Abstract: Chimeric antigen receptor-T (CAR-T) cell therapy, as a novel cellular immunotherapy, has dramatically reshaped the landscape of cancer treatment, especially in hematological malignancies. However, relapse is still one of the most troublesome obstacles to achieving broad clinical application. The intrinsic factors and superior adaptability of tumor cells mark a fundamental aspect of relapse. The unique biological function of CAR-T cells governed by their special CAR construction also affects treatment efficacy. Moreover, complex cross-interactions among CAR-T cells, tumor cells, and the tumor microenvironment (TME) profoundly influence clinical outcomes concerning CAR-T cell function and persistence. Therefore, in this review, based on the most recent discoveries, we focus on the challenges of relapse after CAR-T cell therapy in B-cell malignancies from the perspective of tumor cells, CAR-T cells, and the TME. We also discuss the corresponding basic and clinical approaches that may overcome the problem in the future. We aim to provide a comprehensive understanding for scientists and physicians that will help improve research and clinical practice.

B细胞恶性肿瘤经CAR-T细胞治疗后复发：挑战与未来

[1]AdachiK, KanoY, NagaiT, et al., 2018. IL-7 and CCL19 expression in CAR-T cells improves immune cell infiltration and CAR-T cell survival in the tumor. Nat Biotechnol, 36(4):346-351.

[2]AjinaA, MaherJ, 2018. Strategies to address chimeric antigen receptor tonic signaling. Mol Cancer Ther, 17(9):1795-1815.

[3]AlabanzaL, PeguesM, GeldresC, et al., 2017. Function of novel anti-CD19 chimeric antigen receptors with human variable regions is affected by hinge and transmembrane domains. Mol Ther, 25(11):2452-2465.

[4]Ancos-PintadoR, Bragado-GarcíaI, MoralesML, et al., 2022. High-throughput CRISPR screening in hematological neoplasms. Cancers (Basel), 14(15):3612.

[5]ArtyomovMN, van den BosscheJ, 2020. Immunometabolism in the single-cell era. Cell Metab, 32(5):710-725.

[6]AsnaniM, HayerKE, NaqviAS, et al., 2020. Retention of CD19 intron 2 contributes to CART-19 resistance in leukemias with subclonal frameshift mutations in CD19. Leukemia, 34(4):1202-1207.

[7]BaiZL, WoodhouseS, ZhaoZR, et al., 2022. Single-cell antigen-specific landscape of CAR T infusion product identifies determinants of CD19-positive relapse in patients with ALL. Sci Adv, 8(23):eabj2820.

[8]BairdJH, FrankMJ, CraigJ, et al., 2021. CD22-directed CAR T-cell therapy induces complete remissions in CD19-directed CAR-refractory large B-cell lymphoma. Blood, 137(17):2321-2325.

[9]BaoC, GaoQL, LiLL, et al., 2021. The application of nanobody in CAR-T therapy. Biomolecules, 11(2):238.

[10]BiondiM, CerinaB, TomasoniC, et al., 2021. Combining the expression of CD33.‍CAR and CXCR4 to increase CAR-CIK cell homing to bone marrow niche and leukemic stem cell eradication in acute myeloid leukemia. Blood, 138(S1):2791-2791.

[11]BoulchM, CazauxM, Loe-MieY, et al., 2021. A cross-talk between CAR T cell subsets and the tumor microenvironment is essential for sustained cytotoxic activity. Sci Immunol, 6(57):eabd4344.

[12]CalderonH, MamonkinM, GuedanS, 2020. Analysis of CAR-mediated tonic signaling. In: Swiech K, Malmegrim KCR, Picanço-Castro V (Eds.), Chimeric Antigen Receptor T Cells. Springer, New York, p.223-236.

[13]CancillaD, RettigMP, DipersioJF, 2020. Targeting CXCR4 in AML and ALL. Front Oncol, 10:1672.

[14]CaoY, XiaoY, WangN, et al., 2021. CD19/CD22 chimeric antigen receptor T cell cocktail therapy following autologous transplantation in patients with relapsed/refractory aggressive B cell lymphomas. Transplant Cell Ther, 27(11):910.e1-910.e11.

[15]CappellKM, SherryRM, YangJC, et al., 2020. Long-term follow-up of anti-CD19 chimeric antigen receptor T-cell therapy. J Clin Oncol, 38(32):3805-3815.

[16]ChenC, LiuJM, LuoYP, 2020. MicroRNAs in tumor immunity: functional regulation in tumor-associated macrophages. J Zhejiang Univ-Sci B (Biomed & Biotechnol), 21(1):12-28.

[17]ChenGM, ChenCY, DasRK, et al., 2021. Integrative bulk and single-cell profiling of premanufacture T-cell populations reveals factors mediating long-term persistence of CAR T-cell therapy. Cancer Discov, 11(9):2186-2199.

[18]ChenJ, López-MoyadoIF, SeoH, et al., 2019. NR4A transcription factors limit CAR T cell function in solid tumours. Nature, 567(7749):530-534.

[19]ChenPH, LipschitzM, WeiratherJL, et al., 2020. Activation of CAR and non-CAR T cells within the tumor microenvironment following CAR T cell therapy. JCI Insight, 5(12):e134612

[20]ChenYH, SunC, LandoniE, et al., 2019. Eradication of neuroblastoma by T cells redirected with an optimized GD2-specific chimeric antigen receptor and interleukin-15. Clin Cancer Res, 25(9):2915-2924.

[21]ChongEA, MelenhorstJJ, LaceySF, et al., 2017. PD-1 blockade modulates chimeric antigen receptor (CAR)‍-modified T cells: refueling the CAR. Blood, 129(8):1039-1041.

[22]ColmoneA, AmorimM, PontierAL, et al., 2008. Leukemic cells create bone marrow niches that disrupt the behavior of normal hematopoietic progenitor cells. Science, 322(5909):1861-1865.

[23]DaiHR, WuZQ, JiaHJ, et al., 2020. Bispecific CAR-T cells targeting both CD19 and CD22 for therapy of adults with relapsed or refractory B cell acute lymphoblastic leukemia. J Hematol Oncol, 13:30.

[24]DavenportAJ, CrossRS, WatsonKA, et al., 2018. Chimeric antigen receptor T cells form nonclassical and potent immune synapses driving rapid cytotoxicity. Proc Natl Acad Sci USA, 115(9):E2068-E2076.

[25]da ViàMC, DietrichO, TrugerM, et al., 2021. Homozygous BCMA gene deletion in response to anti-BCMA CAR T cells in a patient with multiple myeloma. Nat Med, 27(4):616-619.

[26]DengQ, HanGC, Puebla-OsorioN, et al., 2020. Characteristics of anti-CD19 CAR T cell infusion products associated with efficacy and toxicity in patients with large B cell lymphomas. Nat Med, 26(12):1878-1887.

[27]EnbladG, KarlssonH, GammelgårdG, et al., 2018. A phase I/IIa trial using CD19-targeted third-generation CAR T cells for lymphoma and leukemia. Clin Cancer Res, 24(24):6185-6194.

[28]EvansAG, RothbergPG, BurackWR, et al., 2015. Evolution to plasmablastic lymphoma evades CD19-directed chimeric antigen receptor T cells. Br J Haematol, 171(2):205-209.

[29]FanTWM, BanduraLL, HigashiRM, et al., 2005. Metabolomics-edited transcriptomics analysis of Se anticancer action in human lung cancer cells. Metabolomics, 1(4):325-339.

[30]FanTWM, LaneAN, HigashiRM, 2016. Stable isotope resolved metabolomics studies in ex vivo tissue slices. Bio Protoc, 6(3):e1730.

[31]FischerJ, ParetC, el MalkiK, et al., 2017. CD19 isoforms enabling resistance to CART-19 immunotherapy are ex

[32]pressed in B-ALL patients at initial diagnosis. J Immunother, 40(5):187-195.

[33]FraiettaJA, LaceySF, OrlandoEJ, et al., 2018a. Determinants of response and resistance to CD19 chimeric antigen receptor (CAR) T cell therapy of chronic lymphocytic leukemia. Nat Med, 24(5):563-571.

[34]FraiettaJA, NoblesCL, SammonsMA, et al., 2018b. Disruption of TET2 promotes the therapeutic efficacy of CD19-targeted T cells. Nature, 558(7709):307-312.

[35]FrankMJ, HossainNM, BukhariA, et al., 2021. Monitoring of circulating tumor DNA improves early relapse detection after axicabtagene ciloleucel infusion in large B-cell lymphoma: results of a prospective multi-institutional trial. J Clin Oncol, 39(27):3034-3043.

[36]FryTJ, ShahNN, OrentasRJ, et al., 2018. CD22-targeted CAR T cells induce remission in B-ALL that is naive or resistant to CD19-targeted CAR immunotherapy. Nat Med, 24(1):20-28.

[37]FultangL, BoothS, YogevO, et al., 2020. Metabolic engin

[38]eering against the arginine microenvironment enhances CAR-T cell proliferation and therapeutic activity. Blood, 136(10):1155-1160.

[39]GardnerR, WuD, CherianS, et al., 2016. Acquisition of a CD19-negative myeloid phenotype allows immune escape of MLL-rearranged B-ALL from CD19 CAR-T-cell therapy. Blood, 127(20):2406-2410.

[40]GaudichonJ, JakobczykH, DebaizeL, et al., 2019. Mechanisms of extramedullary relapse in acute lymphoblastic leukemia: reconciling biological concepts and clinical issues. Blood Rev, 36:40-56.

[41]GennertDG, LynnRC, GranjaJM, et al., 2021. Dynamic chroma

[42]tin regulatory landscape of human CAR T cell exhaustion. Proc Natl Acad Sci USA, 118(30):e2104758118.

[43]GhoneimHE, FanYP, MoustakiA, et al., 2017. De novo epigenetic programs inhibit PD-1 blockade-mediated T cell rejuvenation. Cell, 170(1):142-157.e19.

[44]GruppSA, KalosM, BarrettD, et al., 2013. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med, 368(16):1509-1518.

[45]GuedanS, PoseyAD, ShawC, et al., 2018. Enhancing CAR T cell persistence through ICOS and 4-1BB costimulation. JCI Insight, 3(1):e96976.

[46]GuerrouahenBS, SidahmedH, al SulaitiA, et al., 2019. Enhancing mesenchymal stromal cell immunomodulation for treating conditions influenced by the immune system. Stem Cells Int, 2019:7219297.

[47]HamiehM, DobrinA, CabrioluA, et al., 2019. CAR T cell trogocytosis and cooperative killing regulate tumour antigen escape. Nature, 568(7750):112-116.

[48]HanahanD, 2022. Hallmarks of cancer: new dimensions. Cancer Discov, 12(1):31-46.

[49]HarrisDT, HagerMV, SmithSN, et al., 2018. Comparison of T cell activities mediated by human TCRs and CARs that use the same recognition domains. J Immunol, 200(3):1088-1100.

[50]HongMH, ClubbJD, ChenYY, 2020. Engineering CAR-T cells for next-generation cancer therapy. Cancer Cell, 38(4):473-488.

[51]HuTY, MurdaughR, NakadaD, 2017. Transcriptional and microenvironmental regulation of lineage ambiguity in leukemia. Front Oncol, 7:268.

[52]HuWH, ZiZG, JinYL, et al., 2019. CRISPR/Cas9-mediated PD-1 disruption enhances human mesothelin-targeted CAR T cell effector functions. Cancer Immunol Immunother, 68(3):365-377.

[53]HuY, ZhouY, ZhangM, et al., 2021. CRISPR/Cas9-engineered universal CD19/CD22 dual-targeted CAR-T cell therapy for relapsed/refractory B-cell acute lymphoblastic leukemia. Clin Cancer Res, 27(10):2764-2772.

[54]HuangH, WuHW, HuYX, 2020. Current advances in chimeric antigen receptor T-cell therapy for refractory/relapsed multiple myeloma. J Zhejiang Univ-Sci B (Biomed & Biotechnol), 21(1):29-41.

[55]HudecekM, SommermeyerD, KosasihPL, et al., 2015. The nonsignaling extracellular spacer domain of chimeric antigen receptors is decisive for in vivo antitumor activity. Cancer Immunol Res, 3(2):125-135.

[56]JacobsonC, LockeFL, GhobadiA, et al., 2021. Long-term (≥4 year and ≥5 year) overall survival (OS) by 12- and 24-month event-free survival (EFS): an updated analysis of ZUMA-1, the pivotal study of axicabtagene ciloleucel (axi-cel) in patients (pts) with refractory large B-cell lymphoma (LBCL). Blood, 138(S1):1764-1764.

[57]JacobyE, NguyenSM, FountaineTJ, et al., 2016. CD19 CAR immune pressure induces B-precursor acute lymphoblastic leukaemia lineage switch exposing inherent leukaemic plasticity. Nat Commun, 7:12320.

[58]JainMD, ZhaoH, WangXF, et al., 2021. Tumor interferon signaling and suppressive myeloid cells are associated with CAR T-cell failure in large B-cell lymphoma. Blood, 137(19):2621-2633.

[59]JingXM, YangFM, ShaoCC, et al., 2019. Role of hypoxia in cancer therapy by regulating the tumor microenvironment. Mol Cancer, 18:157.

[60]JohnS, PulsipherMA, MoskopA, et al., 2021. Real-world outcomes for pediatric and young adult patients with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (ALL) treated with tisagenlecleucel: update from the center for international blood and marrow transplant research (CIBMTR) registry. Blood, 138(S1):428.

[61]KadomotoS, IzumiK, MizokamiA, 2021. Macrophage polarity and disease control. Int J Mol Sci, 23(1):144.

[62]KailayangiriS, AltvaterB, WiebelM, et al., 2020. Overcoming heterogeneity of antigen expression for effective CAR T cell targeting of cancers. Cancers (Basel), 12(5):1075.

[63]KhanO, GilesJR, McdonaldS, et al., 2019. TOX transcriptionally and epigenetically programs CD8⁺ T cell exhaustion. Nature, 571(7764):211-218.

[64]KongWM, DimitriA, WangWL, et al., 2021. BET bromodomain protein inhibition reverses chimeric antigen receptor extinction and reinvigorates exhausted T cells in chronic lymphocytic leukemia. J Clin Invest, 131(16):e145459.

[65]KumarV, PatelSM, TcyganovE, et al., 2016. The nature of myeloid-derived suppressor cells in the tumor microenvironment. Trends Immunol, 37(3):208-220.

[66]LangierS, SadeK, KivityS, 2010. Regulatory T cells: the suppressor arm of the immune system. Autoimmun Rev, 10(2):112-115.

[67]LarsonRC, MausMV, 2021. Recent advances and discoveries in the mechanisms and functions of CAR T cells. Nat Rev Cancer, 21(3):145-161.

[68]LiN, HuaJL, 2017. Interactions between mesenchymal stem cells and the immune system. Cell Mol Life Sci, 74(13):2345-2360.

[69]LiS, SiriwonN, ZhangXY, et al., 2017. Enhanced cancer immunotherapy by chimeric antigen receptor-modified T cells engineered to secrete checkpoint inhibitors. Clin Cancer Res, 23(22):6982-6992.

[70]LiYR, YuYQ, KramerA, et al., 2022. An ex vivo 3D tumor microenvironment-mimicry culture to study TAM modulation of cancer immunotherapy. Cells, 11(9):1583.

[71]LindoL, WilkinsonLH, HayKA, 2021. Befriending the hostile tumor microenvironment in CAR T-cell therapy. Front Immunol, 11:618387.

[72]LongAH, HasoWM, ShernJF, et al., 2015. 4-1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of chimeric antigen receptors. Nat Med, 21(6):581-590.

[73]LynnRC, WeberEW, SotilloE, et al., 2019. c-Jun overexpression in CAR T cells induces exhaustion resistance. Nature, 576(7786):293-300.

[74]MacianF, 2005. NFAT proteins: key regulators of T-cell development and function. Nat Rev Immunol, 5(6):472-484.

[75]MajznerRG, MackallCL, 2018. Tumor antigen escape from CAR T-cell therapy. Cancer Discov, 8(10):1219-1226.

[76]MausMV, HaasAR, BeattyGL, et al., 2013. T cells expressing chimeric antigen receptors can cause anaphylaxis in humans. Cancer Immunol Res, 1(1):26-31.

[77]McgranahanN, SwantonC, 2017. Clonal heterogeneity and tumor evolution: past, present, and the future. Cell, 168(4):613-628.

[78]MelenhorstJJ, ChenGM, WangM, et al., 2022. Decade-long leukaemia remissions with persistence of CD4⁺ CAR T cells. Nature, 602(7897):503-509.

[79]MiaoLL, ZhangZC, RenZJ, et al., 2021. Reactions related to CAR-T cell therapy. Front Immunol, 12:663201.

[80]MuñozL, NomdedéuJF, LópezO, et al., 2001. Interleukin-3 receptor alpha chain (CD123) is widely expressed in hematologic malignancies. Haematologica, 86(12):1261-1269.

[81]OrlandoEJ, HanX, TribouleyC, et al., 2018. Genetic mechanisms of target antigen loss in CAR19 therapy of acute lymphoblastic leukemia. Nat Med, 24(10):1504-1506.

[82]PaukenKE, SammonsMA, OdorizziPM, et al., 2016. Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade. Science, 354(6316):1160-1165.

[83]PeledA, KleinS, BeiderK, et al., 2018. Role of CXCL12 and CXCR4 in the pathogenesis of hematological malignancies. Cytokine, 109:11-16.

[84]PinhoS, FrenettePS, 2019. Haematopoietic stem cell activity and interactions with the niche. Nat Rev Mol Cell Biol, 20(5):303-320.

[85]PrasetyantiPR, MedemaJP, 2017. Intra-tumor heterogeneity from a cancer stem cell perspective. Mol Cancer, 16:41.

[86]PrinzingB, ZebleyCC, PetersenCT, et al., 2021. Deleting DNMT3A in CAR T cells prevents exhaustion and enhances antitumor activity. Sci Transl Med, 13(620):eabh0272.

[87]QiYK, ZhaoMF, HuYX, et al., 2022. Efficacy and safety of CD19-specific CAR T cell-based therapy in B-cell acute lymphoblastic leukemia patients with CNSL. Blood, 139(23):3376-3386.

[88]RafeiH, DaherM, RezvaniK, 2021. Chimeric antigen receptor (CAR) natural killer (NK)-cell therapy: leveraging the power of innate immunity. Br J Haematol, 193(2):‍216-230.

[89]RafiqS, YekuOO, JacksonHJ, et al., 2018. Targeted delivery of a PD-1-blocking scFv by CAR-T cells enhances anti-tumor efficacy in vivo. Nat Biotechnol, 36(9):847-856.

[90]RamakrishnaS, HighfillSL, WalshZ, et al., 2019. Modulation of target antigen density improves CAR T-cell functionality and persistence. Clin Cancer Res, 25(17):5329-5341.

[91]RamosCA, GroverNS, BeavenAW, et al., 2020. Anti-CD30 CAR-T cell therapy in relapsed and refractory hodgkin lymphoma. J Clin Oncol, 38(32):3794-3804.

[92]RegmiS, PathakS, KimJO, et al., 2019. Mesenchymal stem cell therapy for the treatment of inflammatory diseases: challenges, opportunities, and future perspectives. Eur J Cell Biol, 98(5-8):151041.

[93]RenXW, ZhangL, ZhangYY, et al., 2021. Insights gained from single-cell analysis of immune cells in the tumor microenvironment. Annu Rev Immunol, 39:583-609.

[94]RoselliE, FaramandR, DavilaML, 2021. Insight into next-generation CAR therapeutics: designing CAR T cells to improve clinical outcomes. J Clin Invest, 131(2):e142030.

[95]RuellaM, BarrettDM, KenderianSS, et al., 2016. Dual CD19 and CD123 targeting prevents antigen-loss relapses after CD19-directed immunotherapies. J Clin Invest, 126(10):3814-3826.

[96]RuellaM, XuJ, BarrettDM, et al., 2018. Induction of resistance to chimeric antigen receptor T cell therapy by transduction of a single leukemic B cell. Nat Med, 24(10):1499-1503.

[97]Sadeqi NezhadM, Abdollahpour-AlitappehM, RezaeiB, et al., 2021. Induced pluripotent stem cells (iPSCs) provide a potentially unlimited T cell source for CAR-T cell development and off-the-shelf products. Pharm Res, 38(6):931-945.

[98]SakaguchiS, OnoM, SetoguchiR, et al., 2006. Foxp3⁺CD25+CD4+ natural regulatory T cells in dominant self-tolerance and autoimmune disease. Immunol Rev, 212(1):8-27.

[99]SalterAI, RajanA, KennedyJJ, et al., 2021. Comparative analysis of TCR and CAR signaling informs CAR designs with superior antigen sensitivity and in vivo function. Sci Signal, 14(697):eabe2606.

[100]SavoldoB, RamosCA, LiuEL, et al., 2011. CD28 costimulation improves expansion and persistence of chimeric antigen receptor-modified T cells in lymphoma patients. J Clin Invest, 121(5):1822-1826.

[101]ScarfòI, OrmhøjM, FrigaultMJ, et al., 2018. Anti-CD37 chimeric antigen receptor T cells are active against B- and T-cell lymphomas. Blood, 132(14):1495-1506.

[102]SchererF, KurtzDM, NewmanAM, et al., 2016. Distinct biological subtypes and patterns of genome evolution in lymphoma revealed by circulating tumor DNA. Sci Transl Med, 8(364):364ra155.

[103]SchneiderD, XiongY, WuDR, et al., 2017. A tandem CD19/CD20 CAR lentiviral vector drives on-target and off-target antigen modulation in leukemia cell lines. J Immunother Cancer, 5(1):42.

[104]SenDR, KaminskiJ, BarnitzRA, et al., 2016. The epigenetic landscape of T cell exhaustion. Science, 354(6316):1165-1169.

[105]SeoH, ChenJ, González-AvalosE, et al., 2019. TOX and TOX2 transcription factors cooperate with NR4A transcription factors to impose CD8⁺ T cell exhaustion. Proc Natl Acad Sci USA, 116(25):12410-12415.

[106]ShafferDR, SavoldoB, YiZZ, et al., 2011. T cells redirected against CD70 for the immunotherapy of CD70-positive malignancies. Blood, 117(16):4304-4314.

[107]ShahNN, QinHY, YatesB, et al., 2019. Clonal expansion of CAR T cells harboring lentivector integration in the CBL gene following anti-CD22 CAR T-cell therapy. Blood Adv, 3(15):2317-2322.

[108]ShalabiH, KraftIL, WangHW, et al., 2018. Sequential loss of tumor surface antigens following chimeric antigen receptor T-cell therapies in diffuse large B-cell lymphoma. Haematologica, 103(5):e215-e218.

[109]ShaoM, TengXY, GuoX, et al., 2022. Inhibition of calcium signaling prevents exhaustion and enhances anti-leukemia efficacy of CAR-T cells via SOCE-calcineurin-NFAT and glycolysis pathways. Adv Sci (Weinh), 9(9):2103508.

[110]SiXH, XiaoL, BrownCE, et al., 2022. Preclinical evaluation of CAR T cell function: in vitro and in vivo models. Int J Mol Sci, 23(6):3154.

[111]SiddiqiT, WangXL, BlanchardMS, et al., 2021. CD19-directed CAR T-cell therapy for treatment of primary CNS lymphoma. Blood Adv, 5(20):4059-4063.

[112]SinghN, LeeYG, ShestovaO, et al., 2020. Impaired death receptor signaling in leukemia causes antigen-independent resistance by inducing CAR T-cell dysfunction. Cancer Discov, 10(4):552-567.

[113]SotilloE, BarrettDM, BlackKL, et al., 2015. Convergence of acquired mutations and alternative splicing of CD19 enables resistance to CART-19 immunotherapy. Cancer Discov, 5(12):1282-1295.

[114]StepanovAV, MarkovOV, ChernikovIV, et al., 2018. Autocrine-based selection of ligands for personalized CAR-T therapy of lymphoma. Sci Adv, 4(11):eaau4580.

[115]SternerRC, SternerRM, 2021. CAR-T cell therapy: current limitations and potential strategies. Blood Cancer J, 11(4):69.

[116]SunY, SuYF, WangYZ, et al., 2021. CD19 CAR-T cells with membrane-bound IL-15 for B-cell acute lymphoblastic leukemia after failure of CD19 and CD22 CAR-T cells: case report. Front Immunol, 12:728962.

[117]TallenG, RateiR, MannG, et al., 2010. Long-term outcome in children with relapsed acute lymphoblastic leukemia after time-point and site-of-relapse stratification and intensified short-course multidrug chemotherapy: results of trial ALL-REZ BFM 90. J Clin Oncol, 28(14):2339-2347.

[118]TanY, PanJ, DengBP, et al., 2021. Toxicity and effectiveness of CD19 CAR T therapy in children with high-burden central nervous system refractory B-ALL. Cancer Immunol Immunother, 70(7):1979-1993.

[119]ThankamonyAP, SubbalakshmiAR, JollyMK, et al., 2021. Lineage plasticity in cancer: the tale of a skin-walker. Cancers (Basel), 13(14):3602.

[120]ThomsJAI, PimandaJE, HeidenreichO, 2021. To switch or not to switch: PU.‍1 expression is the question. Blood, 138(15):1289-1291.

[121]TongC, ZhangY, LiuY, et al., 2020. Optimized tandem CD19/CD20 CAR-engineered T cells in refractory/relapsed B-cell lymphoma. Blood, 136(14):1632-1644.

[122]TuSF, ZhouX, GuoZL, et al., 2019. CD19 and CD70 dual-target chimeric antigen receptor T-cell therapy for the treatment of relapsed and refractory primary central nervous system diffuse large B-cell lymphoma. Front Oncol, 9:1350.

[123]van BruggenJAC, MartensAWJ, FraiettaJA, et al., 2019. Chronic lymphocytic leukemia cells impair mitochondrial fitness in CD8⁺ T cells and impede CAR T-cell efficacy. Blood, 134(1):44-58.

[124]WalkerAJ, MajznerRG, ZhangL, et al., 2017. Tumor antigen and receptor densities regulate efficacy of a chimeric antigen receptor targeting anaplastic lymphoma kinase. Mol Ther, 25(9):2189-2201.

[125]WangDR, PragerBC, GimpleRC, et al., 2021. CRISPR screening of CAR T cells and cancer stem cells reveals critical dependencies for cell-based therapies. Cancer Discov, 11(5):1192-1211.

[126]WangH, KaurG, SankinAI, et al., 2019. Immune checkpoint blockade and CAR-T cell therapy in hematologic malignancies. J Hematol Oncol, 12:59.

[127]WangJS, HuYX, HuangH, 2017. Acute lymphoblastic leukemia relapse after CD19-targeted chimeric antigen receptor T cell therapy. J Leukoc Biol, 102(6):1347-1356.

[128]WangWL, FasolinoM, CattauB, et al., 2020. Joint profiling of chromatin accessibility and CAR-T integration site analysis at population and single-cell levels. Proc Natl Acad Sci USA, 117(10):5442-5452.

[129]WangY, TongC, DaiHR, et al., 2021. Low-dose decitabine priming endows CAR T cells with enhanced and persistent antitumour potential via epigenetic reprogramming. Nat Commun, 12:409.

[130]WeberEW, ParkerKR, SotilloE, et al., 2021. Transient rest restores functionality in exhausted CAR-T cells through epigenetic remodeling. Science, 372(6537):eaba1786.

[131]WebsterB, XiongY, HuPR, et al., 2021. Self-driving armored CAR-T cells overcome a suppressive milieu and eradicate CD19⁺ Raji lymphoma in preclinical models. Mol Ther, 29(9):2691-2706.

[132]WilliamsMTS, YousafzaiYM, ElderA, et al., 2016. The ability to cross the blood-cerebrospinal fluid barrier is a generic property of acute lymphoblastic leukemia blasts. Blood, 127(16):1998-2006.

[133]WilsonWR, HayMP, 2011. Targeting hypoxia in cancer therapy. Nat Rev Cancer, 11(6):393-410.

[134]XiaLZ, OyangL, LinJG, et al., 2021. The cancer metabolic reprogramming and immune response. Mol Cancer, 20:28.

[135]XuXQ, GnanaprakasamJNR, ShermanJ, et al., 2019. A metabolism toolbox for CAR T therapy. Front Oncol, 9:322.

[136]YanLE, ZhangHY, WadaM, et al., 2020. Targeting two antigens associated with B-ALL with CD19-CD123 compound CAR T cell therapy. Stem Cell Rev Rep, 16(2):385-396.

[137]YanN, WangN, WangGX, et al., 2022. CAR19/22 T cell cocktail therapy for B-ALL relapsed after allogeneic hematopoietic stem cell transplantation. Cytotherapy, 24(8):841-849.

[138]YanX, ChenDY, WangY, et al., 2022. Identification of NOXA as a pivotal regulator of resistance to CAR T-cell therapy in B-cell malignancies. Signal Transduct Target Ther, 7:98.

[139]YanZX, LiL, WangW, et al., 2019. Clinical efficacy and tumor microenvironment influence in a dose-escalation study of anti-CD19 chimeric antigen receptor T cells in refractory B-cell non-Hodgkin’s lymphoma. Clin Cancer Res, 25(23):6995-7003.

[140]YangX, YuQX, XuH, et al., 2021. Upregulation of CD22 by chidamide promotes CAR T cells functionality. Sci Rep, 11(1):20637.

[141]YangXO, NurievaR, MartinezGJ, et al., 2008. Molecular antagonism and plasticity of regulatory and inflammatory T cell programs. Immunity, 29:44-56.

[142]YingZT, HeT, WangXP, et al., 2019. Parallel comparison of 4-1BB or CD28 co-stimulated CD19-targeted CAR-T cells for B cell non-Hodgkin’s lymphoma. Mol Ther Oncolytics, 15:60-68.

[143]YouLS, HanQM, ZhuL, et al., 2020. Decitabine-mediated epigenetic reprograming enhances anti-leukemia efficacy of CD123-targeted chimeric antigen receptor T-cells. Front Immunol, 11:1787.

[144]YuH, SotilloE, HarringtonC, et al., 2017. Repeated loss of target surface antigen after immunotherapy in primary mediastinal large B cell lymphoma. Am J Hematol, 92(1):E11-E13.

[145]ZahE, LinMY, Silva-BenedictA, et al., 2016. T cells expressing CD19/CD20 bispecific chimeric antigen receptors prevent antigen escape by malignant B cells. Cancer Immunol Res, 4(6):498-508.

[146]ZanettiSR, RomecinPA, VinyolesM, et al., 2020. Bone marrow MSC from pediatric patients with B-ALL highly immunosuppress T-cell responses but do not compromise CD19-CAR T-cell activity. J Immunother Cancer, 8(2):e001419.

[147]ZebleyCC, BrownC, MiT, et al., 2021. CD19-CAR T cells undergo exhaustion DNA methylation programming in patients with acute lymphoblastic leukemia. Cell Rep, 37(9):110079.

[148]ZhangL, TianL, DaiXY, et al., 2020. Pluripotent stem cell-derived CAR-macrophage cells with antigen-dependent anti-cancer cell functions. J Hematol Oncol, 13:153.

[149]ZhangZ, ChenXF, TianYG, et al., 2020. Point mutation in CD19 facilitates immune escape of B cell lymphoma from CAR-T cell therapy. J Immunother Cancer, 8(2):e001150.

[150]ZhengWC, XueQF, ShaXP, et al., 2021. Successful PD-1 inhibitor treatment in a patient with refractory transformed follicular lymphoma who failed to respond to CAR-T cell therapy: a case report and literature review. Cancer Biol Ther, 22(10-12):537-543.

[151]ZhouZ, HanY, PanHB, et al., 2021. Tri-specific CD19×CD20×CD22 VHH CAR-T cells (LCAR-AIO) eradicate antigen-heterogeneous B cell tumors, enhance expansion, and prolong persistence in preclinical in vivo models. Blood, 138(S1):1700.

[152]ZhouZL, van der JeughtK, FangYZ, et al., 2021. An organoid-based screen for epigenetic inhibitors that stimulate antigen presentation and potentiate T-cell-mediated cytotoxicity. Nat Biomed Eng, 5(11):1320-1335.