Advancing CAR T-cell therapy for chronic lymphocytic leukemia: exploring resistance mechanisms and the innovative strategies to overcome them

Abstract

Chimeric antigen receptor (CAR) T-cell therapy has ushered in substantial advancements in the management of various B-cell malignancies. However, its integration into chronic lymphocytic leukemia (CLL) treatment has been challenging, attributed largely to the development of very effective chemo-free alternatives. Additionally, CAR T-cell responses in CLL have not been as high as in other B-cell lymphomas or leukemias. However, a critical void exists in therapeutic options for patients with high-risk diseases who are resistant to the current CLL therapies, underscoring the urgency for adoptive immunotherapies in these patients. The diminished CAR T-cell efficacy within CLL can be traced to factors such as compromised T-cell fitness due to persistent antigenic stimulation inherent to CLL. Resistance mechanisms encompass tumor-related factors like antigen escape, CAR T-cell-intrinsic factors like T-cell exhaustion, and a suppressive tumor microenvironment (TME). New strategies to combat CAR T-cell resistance include the concurrent administration of therapies that augment CAR T-cell endurance and function, as well as the engineering of novel CAR T-cells targeting different antigens. Moreover, the concept of “armored” CAR T-cells, armed with transgenic modulators to modify both CAR T-cell function and the tumor milieu, is gaining traction. Beyond this, the development of readily available, allogeneic CAR T-cells and natural killer (NK) cells presents a promising countermeasure to innate T-cell defects in CLL patients. In this review, we explore the role of CAR T-cell therapy in CLL, the intricate tapestry of resistance mechanisms, and the pioneering methods studied to overcome resistance.

Keywords

CAR T-cells / CLL / resistance mechanisms / allogeneic CART

References

[1] Hartmann J,Bondanza A.Clinical development of CAR T cells - challenges and opportunities in translating innovative treatment concepts.EMBO Mol Med2017;9:1183-97 PMCID:PMC5582407

[2] June CH.Chimeric antigen receptor therapy.N Engl J Med2018;379:64-73 PMCID:PMC7433347

[3] Neelapu SS,Ghobadi A.Five-year follow-up of ZUMA-1 supports the curative potential of axicabtagene ciloleucel in refractory large B-cell lymphoma.Blood2023;141:2307-15

[4] Chihara D,Tkacz J.Real-world experience of CAR T-cell therapy in older patients with relapsed/refractory diffuse large B-cell lymphoma.Blood2023;142:1047-55

[5] Shanafelt TD,Hanson CA.Long-term outcomes for ibrutinib-rituximab and chemoimmunotherapy in CLL: updated results of the E1912 trial.Blood2022;140:112-20 PMCID:PMC9283968

[6] Fischer K,Fink AM.Venetoclax and obinutuzumab in chronic lymphocytic leukemia. Blood. 2017;129(19):2702-2705.Blood2017;130:232 PMCID:PMC5510794

[7] Gauthier J,Purushe J.Feasibility and efficacy of CD19-targeted CAR T cells with concurrent ibrutinib for CLL after ibrutinib failure.Blood2020;135:1650-60 PMCID:PMC7205814

[8] Frey NV,Hexner EO.Long-term outcomes from a randomized dose optimization study of chimeric antigen receptor modified T cells in relapsed chronic lymphocytic leukemia.J Clin Oncol2020;38:2862-71 PMCID:PMC8265376

[9] Siddiqi T,Kenderian SS.Lisocabtagene maraleucel in chronic lymphocytic leukaemia and small lymphocytic lymphoma (TRANSCEND CLL 004): a multicentre, open-label, single-arm, phase 1-2 study.Lancet2023;402:641-54

[10] Döhner H,Benner A.Genomic aberrations and survival in chronic lymphocytic leukemia.N Engl J Med2000;343:1910-6

[11] Stilgenbauer S,Paschka P.Gene mutations and treatment outcome in chronic lymphocytic leukemia: results from the CLL8 trial.Blood2014;123:3247-54

[12] Brocker T,Traunecker A.New simplified molecular design for functional T cell receptor.Eur J Immunol1993;23:1435-9

[13] Brocker T.Signals through T cell receptor-zeta chain alone are insufficient to prime resting T lymphocytes.J Exp Med1995;181:1653-9 PMCID:PMC2192006

[14] Maher J,Gunset G,Sadelain M.Human T-lymphocyte cytotoxicity and proliferation directed by a single chimeric TCRzeta /CD28 receptor.Nat Biotechnol2002;20:70-5

[15] Hoyos V,Quintarelli C.Engineering CD19-specific T lymphocytes with interleukin-15 and a suicide gene to enhance their anti-lymphoma/leukemia effects and safety.Leukemia2010;24:1160-70 PMCID:PMC2888148

[16] Chmielewski M.CAR T Cells Releasing IL-18 convert to T-Bet^high FoxO1^low effectors that exhibit augmented activity against advanced solid tumors.Cell Rep2017;21:3205-19

[17] Bell M.Engineered cytokine signaling to improve CAR T cell effector function.Front Immunol2021;12:684642 PMCID:PMC8220823

[18] Lanitis E,Kosti P.Optimized gene engineering of murine CAR-T cells reveals the beneficial effects of IL-15 coexpression.J Exp Med2021;218:e20192203 PMCID:PMC7653685

[19] Pegram HJ,van Leeuwen DG.IL-12-secreting CD19-targeted cord blood-derived T cells for the immunotherapy of B-cell acute lymphoblastic leukemia.Leukemia2015;29:415-22 PMCID:PMC5189717

[20] Chmielewski M.TRUCKs: the fourth generation of CARs.Expert Opin Biol Ther2015;15:1145-54

[21] Wang M,Goy A.KTE-X19 CAR T-cell therapy in relapsed or refractory mantle-cell lymphoma.N Engl J Med2020;382:1331-42 PMCID:PMC7731441

[22] Porter DL,Kalos M,June CH.Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia.N Engl J Med2011;365:725-33 PMCID:PMC3387277

[23] Melenhorst JJ,Wang M.Decade-long leukaemia remissions with persistence of CD4⁺ CAR T cells.Nature2022;602:503-9 PMCID:PMC9166916

[24] Turtle CJ,Hanafi LA.Durable molecular remissions in chronic lymphocytic leukemia treated with CD19-specific chimeric antigen receptor-modified T cells after failure of ibrutinib.J Clin Oncol2017;35:3010-20 PMCID:PMC5590803

[25] Cappell KM,Yang JC.Long-term follow-up of anti-CD19 chimeric antigen receptor T-cell therapy.J Clin Oncol2020;38:3805-15 PMCID:PMC7655016

[26] Siddiqi T,Kenderian SS.Lisocabtagene maraleucel (liso-cel) in R/R CLL/SLL: 24-month median follow-up of TRANSCEND CLL 004.Blood2023;142:330

[27] Kharfan-Dabaja MA,Gadd ME.Driving out chronic lymphocytic leukemia with CAR T cells.Transplant Cell Ther2022;28:5-17

[28] Vitale C,Perutelli F.CAR-modified cellular therapies in chronic lymphocytic leukemia: is the uphill road getting less steep?.Hemasphere2023;7:e988 PMCID:PMC10691795

[29] Hampel PJ,Wang Y.Incidence of richter transformation in patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL): a cohort study evaluating different therapeutic eras.Blood2023;142:3271

[30] Kittai AS,Huang Y.Anti-CD19 chimeric antigen receptor T-cell therapy for Richter’s transformation: an international multicenter retrospective study.Blood2023;142:108

[31] Shalabi H,Wang HW.Sequential loss of tumor surface antigens following chimeric antigen receptor T-cell therapies in diffuse large B-cell lymphoma.Haematologica2018;103:e215-8 PMCID:PMC5927974

[32] Sotillo E,Black KL.Convergence of acquired mutations and alternative splicing of CD19 enables resistance to CART-19 immunotherapy.Cancer Discov2015;5:1282-95 PMCID:PMC4670800

[33] Gardner R,Cherian S.Acquisition of a CD19-negative myeloid phenotype allows immune escape of MLL-rearranged B-ALL from CD19 CAR-T-cell therapy.Blood2016;127:2406-10 PMCID:PMC4874221

[34] Wang J,Huang H.Acute lymphoblastic leukemia relapse after CD19-targeted chimeric antigen receptor T cell therapy.J Leukoc Biol2017;102:1347-56

[35] Maude SL,Buechner J.Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia.N Engl J Med2018;378:439-48 PMCID:PMC5996391

[36] Plaks V,Chou J.CD19 target evasion as a mechanism of relapse in large B-cell lymphoma treated with axicabtagene ciloleucel.Blood2021;138:1081-5 PMCID:PMC8462361

[37] Fischer J,El Malki K.CD19 isoforms enabling resistance to CART-19 immunotherapy are expressed in B-ALL patients at initial diagnosis.J Immunother2017;40:187-95 PMCID:PMC5424577

[38] Rabilloud T,Pankaew S,Loosveld M.Single-cell profiling identifies pre-existing CD19-negative subclones in a B-ALL patient with CD19-negative relapse after CAR-T therapy.Nat Commun2021;12:865 PMCID:PMC7870924

[39] Zhang Z,Tian Y.Point mutation in CD19 facilitates immune escape of B cell lymphoma from CAR-T cell therapy.J Immunother Cancer2020;8:e001150 PMCID:PMC7539592

[40] Evans AG,Burack WR.Evolution to plasmablastic lymphoma evades CD19-directed chimeric antigen receptor T cells.Br J Haematol2015;171:205-9

[41] Hamieh M,Cabriolu A.CAR T cell trogocytosis and cooperative killing regulate tumour antigen escape.Nature2019;568:112-6 PMCID:PMC6707377

[42] Riches JC,Gribben JG.Immune reconstitution in chronic lymphocytic leukemia.Curr Hematol Malig Rep2012;7:13-20 PMCID:PMC4533917

[43] Riches JC,Gribben JG.Immune dysfunction in chronic lymphocytic leukemia: the role for immunotherapy.Curr Pharm Des2012;18:3389-98

[44] Blank CU,Held W.Defining ‘T cell exhaustion’.Nat Rev Immunol2019;19:665-74 PMCID:PMC7286441

[45] Herrmann F,Philippen H,Rühl H.Imbalance of T cell subpopulations in patients with chronic lymphocytic leukaemia of the B cell type.Clin Exp Immunol1982;49:157-62 PMCID:PMC1536649

[46] Van den Hove LE,Van Gool SW.Peripheral blood lymphocyte subset shifts in patients with untreated hematological tumors: evidence for systemic activation of the T cell compartment.Leuk Res1998;22:175-84

[47] Mu X,Gosland MP.Analysis of blood T-cell cytokine expression in B-chronic lymphocytic leukaemia: evidence for increased levels of cytoplasmic IL-4 in resting and activated CD8 T cells.Br J Haematol1997;96:733-5

[48] Dancescu M,Biron G,Delespesse G.Interleukin 4 protects chronic lymphocytic leukemic B cells from death by apoptosis and upregulates Bcl-2 expression.J Exp Med1992;176:1319-26 PMCID:PMC2119420

[49] D’Arena G,Minervini MM.Regulatory T-cell number is increased in chronic lymphocytic leukemia patients and correlates with progressive disease.Leuk Res2011;35:363-8

[50] Lindqvist CA,Simonsson B,Olsson-Strömberg U.T regulatory cells control T-cell proliferation partly by the release of soluble CD25 in patients with B-cell malignancies.Immunology2010;131:371-6 PMCID:PMC2996557

[51] Riches JC,McClanahan F.T cells from CLL patients exhibit features of T-cell exhaustion but retain capacity for cytokine production.Blood2013;121:1612-21 PMCID:PMC3587324

[52] Ramsay AG,Fatah R.Multiple inhibitory ligands induce impaired T-cell immunologic synapse function in chronic lymphocytic leukemia that can be blocked with lenalidomide: establishing a reversible immune evasion mechanism in human cancer.Blood2012;120:1412-21 PMCID:PMC3423779

[53] Ramsay AG,Lee AM.Chronic lymphocytic leukemia T cells show impaired immunological synapse formation that can be reversed with an immunomodulating drug.J Clin Invest2008;118:2427-37 PMCID:PMC2423865

[54] Mueller KT,Porter DL.Cellular kinetics of CTL019 in relapsed/refractory B-cell acute lymphoblastic leukemia and chronic lymphocytic leukemia.Blood2017;130:2317-25 PMCID:PMC5731220

[55] Hoffmann JM,Wang L.Differences in expansion potential of naive chimeric antigen receptor T cells from healthy donors and untreated chronic lymphocytic leukemia patients.Front Immunol2017;8:1956 PMCID:PMC5767585

[56] Fraietta JA,Orlando EJ.Determinants of response and resistance to CD19 chimeric antigen receptor (CAR) T cell therapy of chronic lymphocytic leukemia.Nat Med2018;24:563-71 PMCID:PMC6117613

[57] Ying Z,Wang X.Parallel comparison of 4-1BB or CD28 co-stimulated CD19-targeted CAR-T cells for B cell non-Hodgkin’s lymphoma.Mol Ther Oncolytics2019;15:60-8 PMCID:PMC6804784

[58] Long AH,Shern JF.4-1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of chimeric antigen receptors.Nat Med2015;21:581-90 PMCID:PMC4458184

[59] Vercellino L,Kanoun S.Predictive factors of early progression after CAR T-cell therapy in relapsed/refractory diffuse large B-cell lymphoma.Blood Adv2020;4:5607-15 PMCID:PMC7686887

[60] Sesques P,Ferrant E.Prognostic impact of 18F-FDG PET/CT in patients with aggressive B-cell lymphoma treated with anti-CD19 chimeric antigen receptor T cells.Clin Nucl Med2021;46:627-34

[61] Porter DL,Frey NV.Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia.Sci Transl Med2015;7:303ra139 PMCID:PMC5909068

[62] Jain MD,Wang X.Tumor interferon signaling and suppressive myeloid cells are associated with CAR T-cell failure in large B-cell lymphoma.Blood2021;137:2621-33 PMCID:PMC8120145

[63] Paggetti J,Seiffert M.Exosomes released by chronic lymphocytic leukemia cells induce the transition of stromal cells into cancer-associated fibroblasts.Blood2015;126:1106-17 PMCID:PMC4560344

[64] Sterner RM.Myeloid cell and cytokine interactions with chimeric antigen receptor-T-cell therapy: implication for future therapies.Curr Opin Hematol2020;27:41-8

[65] Burger JA,Burger M,Dell’Aquila M.Blood-derived nurse-like cells protect chronic lymphocytic leukemia B cells from spontaneous apoptosis through stromal cell-derived factor-1.Blood2000;96:2655-63

[66] Jitschin R,Büttner M.CLL-cells induce IDOhi CD14+HLA-DRlo myeloid-derived suppressor cells that inhibit T-cell responses and promote TRegs.Blood2014;124:750-60

[67] Cox MJ,Sakemura R.Leukemic extracellular vesicles induce chimeric antigen receptor T cell dysfunction in chronic lymphocytic leukemia.Mol Ther2021;29:1529-40 PMCID:PMC8058445

[68] Ninomiya S,Huye L.Tumor indoleamine 2,3-dioxygenase (IDO) inhibits CD19-CAR T cells and is downregulated by lymphodepleting drugs.Blood2015;125:3905-16 PMCID:PMC4473118

[69] Borogovac A.Transforming CLL management with immunotherapy: investigating the potential of CAR T-cells and bispecific antibodies.Semin Hematol2024;S0037-1963(24)00003-9

[70] Fraietta JA,Patel PR.Ibrutinib enhances chimeric antigen receptor T-cell engraftment and efficacy in leukemia.Blood2016;127:1117-27 PMCID:PMC4778162

[71] Ruella M,Shestova O.Kinase inhibitor ibrutinib to prevent cytokine-release syndrome after anti-CD19 chimeric antigen receptor T cells for B-cell neoplasms.Leukemia2017;31:246-8

[72] Long M,Do P.Ibrutinib treatment improves T cell number and function in CLL patients.J Clin Invest2017;127:3052-64 PMCID:PMC5531425

[73] Gill S,Frey NV.Anti-CD19 CAR T cells in combination with ibrutinib for the treatment of chronic lymphocytic leukemia. Blood Adv. 2022;6(21):5774-5785.Blood Adv2023;7:6567 PMCID:PMC10692278

[74] Siddiqi T,Dorritie KA.Phase 1 TRANSCEND CLL 004 study of lisocabtagene maraleucel in patients with relapsed/refractory CLL or SLL.Blood2022;139:1794-806 PMCID:PMC10652916

[75] Wierda WG,Munoz J.Transcend CLL 004: phase 1 cohort of lisocabtagene maraleucel (LISO-CEL) combined with ibrutinib (IBR) for patients (PTS) with r/r CLL/SLL.Hematol Oncol2021;39:hon.86_2879

[76] Thorpe J,Gillenwater H.449 Concurrent ibrutinib enhances T cell function in patients with chronic lymphocytic leukemia (CLL) treated with lisocabtagene maraleucel (liso-cel), a chimeric antigen receptor (CAR) T cell therapy.J Immunother Cancer2021;9:A477

[77] Tettamanti S,Giordano Attianese GMP.Lenalidomide enhances CD23.CAR T cell therapy in chronic lymphocytic leukemia.Leuk Lymphoma2022;63:1566-79 PMCID:PMC9828187

[78] Otáhal P,Král V.Lenalidomide enhances antitumor functions of chimeric antigen receptor modified T cells.Oncoimmunology2016;5:e1115940 PMCID:PMC4839314

[79] Ding W,Call TG.Pembrolizumab in patients with CLL and Richter transformation or with relapsed CLL.Blood2017;129:3419-27 PMCID:PMC5492091

[80] McClanahan F,Miller S.PD-L1 checkpoint blockade prevents immune dysfunction and leukemia development in a mouse model of chronic lymphocytic leukemia.Blood2015;126:203-11 PMCID:PMC4497961

[81] Siddiqi T,Lee H.Safety of lisocabtagene maraleucel given with durvalumab in patients with relapsed/refractory aggressive B-cell non hodgkin lymphoma: first results from the platform study.Hematol Oncol2019;37:171-2

[82] Jacobson CA,Miklos DB.End of phase 1 results from zuma-6: axicabtagene ciloleucel (Axi-Cel) in combination with atezolizumab for the treatment of patients with refractory diffuse large B cell lymphoma.Blood2018;132:4192

[83] Jaeger U,McGuirk JP.Safety and efficacy of tisagenlecleucel plus pembrolizumab in patients with r/r DLBCL: phase 1b PORTIA study results.Blood Adv2023;7:2283-6 PMCID:PMC10225880

[84] Mestermann K,Weber J.The tyrosine kinase inhibitor dasatinib acts as a pharmacologic on/off switch for CAR T cells.Sci Transl Med2019;11:eaau5907 PMCID:PMC7523030

[85] Braun AH,Ho N.Dasatinib is a potent enhancer for CAR T cell generation by CD3-targeted lentiviral vectors.Mol Ther Methods Clin Dev2023;28:90-8 PMCID:PMC9801082

[86] Zhang H,Shao M.Dasatinib enhances anti-leukemia efficacy of chimeric antigen receptor T cells by inhibiting cell differentiation and exhaustion.J Hematol Oncol2021;14:113 PMCID:PMC8293573

[87] Yang X,Zhou J.Overcoming resistance to anti-CD19 CAR T-cell therapy in B-cell malignancies.Hematol Oncol2022;40:821-34

[88] Tan Su Yin E, Hu YX, Huang H. The breakthrough and the future: CD20 chimeric antigen receptor T-cell therapy for hematologic malignancies.ImmunoMedicine2022;2:e1039

[89] Till BG,Wang J.CD20-specific adoptive immunotherapy for lymphoma using a chimeric antigen receptor with both CD28 and 4-1BB domains: pilot clinical trial results.Blood2012;119:3940-50

[90] Almasri NM,Iturraspe J,Braylan RC.Reduced expression of CD20 antigen as a characteristic marker for chronic lymphocytic leukemia.Am J Hematol1992;40:259-63

[91] Watanabe K,Martens AC.Target antigen density governs the efficacy of anti-CD20-CD28-CD3ζ chimeric antigen receptor-modified effector CD8+ T cells.J Immunol2015;194:911-20

[92] Zah E,Silva-Benedict A,Chen YY.T cells expressing CD19/CD20 bispecific chimeric antigen receptors prevent antigen escape by malignant B cells.Cancer Immunol Res2016;4:498-508 PMCID:PMC4933590

[93] Schneider D,Wu D.A tandem CD19/CD20 CAR lentiviral vector drives on-target and off-target antigen modulation in leukemia cell lines.J Immunother Cancer2017;5:42 PMCID:PMC5433150

[94] Shah NN,Schneider D.Bispecific anti-CD20, anti-CD19 CAR T cells for relapsed B cell malignancies: a phase 1 dose escalation and expansion trial.Nat Med2020;26:1569-75

[95] Lee BK,Chin ZL.Developing ROR1 targeting CAR-T cells against solid tumors in preclinical studies.Cancers2022;14:3618 PMCID:PMC9331269

[96] Hudecek M,Baskar S.The B-cell tumor-associated antigen ROR1 can be targeted with T cells modified to express a ROR1-specific chimeric antigen receptor.Blood2010;116:4532-41 PMCID:PMC2996114

[97] Cui B,Chen L.High-level ROR1 associates with accelerated disease progression in chronic lymphocytic leukemia.Blood2016;128:2931-40 PMCID:PMC5179332

[98] Prussak CE, Oh C, Velez Lujan J, et al; University of California, San Diego Moores Cancer Center. Preclinical evaluation of anti-ROR1 CAR T cells employing a ROR1 binding SCFV derived from the clinical stage mab cirmtuzumab. J Clin Oncol 2020;38:41.

[99] Ranganathan R,Ahn S.CAR T cells targeting human immunoglobulin light chains eradicate mature B-cell malignancies while sparing a subset of normal B cells.Clin Cancer Res2021;27:5951-60 PMCID:PMC8575489

[100] Ramos CA,Torrano V.Clinical responses with T lymphocytes targeting malignancy-associated κ light chains.J Clin Invest2016;126:2588-96 PMCID:PMC4922690

[101] Qin H,Sakamaki I.Novel BAFF-receptor antibody to natively folded recombinant protein eliminates drug-resistant human B-cell malignancies in vivo.Clin Cancer Res2018;24:1114-23 PMCID:PMC8953840

[102] Luo Y,To TT.Abstract 2855: antitumor activity of BAFF-R targeting CAR T-cells on chronic lymphocytic leukemia.Cancer Res2022;82:2855

[103] Dong Z,Smith DL.Antitumor efficacy of BAFF-R targeting CAR T cells manufactured under clinic-ready conditions.Cancer Immunol Immunother2020;69:2139-45 PMCID:PMC7511472

[104] Qin H,Wang X.CAR T cells targeting BAFF-R can overcome CD19 antigen loss in B cell malignancies.Sci Transl Med2019;11:eaaw9414 PMCID:PMC7015136

[105] Wang X,Awuah D.CD19/BAFF-R dual-targeted CAR T cells for the treatment of mixed antigen-negative variants of acute lymphoblastic leukemia.Leukemia2022;36:1015-24 PMCID:PMC8983465

[106] Udd KA,Wirtschafter E.Plasma B-cell maturation antigen levels are elevated and correlate with disease activity in patients with chronic lymphocytic leukemia.Target Oncol2019;14:551-61

[107] Munshi NC,Shah N.Idecabtagene vicleucel in relapsed and refractory multiple myeloma.N Engl J Med2021;384:705-16

[108] Berdeja JG,Usmani SZ.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.Lancet2021;398:314-24

[109] Faitschuk E,Frenzel LP,Abken H.Chimeric antigen receptor T cells targeting Fc μ receptor selectively eliminate CLL cells while sparing healthy B cells.Blood2016;128:1711-22

[110] Alwan LM,Sageser D,Agarwal N.Comparison of acute toxicity and mortality after two different dosing regimens of high-dose interleukin-2 for patients with metastatic melanoma.Target Oncol2014;9:63-71

[111] Palomba ML,Caimi PF.Abstract CT125: a phase 1 study to evaluate the safety and tolerability of a combination autologous CD19 CAR T cell therapy (SYNCAR-001) and orthogonal IL-2 (STK-009) in subjects with relapsed or refractory  CD19 expressing hematologic malignancies (NCT05665062).Cancer Res2023;83:CT125

[112] Morgan MA,Sauer M.Use of cell and genome modification technologies to generate improved “off-the-shelf” CAR T and CAR NK cells.Front Immunol2020;11:1965 PMCID:PMC7438733

[113] Brudno JN,Shi V.Allogeneic T cells that express an anti-CD19 chimeric antigen receptor induce remissions of B-cell malignancies that progress after allogeneic hematopoietic stem-cell transplantation without causing graft-versus-host disease.J Clin Oncol2016;34:1112-21 PMCID:PMC4872017

[114] Mehta A,Chen A.Interim phase I clinical data of FT819-101, a study of the first-ever, off-the-shelf, iPSC-derived TCR-less CD19 CAR T-cell therapy for patients with relapsed/refractory B-cell malignancies.Blood2022;140:4577-8

[115] Neelapu SS,Mcguirk JP.Phase 1 study of SC291, a hypoimmune, allogeneic CD19-directed CAR T cell therapy for relapsed/refractory B-cell malignancies (ARDENT) - initial clinical data.Blood2023;142:6852

[116] Hermanson DL.Utilizing chimeric antigen receptors to direct natural killer cell activity.Front Immunol2015;6:195 PMCID:PMC4412125

[117] Liu E,Dotti G.Cord blood NK cells engineered to express IL-15 and a CD19-targeted CAR show long-term persistence and potent antitumor activity.Leukemia2018;32:520-31 PMCID:PMC6063081

[118] Herrera L,Eguizabal C.Purification, culture, and CD19-CAR lentiviral transduction of adult and umbilical cord blood NK cells.Curr Protoc Immunol2020;131:e108

[119] Wang ZH,Dong H.Current state of NK cell-mediated immunotherapy in chronic lymphocytic leukemia.Front Oncol2022;12:1077436 PMCID:PMC10107371

[120] Liu E,Banerjee P.Use of CAR-transduced natural killer cells in CD19-positive lymphoid tumors.N Engl J Med2020;382:545-53 PMCID:PMC7101242