Improving CAR-T immunotherapy: Overcoming the challenges of T cell exhaustion

EBioMedicine - Tập 77 - Trang 103941 - 2022
Diana Gumber1,2, Leo D. Wang1,3,2
1Department of Immunooncology, City of Hope National Medical Center, Beckman Research Institute, Duarte, CA, United States
2Irell and Manella Graduate School of Biological Sciences, City of Hope National Medical Center, Beckman Research Institute, Duarte CA, United States
3Department of Pediatrics, City of Hope National Medical Center, Duarte, CA, United States

Tóm tắt

Từ khóa


Tài liệu tham khảo

Tan, 2020, Adoptive T-cell therapy for HBV-associated HCC and HBV infection, Antivir Res, 176, 10.1016/j.antiviral.2020.104748

Laskowski, 2020, Adoptive cell therapy: living drugs against cancer, J Exp Med, 217, e20200377, 10.1084/jem.20200377

Zhou, 2021, Challenges and opportunities of using adoptive T-cell therapy as part of an HIV cure strategy, J Infect Dis, 223, 38, 10.1093/infdis/jiaa223

Fong, 2002, Immunotherapy in autoimmune diseases, Ann Acad Med Singap, 31, 702

Duffy, 2019, Adoptive transfer of regulatory T cells as a promising immunotherapy for the treatment of multiple sclerosis, Front Neurosci, 13, 1107, 10.3389/fnins.2019.01107

Eshhar, 1993, Specific activation and targeting of cytotoxic lymphocytes through chimeric single chains consisting of antibody-binding domains and the gamma or zeta subunits of the immunoglobulin and T-cell receptors, Proc Natl Acad Sci USA, 90, 720, 10.1073/pnas.90.2.720

Marofi, 2021, CAR T cells in solid tumors: challenges and opportunities, Stem Cell Res Ther, 12, 81, 10.1186/s13287-020-02128-1

Zmievskaya, 2021, Application of CAR-T cell therapy beyond oncology: autoimmune diseases and viral infections, Biomedicines, 9, 59, 10.3390/biomedicines9010059

Finney, 2019, CD19 CAR T cell product and disease attributes predict leukemia remission durability, J Clin Invest, 129, 2123, 10.1172/JCI125423

Hu, 2021, Anti-CD19 CAR-T cell therapy bridge to HSCT decreases the relapse rate and improves the long-term survival of R/R B-ALL patients: a systematic review and meta-analysis, Ann Hematol, 100, 1003, 10.1007/s00277-021-04451-w

Xu, 2020, Challenges and clinical strategies of CAR T-cell therapy for acute lymphoblastic leukemia: overview and developments, Front Immunol, 11

Majzner, 2018, Tumor antigen escape from CAR T-cell therapy, Cancer Discov, 8, 1219, 10.1158/2159-8290.CD-18-0442

Fraietta, 2018, Determinants of response and resistance to CD19 chimeric antigen receptor (CAR) T cell therapy of chronic lymphocytic leukemia, Nat Med, 24, 563, 10.1038/s41591-018-0010-1

Rodriguez-Garcia, 2020, CAR-T cells hit the tumor microenvironment: strategies to overcome tumor escape, Front Immunol, 11, 1109, 10.3389/fimmu.2020.01109

Lesch, 2020, Determinants of response and resistance to CAR T cell therapy, Semin Cancer Biol, 65, 80, 10.1016/j.semcancer.2019.11.004

Sterner, 2021, CAR-T cell therapy: current limitations and potential strategies, Blood Cancer J, 11, 69, 10.1038/s41408-021-00459-7

Liu, 2021, Enhancing CAR-T cell efficacy in solid tumors by targeting the tumor microenvironment, Cell Mol Immunol, 18, 1085, 10.1038/s41423-021-00655-2

Carmenate, 2018, Blocking IL-2 signal in vivo with an IL-2 antagonist reduces tumor growth through the control of regulatory T cells, J Immunol, 200, 3475, 10.4049/jimmunol.1700433

Louis, 2011, Antitumor activity and long-term fate of chimeric antigen receptor-positive T cells in patients with neuroblastoma, Blood, 118, 6050, 10.1182/blood-2011-05-354449

Majzner, 2019, Clinical lessons learned from the first leg of the CAR T cell journey, Nat Med, 25, 1341, 10.1038/s41591-019-0564-6

Bucks, 2009, Chronic antigen stimulation alone is sufficient to drive CD8+ T cell exhaustion, J Immunol, 182, 6697, 10.4049/jimmunol.0800997

Pauken, 2015, Overcoming T cell exhaustion in infection and cancer, Trends Immunol, 36, 265, 10.1016/j.it.2015.02.008

Wherry, 2011, T cell exhaustion, Nat Immunol, 12, 492, 10.1038/ni.2035

Fraietta, 2021, Author correction: determinants of response and resistance to CD19 chimeric antigen receptor (CAR) T cell therapy of chronic lymphocytic leukemia, Nat Med, 27, 561, 10.1038/s41591-021-01248-2

Wang, 2019, In vitro tumor cell rechallenge for predictive evaluation of chimeric antigen receptor T cell antitumor function, J Vis Exp, e59275

Yang, 2020, TIGIT expression is associated with T-cell suppression and exhaustion and predicts clinical outcome and anti-PD-1 response in follicular lymphoma, Clin Cancer Res, 26, 5217, 10.1158/1078-0432.CCR-20-0558

Lindner, 2020, Chimeric antigen receptor signaling: functional consequences and design implications, Sci Adv, 6, eaaz3223, 10.1126/sciadv.aaz3223

Zajac, 1998, Viral immune evasion due to persistence of activated T cells without effector function, J Exp Med, 188, 2205, 10.1084/jem.188.12.2205

Saeidi, 2018, T-cell exhaustion in chronic infections: reversing the state of exhaustion and reinvigorating optimal protective immune responses, Front Immunol, 9, 2569, 10.3389/fimmu.2018.02569

Wherry, 2015, Molecular and cellular insights into T cell exhaustion, Nat Rev Immunol, 15, 486, 10.1038/nri3862

Dong, 2019, CD4+ T cell exhaustion revealed by high PD-1 and LAG-3 expression and the loss of helper T cell function in chronic hepatitis B, BMC Immunol, 20, 27, 10.1186/s12865-019-0309-9

Han, 2010, Role of antigen persistence and dose for CD4+ T-cell exhaustion and recovery, Proc Natl Acad Sci USA, 107, 20453, 10.1073/pnas.1008437107

Gerlach, 2010, One naive T cell, multiple fates in CD8+ T cell differentiation, J Exp Med, 207, 1235, 10.1084/jem.20091175

Cornberg, 2013, Clonal exhaustion as a mechanism to protect against severe immunopathology and death from an overwhelming CD8 T cell response, Front Immunol, 4, 475, 10.3389/fimmu.2013.00475

Obar, 2010, Memory CD8+ T cell differentiation, Ann N Y Acad Sci, 1183, 251, 10.1111/j.1749-6632.2009.05126.x

Cosma, 2019, Impact of epitope density on CD8+ T cell development and function, Mol Immunol, 113, 120, 10.1016/j.molimm.2019.03.010

Kroger, 2007, Cutting edge: CD8+ T cell clones possess the potential to differentiate into both high- and low-avidity effector cells, J Immunol, 179, 748, 10.4049/jimmunol.179.2.748

Kroger, 2008, Cutting edge: dendritic cells prime a high avidity CTL response independent of the level of presented antigen, J Immunol, 180, 5784, 10.4049/jimmunol.180.9.5784

Sharma, 2011, Increased sensitivity to antigen in high avidity CD8+ T cells results from augmented membrane proximal T-cell receptor signal transduction, Immunology, 133, 307, 10.1111/j.1365-2567.2011.03440.x

Curdy, 2019, Regulatory mechanisms of inhibitory immune checkpoint receptors expression, Trends Cell Biol, 29, 777, 10.1016/j.tcb.2019.07.002

McLane, 2019, CD8 T cell exhaustion during chronic viral infection and cancer, Annu Rev Immunol, 37, 457, 10.1146/annurev-immunol-041015-055318

Khan, 2019, TOX transcriptionally and epigenetically programs CD8+ T cell exhaustion, Nature, 571, 211, 10.1038/s41586-019-1325-x

Ostroumov, 2021, Transcriptome profiling identifies TIGIT as a marker of T-cell exhaustion in liver cancer, Hepatology, 73, 1399, 10.1002/hep.31466

Jiang, 2020, Exhausted CD8+T cells in the tumor immune microenvironment: new pathways to therapy, Front Immunol, 11

Beltra, 2020, Developmental relationships of four exhausted CD8+ T cell subsets reveals underlying transcriptional and epigenetic landscape control mechanisms, Immunity, 52, 825, 10.1016/j.immuni.2020.04.014

Chu, 2020, Charting the roadmap of T cell exhaustion, Immunity, 52, 724, 10.1016/j.immuni.2020.04.019

Philip, 2017, Chromatin states define tumour-specific T cell dysfunction and reprogramming, Nature, 545, 452, 10.1038/nature22367

Chen, 2019, TCF-1-centered transcriptional network drives an effector versus exhausted CD8 T cell-fate decision, Immunity, 51, 840, 10.1016/j.immuni.2019.09.013

Zander, 2019, CD4+ T cell help is required for the formation of a cytolytic CD8+ T cell subset that protects against chronic infection and cancer, Immunity, 51, 1028, 10.1016/j.immuni.2019.10.009

Hudson, 2019, Proliferating transitory T cells with an effector-like transcriptional signature emerge from PD-1+ stem-like CD8+ T Cells During Chronic Infection, Immunity, 51, 1043, 10.1016/j.immuni.2019.11.002

Kim, 2020, Single-cell transcriptome analysis reveals TOX as a promoting factor for T cell exhaustion and a predictor for anti-PD-1 responses in human cancer, Genome Med, 12, 22, 10.1186/s13073-020-00722-9

Liang, 2021, TOX as a potential target for immunotherapy in lymphocytic malignancies, Biomark Res, 9, 20, 10.1186/s40364-021-00275-y

Seo, 2021, Transcriptional regulatory network for the establishment of CD8+ T cell exhaustion, Exp Mol Med, 53, 202, 10.1038/s12276-021-00568-0

Seo, 2019, TOX and TOX2 transcription factors cooperate with NR4A transcription factors to impose CD8+ T cell exhaustion, Proc Natl Acad Sci USA, 116, 12410, 10.1073/pnas.1905675116

Chen, 2019, NR4A transcription factors limit CAR T cell function in solid tumours, Nature, 567, 530, 10.1038/s41586-019-0985-x

Scott, 2019, TOX is a critical regulator of tumour-specific T cell differentiation, Nature, 571, 270, 10.1038/s41586-019-1324-y

Alfei, 2019, TOX reinforces the phenotype and longevity of exhausted T cells in chronic viral infection, Nature, 571, 265, 10.1038/s41586-019-1326-9

Yao, 2019, Single-cell RNA-seq reveals TOX as a key regulator of CD8+ T cell persistence in chronic infection, Nat Immunol, 20, 890, 10.1038/s41590-019-0403-4

McLane, 2021, Role of nuclear localization in the regulation and function of T-bet and Eomes in exhausted CD8 T cells, Cell Rep, 35, 10.1016/j.celrep.2021.109120

Li, 2018, High levels of Eomes promote exhaustion of anti-tumor CD8+ T cells, Front Immunol, 9, 2981, 10.3389/fimmu.2018.02981

Jia, 2019, Eomes+T-bet(low) CD8+ T cells are functionally impaired and are associated with poor clinical outcome in patients with acute myeloid leukemia, Cancer Res, 79, 1635, 10.1158/0008-5472.CAN-18-3107

Riley, 2009, PD-1 signaling in primary T cells, Immunol Rev, 229, 114, 10.1111/j.1600-065X.2009.00767.x

Jubel, 2020, The role of PD-1 in acute and chronic infection, Front Immunol, 11, 487, 10.3389/fimmu.2020.00487

Zuazo, 2017, Molecular mechanisms of programmed cell death-1 dependent T cell suppression: relevance for immunotherapy, Ann Transl Med, 5, 385, 10.21037/atm.2017.06.11

Bardhan, 2016, The PD1:PD-L1/2 pathway from discovery to clinical implementation, Front Immunol, 7, 550, 10.3389/fimmu.2016.00550

Patsoukis, 2012, Selective effects of PD-1 on Akt and Ras pathways regulate molecular components of the cell cycle and inhibit T cell proliferation, Sci Signal, 5, ra46, 10.1126/scisignal.2002796

Ding, 2019, IFN-gamma down-regulates the PD-1 expression and assist nivolumab in PD-1-blockade effect on CD8+ T-lymphocytes in pancreatic cancer, BMC Cancer, 19, 1053, 10.1186/s12885-019-6145-8

Yan, 2018, CX3CR1 identifies PD-1 therapy-responsive CD8+ T cells that withstand chemotherapy during cancer chemoimmunotherapy, JCI Insight, 3, e97828, 10.1172/jci.insight.97828

Yamauchi, 2021, T-cell CX3CR1 expression as a dynamic blood-based biomarker of response to immune checkpoint inhibitors, Nat Commun, 12, 1402, 10.1038/s41467-021-21619-0

Serganova, 2017, Enhancement of PSMA-directed CAR adoptive immunotherapy by PD-1/PD-L1 blockade, Mol Ther Oncolytics, 4, 41, 10.1016/j.omto.2016.11.005

John, 2013, Anti-PD-1 antibody therapy potently enhances the eradication of established tumors by gene-modified T cells, Clin Cancer Res, 19, 5636, 10.1158/1078-0432.CCR-13-0458

Adusumilli, 2021, A phase I trial of regional mesothelin-targeted CAR T-cell therapy in patients with malignant pleural disease, in combination with the anti-PD-1 agent pembrolizumab, Cancer Discov, 11, 2748, 10.1158/2159-8290.CD-21-0407

Rafiq, 2018, Targeted delivery of a PD-1-blocking scFv by CAR-T cells enhances anti-tumor efficacy in vivo, Nat Biotechnol, 36, 847, 10.1038/nbt.4195

Li, 2017, Enhanced cancer immunotherapy by chimeric antigen receptor-modified T cells engineered to secrete checkpoint inhibitors, Clin Cancer Res, 23, 6982, 10.1158/1078-0432.CCR-17-0867

Chen, 2021, Secretion of bispecific protein of anti-PD-1 fused with TGF-beta trap enhances antitumor efficacy of CAR-T cell therapy, Mol Ther Oncolytics, 21, 144, 10.1016/j.omto.2021.03.014

Cherkassky, 2016, Human CAR T cells with cell-intrinsic PD-1 checkpoint blockade resist tumor-mediated inhibition, J Clin Invest, 126, 3130, 10.1172/JCI83092

Liu, 2021, A novel dominant-negative PD-1 armored anti-CD19 CAR T cell is safe and effective against refractory/relapsed B cell lymphoma, Transl Oncol, 14, 10.1016/j.tranon.2021.101085

Lin, 2021, Cytotoxic effect of CLL1 CART cell immunotherapy with PD1 silencing on relapsed/refractory acute myeloid leukemia, Mol Med Rep, 23, 208, 10.3892/mmr.2021.11847

Liu, 2021, PD-1 silencing improves anti-tumor activities of human mesothelin-targeted CAR T cells, Hum Immunol, 82, 130, 10.1016/j.humimm.2020.12.002

Zhu, 2020, EGFRvIII-CAR-T Cells with PD-1 knockout have improved anti-glioma activity, Pathol Oncol Res, 26, 2135, 10.1007/s12253-019-00759-1

Rupp, 2017, CRISPR/Cas9-mediated PD-1 disruption enhances anti-tumor efficacy of human chimeric antigen receptor T cells, Sci Rep, 7, 737, 10.1038/s41598-017-00462-8

Guo, 2018, Disruption of PD-1 enhanced the anti-tumor activity of chimeric antigen receptor T cells against hepatocellular carcinoma, Front Pharmacol, 9, 1118, 10.3389/fphar.2018.01118

Wang, 2021, Phase I study of CAR-T cells with PD-1 and TCR disruption in mesothelin-positive solid tumors, Cell Mol Immunol, 18, 2188, 10.1038/s41423-021-00749-x

Aliahmad, 2011, TOX is required for development of the CD4 T cell lineage gene program, J Immunol, 187, 5931, 10.4049/jimmunol.1101474

Xu, 2019, The transcription factor Tox2 drives T follicular helper cell development via regulating chromatin accessibility, Immunity, 51, 826, 10.1016/j.immuni.2019.10.006

Liu, 2019, Genome-wide analysis identifies NR4A1 as a key mediator of T cell dysfunction, Nature, 567, 525, 10.1038/s41586-019-0979-8

Li, 2019, Targeting NR4As, a new strategy to fine-tune CAR-T cells against solid tumors, Signal Transduct Target Ther, 4, 7, 10.1038/s41392-019-0041-1

Batlle, 2019, Transforming growth factor-beta signaling in immunity and cancer, Immunity, 50, 924, 10.1016/j.immuni.2019.03.024

Dahmani, 2018, TGF-beta in T cell biology: implications for cancer immunotherapy, Cancers, 10, 10.3390/cancers10060194

Ahmadzadeh, 2005, TGF-beta 1 attenuates the acquisition and expression of effector function by tumor antigen-specific human memory CD8 T cells, J Immunol, 174, 5215, 10.4049/jimmunol.174.9.5215

Gunderson, 2020, TGFbeta suppresses CD8+ T cell expression of CXCR3 and tumor trafficking, Nat Commun, 11, 1749, 10.1038/s41467-020-15404-8

Maurice, 2019, CXCR3 enables recruitment and site-specific bystander activation of memory CD8+ T cells, Nat Commun, 10, 4987, 10.1038/s41467-019-12980-2

Li, 2015, Impact of chemokine receptor CXCR3 on tumor-infiltrating lymphocyte recruitment associated with favorable prognosis in advanced gastric cancer, Int J Clin Exp Pathol, 8, 14725

Thomas, 2005, TGF-beta directly targets cytotoxic T cell functions during tumor evasion of immune surveillance, Cancer Cell, 8, 369, 10.1016/j.ccr.2005.10.012

Yang, 2014, TGF-beta upregulates CD70 expression and induces exhaustion of effector memory T cells in B-cell non-Hodgkin's lymphoma, Leukemia, 28, 1872, 10.1038/leu.2014.84

O'Neill, 2017, T cell-derived CD70 delivers an immune checkpoint function in inflammatory T cell responses, J Immunol, 199, 3700, 10.4049/jimmunol.1700380

Leigh, 2017, Host-derived CD70 suppresses murine graft-versus-host disease by limiting donor T cell expansion and effector function, J Immunol, 199, 336, 10.4049/jimmunol.1502181

Park, 2016, TGFbeta1-mediated SMAD3 enhances PD-1 expression on antigen-specific T cells in cancer, Cancer Discov, 6, 1366, 10.1158/2159-8290.CD-15-1347

Gabriel, 2021, Transforming growth factor-beta-regulated mTOR activity preserves cellular metabolism to maintain long-term T cell responses in chronic infection, Immunity, 54, 1698, 10.1016/j.immuni.2021.06.007

Tang, 2020, TGF-beta inhibition via CRISPR promotes the long-term efficacy of CAR T cells against solid tumors, JCI Insight, 5, e133977, 10.1172/jci.insight.133977

Kloss, 2018, Dominant-negative TGF-beta receptor enhances PSMA-targeted human CAR T cell proliferation and augments prostate cancer eradication, Mol Ther, 26, 1855, 10.1016/j.ymthe.2018.05.003

Webster, 2021, Self-driving armored CAR-T cells overcome a suppressive milieu and eradicate CD19+ Raji lymphoma in preclinical models, Mol Ther, 29, 2691, 10.1016/j.ymthe.2021.05.006

Stuber, 2020, Inhibition of TGF-beta-receptor signaling augments the antitumor function of ROR1-specific CAR T-cells against triple-negative breast cancer, J Immunother Cancer, 8, e000676, 10.1136/jitc-2020-000676

Uhl, 2004, SD-208, a novel transforming growth factor beta receptor I kinase inhibitor, inhibits growth and invasiveness and enhances immunogenicity of murine and human glioma cells in vitro and in vivo, Cancer Res, 64, 7954, 10.1158/0008-5472.CAN-04-1013

Li, 2020, Arming anti-EGFRvIII CAR-T With TGFbeta trap improves antitumor efficacy in Glioma mouse models, Front Oncol, 10, 1117, 10.3389/fonc.2020.01117

Hou, 2018, TGF-beta-responsive CAR-T cells promote anti-tumor immune function, Bioeng Transl Med, 3, 75, 10.1002/btm2.10097

Hartley, 2019, Chimeric antigen receptors designed to overcome transforming growth factor-beta-mediated repression in the adoptive T-cell therapy of solid tumors, Clin Transl Immunol, 8, e1064, 10.1002/cti2.1064

Chang, 2018, Rewiring T-cell responses to soluble factors with chimeric antigen receptors, Nat Chem Biol, 14, 317, 10.1038/nchembio.2565

Pang, 2021, IL-7 and CCL19-secreting CAR-T cell therapy for tumors with positive glypican-3 or mesothelin, J Hematol Oncol, 14, 118, 10.1186/s13045-021-01128-9

Singha, 2019, Increased Smad3 and reduced Smad2 levels mediate the functional switch of TGF-beta from growth suppressor to growth and metastasis promoter through TMEPAI/PMEPA1 in triple negative breast cancer, Genes Cancer, 10, 134, 10.18632/genesandcancer.194

Wu, 2020, Discovery of a novel selective water-soluble SMAD3 inhibitor as an antitumor agent, Bioorg Med Chem Lett, 30, 10.1016/j.bmcl.2020.127396

Lutz-Nicoladoni, 2015, Modulation of Immune cell functions by the E3 ligase Cbl-b, Front Oncol, 5, 58, 10.3389/fonc.2015.00058

Kumar, 2021, Deletion of Cbl-b inhibits CD8+ T-cell exhaustion and promotes CAR T-cell function, J Immunother Cancer, 9, e001688, 10.1136/jitc-2020-001688

Sitaram, 2019, Beyond the cell surface: targeting intracellular negative regulators to enhance T cell anti-tumor activity, Int J Mol Sci, 20, 5821, 10.3390/ijms20235821

Chiang, 2007, Ablation of Cbl-b provides protection against transplanted and spontaneous tumors, J Clin Invest, 117, 1029, 10.1172/JCI29472

Fujiwara, 2017, Cbl-b deficiency mediates resistance to programmed death-ligand 1/programmed death-1 regulation, Front Immunol, 8, 42, 10.3389/fimmu.2017.00042

Peer, 2017, Cblb-deficient T cells are less susceptible to PD-L1-mediated inhibition, Oncotarget, 8, 41841, 10.18632/oncotarget.18360

Shah, 2019, Clonal expansion of CAR T cells harboring lentivector integration in the CBL gene following anti-CD22 CAR T-cell therapy, Blood Adv, 3, 2317, 10.1182/bloodadvances.2019000219

Loeser, 2007, Spontaneous tumor rejection by cbl-b-deficient CD8+ T cells, J Exp Med, 204, 879, 10.1084/jem.20061699

Zha, 2007, An adenoviral vector encoding dominant negative Cbl lowers the threshold for T cell activation in post-thymic T cells, Cell Immunol, 247, 95, 10.1016/j.cellimm.2007.07.006

Zhou, 2021, Targeting ubiquitin signaling for cancer immunotherapy, Signal Transduct Target Ther, 6, 16, 10.1038/s41392-020-00421-2

Jeon, 2004, Essential role of the E3 ubiquitin ligase Cbl-b in T cell anergy induction, Immunity, 21, 167, 10.1016/j.immuni.2004.07.013

Chiang, 2000, Cbl-b regulates the CD28 dependence of T-cell activation, Nature, 403, 216, 10.1038/35003235

Weber, 2021, Transient rest restores functionality in exhausted CAR-T cells through epigenetic remodeling, Science, 372, 10.1126/science.aba1786

Richman, 2020, Ligand-induced degradation of a CAR permits reversible remote control of CAR T cell activity in vitro and in vivo, Mol Ther, 28, 1600, 10.1016/j.ymthe.2020.06.004

Juillerat, 2019, Modulation of chimeric antigen receptor surface expression by a small molecule switch, BMC Biotechnol, 19, 44, 10.1186/s12896-019-0537-3

Zhang, 2019, Doxycycline inducible chimeric antigen receptor T cells targeting CD147 for hepatocellular carcinoma therapy, Front Cell Dev Biol, 7, 233, 10.3389/fcell.2019.00233

Gu, 2018, Development of inducible CD19-CAR T cells with a Tet-on system for controlled activity and enhanced clinical safety, Int J Mol Sci, 19, 3455, 10.3390/ijms19113455

Drent, 2018, Feasibility of controlling CD38-CAR T cell activity with a Tet-on inducible CAR design, PLoS One, 13, 10.1371/journal.pone.0197349

Greenshpan, 2021, Synthetic promoters to induce immune-effectors into the tumor microenvironment, Commun Biol, 4, 143, 10.1038/s42003-021-01664-7

Eyquem, 2017, Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumour rejection, Nature, 543, 113, 10.1038/nature21405

Brandt, 2020, Emerging approaches for regulation and control of CAR T cells: a mini review, Front Immunol, 11, 326, 10.3389/fimmu.2020.00326

Liu, 2020, Split chimeric antigen receptor-modified T cells targeting glypican-3 suppress hepatocellular carcinoma growth with reduced cytokine release, Ther Adv Med Oncol, 12, 10.1177/1758835920910347

Leung, 2019, Sensitive and adaptable pharmacological control of CAR T cells through extracellular receptor dimerization, JCI Insight, 5, e124430, 10.1172/jci.insight.124430

Viaud, 2018, Switchable control over in vivo CAR T expansion, B cell depletion, and induction of memory, Proc Natl Acad Sci USA, 115, E10898, 10.1073/pnas.1810060115

Zajc, 2020, A conformation-specific ON-switch for controlling CAR T cells with an orally available drug, Proc Natl Acad Sci USA, 117, 14926, 10.1073/pnas.1911154117

Lee, 2019, Regulation of CAR T cell-mediated cytokine release syndrome-like toxicity using low molecular weight adapters, Nat Commun, 10, 2681, 10.1038/s41467-019-10565-7

Wu, 2015, Remote control of therapeutic T cells through a small molecule-gated chimeric receptor, Science, 350, aab4077, 10.1126/science.aab4077

Mata, 2017, Inducible activation of MyD88 and CD40 in CAR T cells results in controllable and potent antitumor activity in preclinical solid tumor models, Cancer Discov, 7, 1306, 10.1158/2159-8290.CD-17-0263

Poorebrahim, 2021, Counteracting CAR T cell dysfunction, Oncogene, 40, 421, 10.1038/s41388-020-01501-x

Catakovic, 2017, T cell exhaustion: from pathophysiological basics to tumor immunotherapy, Cell Commun Signal, 15, 1, 10.1186/s12964-016-0160-z

Du, 2018, Blockade of tumor-expressed PD-1 promotes lung cancer growth, Oncoimmunology, 7, 10.1080/2162402X.2017.1408747

McGowan, 2020, PD-1 disrupted CAR-T cells in the treatment of solid tumors: promises and challenges, Biomed Pharmacother, 121, 10.1016/j.biopha.2019.109625

Wang, 2020, Tumor cell-intrinsic PD-1 receptor is a tumor suppressor and mediates resistance to PD-1 blockade therapy, Proc Natl Acad Sci USA, 117, 6640, 10.1073/pnas.1921445117

Diaconu, 2017, Inducible caspase-9 selectively modulates the toxicities of CD19-specific chimeric antigen receptor-modified T cells, Mol Ther, 25, 580, 10.1016/j.ymthe.2017.01.011

Zhou, 2015, Inducible caspase-9 suicide gene controls adverse effects from alloreplete T cells after haploidentical stem cell transplantation, Blood, 125, 4103, 10.1182/blood-2015-02-628354

Lynn, 2019, c-Jun overexpression in CAR T cells induces exhaustion resistance, Nature, 576, 293, 10.1038/s41586-019-1805-z

Heitzeneder, 2022, GPC2-CAR T cells tuned for low antigen density mediate potent activity against neuroblastoma without toxicity, Cancer Cell, 40, 53, 10.1016/j.ccell.2021.12.005

Yeku, 2016, Armored CAR T-cells: utilizing cytokines and pro-inflammatory ligands to enhance CAR T-cell anti-tumour efficacy, Biochem Soc Trans, 44, 412, 10.1042/BST20150291

Yeku, 2017, Armored CAR T cells enhance antitumor efficacy and overcome the tumor microenvironment, Sci Rep, 7, 10541, 10.1038/s41598-017-10940-8

Zhao, 2021, Human hyaluronidase PH20 potentiates the antitumor activities of mesothelin-specific CAR-T cells against gastric cancer, Front Immunol, 12