tuning the CAR spacer improves T-cell potency. Oncoimmunology. 2016;5:e1253656. PubMed PMC

Hu Y, Zu C, Zhang M, Wei G, Li W, Fu S, et al. Safety and efficacy of CRISPR-based non-viral PD1 locus specifically integrated anti-CD19 CAR-T cells in patients with relapsed or refractory Non-Hodgkin’s lymphoma: a first-in-human phase I study. EClinicalMedicine. 2023;60:102010. PubMed PMC

Rafiq S, Yeku OO, Jackson HJ, Purdon TJ, van Leeuwen DG, Drakes DJ, et al. Targeted delivery of a PD-1-blocking scFv by CAR-T cells enhances anti-tumor efficacy in vivo. Nat Biotechnol. 2018;36:847–56. PubMed PMC

Cherkassky L, Morello A, Villena-Vargas J, Feng Y, Dimitrov DS, Jones DR, et al. Human CAR T cells with cell-intrinsic PD-1 checkpoint blockade resist tumor-mediated inhibition. J Clin Invest. 2016;126:3130–44. PubMed PMC

Li AM, Hucks GE, Dinofia AM, Seif AE, Teachey DT, Baniewicz D, et al. Checkpoint inhibitors augment CD19-directed chimeric antigen receptor (CAR) T cell therapy in relapsed B-cell acute lymphoblastic leukemia. Blood. 2018;132:556.

Cao Y, Lu W, Sun R, Jin X, Cheng L, He X, et al. Anti-CD19 Chimeric Antigen Receptor T Cells in Combination With Nivolumab Are Safe and Effective Against Relapsed/Refractory B-Cell Non-hodgkin Lymphoma. Front Oncol. 2019;9:767. PubMed PMC

Lynn RC, Weber EW, Sotillo E, Gennert D, Xu P, Good Z, et al. c-Jun overexpression in CAR T cells induces exhaustion resistance. Nature. 2019;576:293–300. PubMed PMC

Seo H, González-Avalos E, Zhang W, Ramchandani P, Yang C, Lio CJ, et al. BATF and IRF4 cooperate to counter exhaustion in tumor-infiltrating CAR T cells. Nat Immunol. 2021;22:983–95. PubMed PMC

Weber EW, Parker KR, Sotillo E, Lynn RC, Anbunathan H, Lattin J, et al. Transient rest restores functionality in exhausted CAR-T cells through epigenetic remodeling. Science. 2021;372:eaba1786. PubMed PMC

Kim C, Williams MA. Nature and nurture: T-cell receptor-dependent and T-cell receptor-independent differentiation cues in the selection of the memory T-cell pool. Immunology. 2010;131:310–7. PubMed PMC

Jameson SC, Masopust D. Understanding Subset Diversity in T Cell Memory. Immunity. 2018;48:214–26. PubMed PMC

Xu Y, Zhang M, Ramos CA, Durett A, Liu E, Dakhova O, et al. Closely related T-memory stem cells correlate with in vivo expansion of CAR.CD19-T cells and are preserved by IL-7 and IL-15. Blood. 2014;123:3750–9. PubMed PMC

Monfrini C, Stella F, Aragona V, Magni M, Ljevar S, Vella C, et al. Phenotypic Composition of Commercial Anti-CD19 CAR T Cells Affects In Vivo Expansion and Disease Response in Patients with Large B-cell Lymphoma. Clin Cancer Res. 2022;28:3378–86. PubMed PMC

Wang Y, Tong C, Lu Y, Wu Z, Guo Y, Liu Y, et al. Characteristics of premanufacture CD8(+)T cells determine CAR-T efficacy in patients with diffuse large B-cell lymphoma. Signal Transduct Target Ther. 2023;8:409. PubMed PMC

Louis CU, Savoldo B, Dotti G, Pule M, Yvon E, Myers GD, et al. Antitumor activity and long-term fate of chimeric antigen receptor-positive T cells in patients with neuroblastoma. Blood. 2011;118:6050–6. PubMed PMC

Locke FL, Rossi JM, Neelapu SS, Jacobson CA, Miklos DB, Ghobadi A, et al. Tumor burden, inflammation, and product attributes determine outcomes of axicabtagene ciloleucel in large B-cell lymphoma. Blood Adv. 2020;4:4898–911. PubMed PMC

Haradhvala NJ, Leick MB, Maurer K, Gohil SH, Larson RC, Yao N, et al. Distinct cellular dynamics associated with response to CAR-T therapy for refractory B cell lymphoma. Nat Med. 2022;28:1848–59. PubMed PMC

Bai Z, Woodhouse S, Zhao Z, Arya R, Govek K, Kim D, et al. Single-cell antigen-specific landscape of CAR T infusion product identifies determinants of CD19-positive relapse in patients with ALL. Sci Adv. 2022;8:eabj2820. PubMed PMC

Štach M, Pytlík R, Šmilauerová K, Rychlá J, Mucha M, Musil J, et al. Characterization of the input material quality for the production of tisagenlecleucel by multiparameter flow cytometry and its relation to the clinical outcome. Pathol Oncol Res. 2023;29:1610914. PubMed PMC

Melenhorst JJ, June CH, Porter DL, Grupp S, Stadtmauer EA, Schuster SJ, et al. Identification and Validation of Predictive Biomarkers to CD19- and BCMA-Specific CAR T-Cell Responses in CAR T-Cell Precursors. Blood. 2019;134:622.

Chen GM, Chen C, Das RK, Gao P, Chen CH, Bandyopadhyay S, et al. Integrative Bulk and Single-Cell Profiling of Premanufacture T-cell Populations Reveals Factors Mediating Long-Term Persistence of CAR T-cell Therapy. Cancer Discov. 2021;11:2186–99. PubMed PMC

Lin Y, Raje NS, Berdeja JG, Siegel DS, Jagannath S, Madduri D, et al. Idecabtagene vicleucel for relapsed and refractory multiple myeloma: post hoc 18-month follow-up of a phase 1 trial. Nat Med. 2023;29:2286–94. PubMed PMC

Arcangeli S, Bove C, Mezzanotte C, Camisa B, Falcone L, Manfredi F, et al. CAR T cell manufacturing from naive/stem memory T lymphocytes enhances antitumor responses while curtailing cytokine release syndrome. J Clin Invest. 2022;132:e150807. PubMed PMC

Drent E, Poels R, Ruiter R, van de Donk N, Zweegman S, Yuan H, et al. Combined CD28 and 4-1BB Costimulation Potentiates Affinity-tuned Chimeric Antigen Receptor-engineered T Cells. Clin Cancer Res. 2019;25:4014–25. PubMed PMC

Kawalekar OU, O’Connor RS, Fraietta JA, Guo L, McGettigan SE, Posey AD Jr, et al. Distinct Signaling of Coreceptors Regulates Specific Metabolism Pathways and Impacts Memory Development in CAR T Cells. Immunity. 2016;44:712. PubMed

Moreno-Cortes E, Franco-Fuquen P, Garcia-Robledo JE, Forero J, Booth N, Castro JE. ICOS and OX40 tandem co-stimulation enhances CAR T-cell cytotoxicity and promotes T-cell persistence phenotype. Front Oncol. 2023;13:1200914. PubMed PMC

Luo M, Gong W, Zhang Y, Li H, Ma D, Wu K, et al. New insights into the stemness of adoptively transferred T cells by γc family cytokines. Cell Commun Signal. 2023;21:347. PubMed PMC

Alizadeh D, Wong RA, Yang X, Wang D, Pecoraro JR, Kuo CF, et al. IL15 Enhances CAR-T Cell Antitumor Activity by Reducing mTORC1 Activity and Preserving Their Stem Cell Memory Phenotype. Cancer Immunol Res. 2019;7:759–72. PubMed PMC

Tian Y, Zajac AJ. IL-21 and T Cell Differentiation: Consider the Context. Trends Immunol. 2016;37:557–68. PubMed PMC

Funk CR, Wang S, Chen KZ, Waller A, Sharma A, Edgar CL, et al. PI3Kδ/γ inhibition promotes human CART cell epigenetic and metabolic reprogramming to enhance antitumor cytotoxicity. Blood. 2022;139:523–37. PubMed PMC

Fan F, Yoo HJ, Stock S, Wang L, Liu Y, Schubert ML, et al. Ibrutinib for improved chimeric antigen receptor T-cell production for chronic lymphocytic leukemia patients. Int J Cancer. 2021;148:419–28. PubMed

Ghassemi S, Durgin JS, Nunez-Cruz S, Patel J, Leferovich J, Pinzone M, et al. Rapid manufacturing of non-activated potent CAR T cells. Nat Biomed Eng. 2022;6:118–28. PubMed PMC

Dickinson MJ, Barba P, Jäger U, Shah NN, Blaise D, Briones J, et al. A Novel Autologous CAR-T Therapy, YTB323, with Preserved T-cell Stemness Shows Enhanced CAR T-cell Efficacy in Preclinical and Early Clinical Development. Cancer Discov. 2023;13:1982–97. PubMed PMC

Garfall AL, Dancy EK, Cohen AD, Hwang WT, Fraietta JA, Davis MM, et al. T-cell phenotypes associated with effective CAR T-cell therapy in postinduction vs relapsed multiple myeloma. Blood Adv. 2019;3:2812–5. PubMed PMC

Das RK, Vernau L, Grupp SA, Barrett DM. Naïve T-cell Deficits at Diagnosis and after Chemotherapy Impair Cell Therapy Potential in Pediatric Cancers. Cancer Discov. 2019;9:492–9. PubMed PMC

Dubnikov Sharon T, Assayag M, Avni B, Kfir-Erenfeld S, Lebel E, Gatt ME, et al. Early lymphocyte collection for anti-CD19 CART production improves T-cell fitness in patients with relapsed/refractory diffuse large B-cell lymphoma. Br J Haematol. 2023;202:74–85. PubMed

Kasakovski D, Xu L, Li Y. T cell senescence and CAR-T cell exhaustion in hematological malignancies. J Hematol Oncol. 2018;11:91. PubMed PMC

Zhang J, He T, Xue L, Guo H. Senescent T cells: a potential biomarker and target for cancer therapy. EBioMedicine. 2021;68:103409. PubMed PMC

Chauvin JM, Zarour HM. TIGIT in cancer immunotherapy. J Immunother Cancer. 2020;8:e000957. PubMed PMC

Noll JH, Levine BL, June CH, Fraietta JA. Beyond youth: Understanding CAR T cell fitness in the context of immunological aging. Semin Immunol. 2023;70:101840. PubMed

Suen H, Brown R, Yang S, Weatherburn C, Ho PJ, Woodland N, et al. Multiple myeloma causes clonal T-cell immunosenescence: identification of potential novel targets for promoting tumour immunity and implications for checkpoint blockade. Leukemia. 2016;30:1716–24. PubMed

Guha P, Cunetta M, Somasundar P, Espat NJ, Junghans RP, Katz SC. Frontline Science: Functionally impaired geriatric CAR-T cells rescued by increased α5β1 integrin expression. J Leukoc Biol. 2017;102:201–8. PubMed PMC

Sakaguchi S, Miyara M, Costantino CM, Hafler DA. FOXP3+ regulatory T cells in the human immune system. Nat Rev Immunol. 2010;10:490–500. PubMed

Sakaguchi S, Mikami N, Wing JB, Tanaka A, Ichiyama K, Ohkura N. Regulatory T Cells and Human Disease. Annu Rev Immunol. 2020;38:541–66. PubMed

Kumagai S, Itahashi K, Nishikawa H. Regulatory T cell-mediated immunosuppression orchestrated by cancer: towards an immuno-genomic paradigm for precision medicine. Nat Rev Clin Oncol. 2024;21:337–53. PubMed

Good Z, Spiegel JY, Sahaf B, Malipatlolla MB, Ehlinger ZJ, Kurra S, et al. Post-infusion CAR T(Reg) cells identify patients resistant to CD19-CAR therapy. Nat Med. 2022;28:1860–71. PubMed PMC

Pan Y, Wang H, An F, Wu F, Tao Q, Li Y, et al. CD4(+)CD25(+)CD127(low) regulatory T cells associated with the effect of CD19 CAR-T therapy for relapsed/refractory B-cell acute lymphoblastic leukemia. Int Immunopharmacol. 2021;96:107742. PubMed

An F, Wang H, Liu Z, Wu F, Zhang J, Tao Q, et al. Influence of patient characteristics on chimeric antigen receptor T cell therapy in B-cell acute lymphoblastic leukemia. Nat Commun. 2020;11:5928. PubMed PMC

Fischer L, Grieb N, Born P, Weiss R, Seiffert S, Boldt A, et al. Cellular dynamics following CAR T cell therapy are associated with response and toxicity in relapsed/refractory myeloma. Leukemia. 2024;38:372–82. PubMed PMC

Beider K, Besser MJ, Schachter J, Grushchenko-Polaq AH, Voevoda V, Wolf I, et al. Upregulation of Senescent/Exhausted Phenotype of CAR T Cells and Induction of Both Treg and Myeloid Suppressive Cells Correlate with Reduced Response to CAR T Cell Therapy in Relapsed/Refractory B Cell Malignancies. Blood. 2019;134:3234.

Pu L, Wang H, Wu F, An F, Xiao H, Wang Y, et al. Predictive model for CAR-T cell therapy success in patients with relapsed/refractory B-cell acute lymphoblastic leukaemia. Scand J Immunol. 2024;99:e13352. PubMed

Ahmadzadeh M, Rosenberg SA. IL-2 administration increases CD4+ CD25(hi) Foxp3+ regulatory T cells in cancer patients. Blood. 2006;107:2409–14. PubMed PMC

Sim GC, Martin-Orozco N, Jin L, Yang Y, Wu S, Washington E, et al. IL-2 therapy promotes suppressive ICOS+ Treg expansion in melanoma patients. J Clin Invest. 2014;124:99–110. PubMed PMC

Zhou J, Jin L, Wang F, Zhang Y, Liu B, Zhao T. Chimeric antigen receptor T (CAR-T) cells expanded with IL-7/IL-15 mediate superior antitumor effects. Protein Cell. 2019;10:764–9. PubMed PMC

Watanabe N, Mo F, McKenna MK. Impact of Manufacturing Procedures on CAR T Cell Functionality. Front Immunol. 2022;13:876339. PubMed PMC

Germain RN. T-cell development and the CD4-CD8 lineage decision. Nat Rev Immunol. 2002;2:309–22. PubMed

Janssen EM, Lemmens EE, Wolfe T, Christen U, von Herrath MG, Schoenberger SP. CD4+ T cells are required for secondary expansion and memory in CD8+ T lymphocytes. Nature. 2003;421:852–6. PubMed

Shedlock DJ, Shen H. Requirement for CD4 T cell help in generating functional CD8 T cell memory. Science. 2003;300:337–9. PubMed

Hung K, Hayashi R, Lafond-Walker A, Lowenstein C, Pardoll D, Levitsky H. The central role of CD4(+) T cells in the antitumor immune response. J Exp Med. 1998;188:2357–68. PubMed PMC

Provine NM, Larocca RA, Aid M, Penaloza-MacMaster P, Badamchi-Zadeh A, Borducchi EN, et al. Immediate Dysfunction of Vaccine-Elicited CD8+ T Cells Primed in the Absence of CD4+ T Cells. J Immunol. 2016;197:1809–22. PubMed PMC

Mackall CL, Fleisher TA, Brown MR, Andrich MP, Chen CC, Feuerstein IM, et al. Age, thymopoiesis, and CD4+ T-lymphocyte regeneration after intensive chemotherapy. N. Engl J Med. 1995;332:143–9. PubMed

Turtle CJ, Hanafi LA, Berger C, Hudecek M, Pender B, Robinson E, et al. Immunotherapy of non-Hodgkin’s lymphoma with a defined ratio of CD8+ and CD4+ CD19-specific chimeric antigen receptor-modified T cells. Sci Transl Med. 2016;8:355ra116. PubMed PMC

Turtle CJ, Hanafi LA, Berger C, Gooley TA, Cherian S, Hudecek M, et al. CD19 CAR-T cells of defined CD4+:CD8+ composition in adult B cell ALL patients. J Clin Invest. 2016;126:2123–38. PubMed PMC

Abramson, Palomba JS, Gordon LI ML, Lunning MA, Wang M, Arnason J, et al. Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study. Lancet. 2020;396:839–52. PubMed

Aleksandrova K, Leise J, Priesner C, Melk A, Kubaink F, Abken H, et al. Functionality and Cell Senescence of CD4/ CD8-Selected CD20 CAR T Cells Manufactured Using the Automated CliniMACS Prodigy® Platform. Transfus Med Hemother. 2019;46:47–54. PubMed PMC

Jo T, Yoshihara S, Okuyama Y, Fujii K, Henzan T, Kahata K, et al. Risk factors for CAR-T cell manufacturing failure among DLBCL patients: A nationwide survey in Japan. Br J Haematol. 2023;202:256–66. PubMed

Sommermeyer D, Hudecek M, Kosasih PL, Gogishvili T, Maloney DG, Turtle CJ, et al. Chimeric antigen receptor-modified T cells derived from defined CD8+ and CD4+ subsets confer superior antitumor reactivity in vivo. Leukemia. 2016;30:492–500. PubMed PMC

Moeller M, Kershaw MH, Cameron R, Westwood JA, Trapani JA, Smyth MJ, et al. Sustained antigen-specific antitumor recall response mediated by gene-modified CD4+ T helper-1 and CD8+ T cells. Cancer Res. 2007;67:11428–37. PubMed

Moeller M, Haynes NM, Kershaw MH, Jackson JT, Teng MW, Street SE, et al. Adoptive transfer of gene-engineered CD4+ helper T cells induces potent primary and secondary tumor rejection. Blood. 2005;106:2995–3003. PubMed

Gardner RA, Finney O, Annesley C, Brakke H, Summers C, Leger K, et al. Intent-to-treat leukemia remission by CD19 CAR T cells of defined formulation and dose in children and young adults. Blood. 2017;129:3322–31. PubMed PMC

Galli E, Bellesi S, Pansini I, Di Cesare G, Iacovelli C, Malafronte R, et al. The CD4/CD8 ratio of infused CD19-CAR-T is a prognostic factor for efficacy and toxicity. Br J Haematol. 2023;203:564–70. PubMed

Teoh J, Johnstone TG, Christin B, Yost R, Haig NA, Mallaney M, et al. Lisocabtagene maraleucel (liso-cel) manufacturing process control and robustness across CD19+ hematological malignancies. Blood. 2019;134:593.

Sehgal A, Hoda D, Riedell PA, Ghosh N, Hamadani M, Hildebrandt GC, et al. Lisocabtagene maraleucel as second-line therapy in adults with relapsed or refractory large B-cell lymphoma who were not intended for haematopoietic stem cell transplantation (PILOT): an open-label, phase 2 study. Lancet Oncol. 2022;23:1066–77. PubMed

Lee SY, Lee DH, Sun W, Cervantes-Contreras F, Basom RS, Wu F, et al. CD8(+) chimeric antigen receptor T cells manufactured in absence of CD4(+) cells exhibit hypofunctional phenotype. J Immunother Cancer. 2023;11:e007803. PubMed PMC

Wang R, Dillon CP, Shi LZ, Milasta S, Carter R, Finkelstein D, et al. The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation. Immunity. 2011;35:871–82. PubMed PMC

Gubser PM, Bantug GR, Razik L, Fischer M, Dimeloe S, Hoenger G, et al. Rapid effector function of memory CD8+ T cells requires an immediate-early glycolytic switch. Nat Immunol. 2013;14:1064–72. PubMed

Rangel Rivera GO, Knochelmann HM, Dwyer CJ, Smith AS, Wyatt MM, Rivera-Reyes AM, et al. Fundamentals of T Cell Metabolism and Strategies to Enhance Cancer Immunotherapy. Front Immunol. 2021;12:645242. PubMed PMC

Ron-Harel N, Santos D, Ghergurovich JM, Sage PT, Reddy A, Lovitch SB, et al. Mitochondrial Biogenesis and Proteome Remodeling Promote One-Carbon Metabolism for T Cell Activation. Cell Metab. 2016;24:104–17. PubMed PMC

Chang WK, Yang KD, Chuang H, Jan JT, Shaio MF. Glutamine protects activated human T cells from apoptosis by up-regulating glutathione and Bcl-2 levels. Clin Immunol. 2002;104:151–60. PubMed

Ma EH, Bantug G, Griss T, Condotta S, Johnson RM, Samborska B, et al. Serine Is an Essential Metabolite for Effector T Cell Expansion. Cell Metab. 2017;25:482. PubMed

Ye L, Park JJ, Peng L, Yang Q, Chow RD, Dong MB, et al. A genome-scale gain-of-function CRISPR screen in CD8 T cells identifies proline metabolism as a means to enhance CAR-T therapy. Cell Metab. 2022;34:595–614. PubMed PMC

Rial Saborido J, Völkl S, Aigner M, Mackensen A, Mougiakakos D. Role of CAR T Cell Metabolism for Therapeutic Efficacy. Cancers (Basel). 2022;14:5442. PubMed PMC

Cheng H, Qiu Y, Xu Y, Chen L, Ma K, Tao M, et al. Extracellular acidosis restricts one-carbon metabolism and preserves T cell stemness. Nat Metab. 2023;5:314–30. PubMed PMC

Prochazkova M, Dreyzin A, Shao L, Garces P, Cai Y, Shi R, et al. Deciphering the importance of culture pH on CD22 CAR T-cells characteristics. J Transl Med. 2024;22:384. PubMed PMC

Ma S, Ming Y, Wu J, Cui G. Cellular metabolism regulates the differentiation and function of T-cell subsets. Cell Mol Immunol. 2024;21:419–35. PubMed PMC

Fultang L, Booth S, Yogev O, Martins da Costa B, Tubb V, Panetti S, et al. Metabolic engineering against the arginine microenvironment enhances CAR-T cell proliferation and therapeutic activity. Blood. 2020;136:1155–60. PubMed PMC

Frauwirth KA, Riley JL, Harris MH, Parry RV, Rathmell JC, Plas DR, et al. The CD28 signaling pathway regulates glucose metabolism. Immunity. 2002;16:769–77. PubMed

Menk AV, Scharping NE, Rivadeneira DB, Calderon MJ, Watson MJ, Dunstane D, et al. 4-1BB costimulation induces T cell mitochondrial function and biogenesis enabling cancer immunotherapeutic responses. J Exp Med. 2018;215:1091–100. PubMed PMC

Choi BK, Lee DY, Lee DG, Kim YH, Kim SH, Oh HS, et al. 4-1BB signaling activates glucose and fatty acid metabolism to enhance CD8(+) T cell proliferation. Cell Mol Immunol. 2017;14:748–57. PubMed PMC

Lakhani A, Chen X, Chen LC, Hong M, Khericha M, Chen Y, et al. Extracellular domains of CARs reprogramme T cell metabolism without antigen stimulation. Nat Metab. 2024;6:1143–60. PubMed PMC

Nikolich-Zugich J, Slifka MK, Messaoudi I. The many important facets of T-cell repertoire diversity. Nat Rev Immunol. 2004;4:123–32. PubMed

Qi Q, Liu Y, Cheng Y, Glanville J, Zhang D, Lee JY, et al. Diversity and clonal selection in the human T-cell repertoire. Proc Natl Acad Sci USA. 2014;111:13139–44. PubMed PMC

Pai JA, Satpathy AT. High-throughput and single-cell T cell receptor sequencing technologies. Nat Methods. 2021;18:881–92. PubMed PMC

Han J, Duan J, Bai H, Wang Y, Wan R, Wang X, et al. TCR Repertoire Diversity of Peripheral PD-1(+)CD8(+) T Cells Predicts Clinical Outcomes after Immunotherapy in Patients with Non-Small Cell Lung Cancer. Cancer Immunol Res. 2020;8:146–54. PubMed

Pothuri VS, Hogg GD, Conant L, Borcherding N, James CA, Mudd J, et al. Intratumoral T-cell receptor repertoire composition predicts overall survival in patients with pancreatic ductal adenocarcinoma. Oncoimmunology. 2024;13:2320411. PubMed PMC

Reuben A, Zhang J, Chiou SH, Gittelman RM, Li J, Lee WC, et al. Comprehensive T cell repertoire characterization of non-small cell lung cancer. Nat Commun. 2020;11:603. PubMed PMC

Abbas HA, Hao D, Tomczak K, Barrodia P, Im JS, Reville PK, et al. Single cell T cell landscape and T cell receptor repertoire profiling of AML in context of PD-1 blockade therapy. Nat Commun. 2021;12:6071. PubMed PMC

Keane C, Gould C, Jones K, Hamm D, Talaulikar D, Ellis J, et al. The T-cell Receptor Repertoire Influences the Tumor Microenvironment and Is Associated with Survival in Aggressive B-cell Lymphoma. Clin Cancer Res. 2017;23:1820–8. PubMed

Postow MA, Manuel M, Wong P, Yuan J, Dong Z, Liu C, et al. Peripheral T cell receptor diversity is associated with clinical outcomes following ipilimumab treatment in metastatic melanoma. J Immunother Cancer. 2015;3:23. PubMed PMC

Abed A, Beasley AB, Reid AL, Law N, Calapre L, Millward M, et al. Circulating pre-treatment T-cell receptor repertoire as a predictive biomarker in advanced or metastatic non-small-cell lung cancer patients treated with pembrolizumab alone or in combination with chemotherapy. ESMO Open. 2023;8:102066. PubMed PMC

Charles J, Mouret S, Challende I, Leccia MT, De Fraipont F, Perez S, et al. T-cell receptor diversity as a prognostic biomarker in melanoma patients. Pigment Cell Melanoma Res. 2020;33:612–24. PubMed

Roh W, Chen PL, Reuben A, Spencer CN, Prieto PA, Miller JP, et al. Integrated molecular analysis of tumor biopsies on sequential CTLA-4 and PD-1 blockade reveals markers of response and resistance. Sci Transl Med. 2017;9:eaah3560. PubMed PMC

Weber J, Horak C, Hodi F, Chang H, Woods D, Sanders C, et al. Baseline tumor T cell receptor (TcR) sequencing analysis and neo antigen load is associated with benefit in melanoma patients receiving sequential nivolumab and ipilimumab. Ann Oncol. 2016;27:vi359.

Valpione S, Mundra PA, Galvani E, Campana LG, Lorigan P, De Rosa F, et al. The T cell receptor repertoire of tumor infiltrating T cells is predictive and prognostic for cancer survival. Nat Commun. 2021;12:4098. PubMed PMC

Liu YY, Yang QF, Yang JS, Cao RB, Liang JY, Liu YT, et al. Characteristics and prognostic significance of profiling the peripheral blood T-cell receptor repertoire in patients with advanced lung cancer. Int J Cancer. 2019;145:1423–31. PubMed

Kjær A, Kristjánsdóttir N, Nordentoft I, Juul RI, Birkenkamp-Demtröder K, Ahrenfeldt J, et al. Peripheral T cell receptor repertoire diversity is associated with outcome in bladder cancer. Cancer Res. 2024;84:5216.

Yu X, Pan M, Ye J, Hathaway CA, Tworoger SS, Lea J, et al. Quantifiable TCR repertoire changes in prediagnostic blood specimens among patients with high-grade ovarian cancer. Cell Rep. Med. 2024;5:101612. PubMed PMC

Dhodapkar KM, Cohen AD, Kaushal A, Garfall AL, Manalo RJ, Carr AR, et al. Changes in Bone Marrow Tumor and Immune Cells Correlate with Durability of Remissions Following BCMA CAR T Therapy in Myeloma. Blood Cancer Discov. 2022;3:490–501. PubMed PMC

Rade M, Grieb N, Weiss R, Sia J, Fischer L, Born P, et al. Single-cell multiomic dissection of response and resistance to chimeric antigen receptor T cells against BCMA in relapsed multiple myeloma. Nat Cancer. 2024;5:1318–33. PubMed

Faruqi AJ, Wang P, Bansal R, Corraes ADMS, Zhang H, Shao Z, et al. T-cell receptor repertoire changes associated with clinical response in patients with B-cell non-Hodgkin’s lymphoma receiving CD19 CAR-T therapy. Cancer Res. 2024;84:53.

Ledergor G, Fan Z, Wu K, McCarthy E, Hyrenius-Wittsten A, Starzinski A, et al. CD4+ CAR T-cell exhaustion associated with early relapse of multiple myeloma after BCMA CAR T-cell therapy. Blood Adv. 2024;8:3562–7. PubMed PMC