CAR-T cells for cancer immunotherapy—the barriers ahead and the paths through

References

• Maude SL, Laetsch TW, Buechner J, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med. 2018;378(5):439–448. doi:10.1056/NEJMoa1709866.
   PubMed Web of Science ®Google Scholar
• Schuster SJ, Bishop MR, Tam CS, JULIET Investigators, et al. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med. 2019;380(1):45–56. doi:10.1056/NEJMoa1804980. [30501490]
   PubMed Web of Science ®Google Scholar
• Locke FL, Ghobadi A, Jacobson CA, et al. Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1-2 trial. Lancet Oncol. 2019;20(1):31–42. doi:10.1016/S1470-2045(18)30864-7.
   PubMed Web of Science ®Google Scholar
• Raje N, Berdeja J, Lin Y, et al. Anti-BCMA CAR T-cell therapy bb2121 in relapsed or refractory multiple myeloma. N Engl J Med. 2019;380(18):1726–1737. doi:10.1056/NEJMoa1817226. [31042825]
   PubMed Web of Science ®Google Scholar
• Zhang W-Y, Wang Y, Guo Y-L, et al. Treatment of CD20-directed chimeric antigen receptor-modified T cells in patients with relapsed or refractory B-cell non-Hodgkin lymphoma: an early phase IIa trial report. Signal Transduct Target Ther. 2016;1:16002. doi:10.1038/sigtrans.2016.2.
   PubMed Web of Science ®Google Scholar
• Fry TJ, Shah NN, Orentas RJ, et al. CD22-targeted CAR T cells induce remission in B-ALL that is naive or resistant to CD19-targeted CAR immunotherapy. Nat Med. 2018;24(1):20–28. doi:10.1038/nm.4441. [29155426]
   PubMed Web of Science ®Google Scholar
• Rouce R. Phase 1 therapy with manufactured autologous T-cells expressing a second generation chimeric antigen receptor (CAR) for treatment of T-cell malignancies expressing CD5 antigen. 2021. https://clinicaltrials.gov/ct2/show/NCT03081910.
   Google Scholar
• Cooper ML, Choi J, Staser K, et al. An ‘off-the-shelf’ fratricide-resistant CAR-T for the treatment of T cell hematologic malignancies. Leukemia. 2018;32(9):1970–1983. doi:10.1038/s41375-018-0065-5. [29483708]
   PubMed Web of Science ®Google Scholar
• Johnson LA, Scholler J, Ohkuri T, et al. Rational development and characterization of humanized anti-EGFR variant III chimeric antigen receptor T cells for glioblastoma. Sci Transl Med. 2015;7(275):275ra22. doi:10.1126/scitranslmed.aaa4963. [25696001]
   PubMed Web of Science ®Google Scholar
• O’Rourke DM, Nasrallah MP, Desai A, et al. A single dose of peripherally infused EGFRvIII-directed CAR T cells mediates antigen loss and induces adaptive resistance in patients with recurrent glioblastoma. Sci Transl Med. 2017;9(399):eaaa0984. doi:10.1126/scitranslmed.aaa0984.
   PubMed Web of Science ®Google Scholar
• Ellebrecht CT, Bhoj VG, Nace A, et al. Reengineering chimeric antigen receptor T cells for targeted therapy of autoimmune disease. Science. 2016;353(6295):179–184. doi:10.1126/science.aaf6756. [27365313]
   PubMed Web of Science ®Google Scholar
• Mougiakakos D, Krönke G, Völkl S, et al. CD19-targeted CAR T cells in refractory systemic lupus erythematosus. N Engl J Med. 2021;385(6):567–569. doi:10.1056/NEJMc2107725. [34347960]
   PubMed Web of Science ®Google Scholar
• Maldini CR, Claiborne DT, Okawa K, et al. Dual CD4-based CAR T cells with distinct costimulatory domains mitigate HIV pathogenesis in vivo. Nat Med. 2020;26(11):1776–1787. doi:10.1038/s41591-020-1039-5. [32868878]
   PubMed Web of Science ®Google Scholar
• Rurik JG, Tombácz I, Yadegari A, et al. CAR T cells produced in vivo to treat cardiac injury. Science. 2022;375(6576):91–96. doi:10.1126/science.abm0594. [34990237]
   PubMed Web of Science ®Google Scholar
• Aghajanian H, Kimura T, Rurik JG, et al. Targeting cardiac fibrosis with engineered T cells. Nature. 2019;573(7774):430–433. doi:10.1038/s41586-019-1546-z. [31511695]
   PubMed Web of Science ®Google Scholar
• Eshhar Z, Waks T, Gross G, Schindler DG. 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 U S A. 1993;90(2):720–724. doi:10.1073/pnas.90.2.720. [8421711]
   PubMed Web of Science ®Google Scholar
• Kawalekar OU, O’Connor RS, Fraietta JA, et al. Distinct signaling of coreceptors regulates specific metabolism pathways and impacts memory development in CAR T cells. Immunity. 2016;44(2):380–390. doi:10.1016/j.immuni.2016.01.021. [26885860]
   PubMed Web of Science ®Google Scholar
• Guedan S, Posey AD, Shaw C, et al. Enhancing CAR T cell persistence through ICOS and 4-1BB costimulation. JCI Insight. 2018;3(1):96976. doi:10.1172/jci.insight.96976.
   PubMed Web of Science ®Google Scholar
• Guercio M, Orlando D, Di Cecca S, et al. CD28.OX40 co-stimulatory combination is associated with long in vivo persistence and high activity of CAR.CD30 T-cells. Haematologica. 2021;106(4):987–999. doi:10.3324/haematol.2019.231183. [32381575]
   PubMed Web of Science ®Google Scholar
• Mata M, Gerken C, Nguyen P, et al. Inducible activation of MyD88 and CD40 in CAR T cells results in controllable and potent antitumor activity in preclinical solid tumor models. Cancer Discov. 2017;7(11):1306–1319. doi:10.1158/2159-8290.CD-17-0263. [28801306]
   PubMed Web of Science ®Google Scholar
• Ramos CA, Rouce R, Robertson CS, et al. In vivo fate and activity of second- versus third-generation CD19-specific CAR-T cells in B cell non-Hodgkin’s lymphomas. Mol Ther. 2018;26(12):2727–2737. doi:10.1016/j.ymthe.2018.09.009. [30309819]
   PubMed Web of Science ®Google Scholar
• Zhong X-S, Matsushita M, Plotkin J, Riviere I, Sadelain M. Chimeric antigen receptors combining 4-1BB and CD28 signaling domains augment PI3kinase/AKT/Bcl-XL activation and CD8+ T cell–mediated Tumor eradication. Mol Ther. 2010;18(2):413–420. doi:10.1038/mt.2009.210. [19773745]
   PubMed Web of Science ®Google Scholar
• Cheng Z, Wei R, Ma Q, et al. In vivo expansion and antitumor activity of coinfused CD28- and 4-1BB-engineered CAR-T cells in patients with B cell leukemia. Mol Ther. 2018;26(4):976–985. doi:10.1016/j.ymthe.2018.01.022. [29503204]
   PubMed Web of Science ®Google Scholar
• Drent E, Poels R, Ruiter R, et al. Combined CD28 and 4-1BB costimulation potentiates affinity-tuned chimeric antigen receptor-engineered T cells. Clin Cancer Res. 2019;25(13):4014–4025. doi:10.1158/1078-0432.CCR-18-2559.
   PubMed Web of Science ®Google Scholar
• Weng J, Lai P, Qin L, et al. A novel generation 1928zT2 CAR T cells induce remission in extramedullary relapse of acute lymphoblastic leukemia. J Hematol Oncol. 2018;11(1):25. doi:10.1186/s13045-018-0572-x. [29458388]
   PubMed Web of Science ®Google Scholar
• Chmielewski M, Abken H. CAR T cells transform to trucks: chimeric antigen receptor–redirected T cells engineered to deliver inducible IL-12 modulate the tumour stroma to combat cancer. Cancer Immunol Immunother. 2012;61(8):1269–1277. doi:10.1007/s00262-012-1202-z. [22274776]
   PubMed Web of Science ®Google Scholar
• Chmielewski M, Hombach AA, Abken H. Of CARs and TRUCKs: chimeric antigen receptor (CAR) T cells engineered with an inducible cytokine to modulate the tumor stroma. Immunol Rev. 2014;257(1):83–90. doi:10.1111/imr.12125. [24329791]
   PubMed Web of Science ®Google Scholar
• Hoyos V, Savoldo B, Quintarelli C, et al. Engineering CD19-specific T lymphocytes with interleukin-15 and a suicide gene to enhance their anti-lymphoma/leukemia effects and safety. Leukemia. 2010;24(6):1160–1170. doi:10.1038/leu.2010.75.
   PubMed Web of Science ®Google Scholar
• Adachi K, Kano Y, Nagai T, et al. IL-7 and CCL19 expression in CAR-T cells improves immune cell infiltration and CAR-T cell survival in the tumor. Nat Biotechnol. 2018;36(4):346–351. doi:10.1038/nbt.4086. [29505028]
   PubMed Web of Science ®Google Scholar
• Yu W-L, Hua Z-C. Chimeric antigen receptor T-cell (CAR T) therapy for hematologic and solid malignancies: efficacy and safety-A systematic review with meta-analysis. Cancers. 2019;11(1):47. doi:10.3390/cancers11010047.
   Web of Science ®Google Scholar
• Deeren D, Maertens JA, Lin TL, et al. Co-expression of an shRNA targeting MICA/Micb improves the clinical activity of a NKG2D-based CAR T in patients with relapsed/refractory AML/MDS. Blood. 2021;138(Suppl. 1):408–408. doi:10.1182/blood-2021-152413.
   Google Scholar
• Sallman DA, Elmariah H, Sweet K, et al. Phase 1/1b safety study of Prgn-3006 ultracar-T in patients with relapsed or refractory CD33-positive acute myeloid leukemia and higher risk myelodysplastic syndromes. Blood. 2021;138(Suppl. 1):825–825. doi:10.1182/blood-2021-152692.
   Google Scholar
• Malone ER, Oliva M, Sabatini PJB, Stockley TL, Siu LL. Molecular profiling for precision cancer therapies. Genome Med. 2020;12(1):8. doi:10.1186/s13073-019-0703-1. [31937368]
   PubMed Web of Science ®Google Scholar
• Varešlija D, Priedigkeit N, Fagan A, et al. Transcriptome characterization of matched primary breast and brain metastatic tumors to detect novel actionable targets. J. Natl. Cancer Inst. 2019;111(4):388–398. doi:10.1093/jnci/djy110.
   PubMedGoogle Scholar
• Berger MF, Mardis ER. The emerging clinical relevance of genomics in cancer medicine. Nat Rev Clin Oncol. 2018;15(6):353–365. doi:10.1038/s41571-018-0002-6. [29599476]
   PubMed Web of Science ®Google Scholar
• Han X, Wang Y, Wei J, Han W. Multi-antigen-targeted chimeric antigen receptor T cells for cancer therapy. J Hematol Oncol. 2019;12(1):128. doi:10.1186/s13045-019-0813-7. [31783889]
   PubMed Web of Science ®Google Scholar
• Garrison BS, Deng H, Yucel G, et al. FLT3 or CD33 not EMCN logic gated CAR-NK cell therapy (SENTI-202) for precise targeting of AML. Blood. 2021;138(Suppl. 1):2799–2799. doi:10.1182/blood-2021-154201.
   PubMedGoogle Scholar
• Rogosic S, Ghorashian S. CAR-T cell therapy in paediatric acute lymphoblastic leukaemia - past, present and future. Br J Haematol. 2020;191(4):617–626. doi:10.1111/bjh.17153.
   PubMed Web of Science ®Google Scholar
• Rodríguez-Lobato LG, Ganzetti M, Fernández de Larrea C, et al. CAR T-cells in multiple myeloma: state of the art and future directions. Front Oncol. 2020;10:1243. doi:10.3389/fonc.2020.01243. [32850376]
   PubMed Web of Science ®Google Scholar
• Mardiana S, Gill S. CAR T cells for acute myeloid leukemia: state of the art and future directions. Front Oncol. 2020;10:697. doi:10.3389/fonc.2020.00697. [32435621]
   PubMed Web of Science ®Google Scholar
• Xu X, Sun Q, Liang X, et al. Mechanisms of relapse after CD19 CAR T-cell therapy for acute lymphoblastic leukemia and its prevention and treatment strategies. Front Immunol. 2019;10:2664. doi:10.3389/fimmu.2019.02664. [31798590]
   PubMed Web of Science ®Google Scholar
• Gardner R, Wu D, Cherian S, et al. Acquisition of a CD19-negative myeloid phenotype allows immune escape of MLL-rearranged B-ALL from CD19 CAR-T-cell therapy. Blood. 2016;127(20):2406–2410. doi:10.1182/blood-2015-08-665547. [26907630]
   PubMed Web of Science ®Google Scholar
• Sotillo E, Barrett DM, Black KL, et al. Convergence of acquired mutations and alternative splicing of CD19 enables resistance to CART-19 immunotherapy. Cancer Discov. 2015;5(12):1282–1295. doi:10.1158/2159-8290.CD-15-1020. [26516065]
   PubMed Web of Science ®Google Scholar
• Park JH, Rivière I, Gonen M, et al. Long-term follow-up of CD19 CAR therapy in acute lymphoblastic leukemia. N Engl J Med. 2018;378(5):449–459. doi:10.1056/NEJMoa1709919.
   PubMed Web of Science ®Google Scholar
• Neelapu SS, Locke FL, Bartlett NL, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med. 2017;377(26):2531–2544. doi:10.1056/NEJMoa1707447.
   PubMed Web of Science ®Google Scholar
• Brown CE, Alizadeh D, Starr R, et al. Regression of glioblastoma after chimeric antigen receptor T-cell therapy. N Engl J Med. 2016;375(26):2561–2569. doi:10.1056/NEJMoa1610497. [28029927]
   PubMed Web of Science ®Google Scholar
• Shah NN, Johnson BD, Schneider D, et al. Bispecific anti-CD20, anti-CD19 CAR T cells for relapsed B cell malignancies: a phase 1 dose escalation and expansion trial. Nat Med. 2020;26(10):1569–1575. doi:10.1038/s41591-020-1081-3. [33020647]
   PubMed Web of Science ®Google Scholar
• Hu Y, Zhou Y, Zhang M, et al. CRISPR/Cas9-engineered universal CD19/CD22 dual-targeted CAR-T cell therapy for relapsed/refractory B-cell acute lymphoblastic leukemia. Clin Cancer Res. 2021;27(10):2764–2772. doi:10.1158/1078-0432.CCR-20-3863. [33627493]
   PubMed Web of Science ®Google Scholar
• Ruella M, Barrett DM, Kenderian SS, et al. Dual CD19 and CD123 targeting prevents antigen-loss relapses after CD19-directed immunotherapies. J Clin Invest. 2016;126(10):3814–3826. doi:10.1172/JCI87366. [27571406]
   PubMed Web of Science ®Google Scholar
• Tong C, Zhang Y, Liu Y, et al. Optimized tandem CD19/CD20 CAR-engineered T cells in refractory/relapsed B cell lymphoma. Blood Blood. 2020;136(14):1632–1644. doi:10.1182/blood.2020005278.
   Web of Science ®Google Scholar
• Yang M, Tang X, Zhang Z, et al. Tandem CAR-T cells targeting CD70 and B7-H3 exhibit potent preclinical activity against multiple solid tumors. Theranostics. 2020;10(17):7622–7634. doi:10.7150/thno.43991. [32685008]
   PubMed Web of Science ®Google Scholar
• Lamers CHJ, Willemsen R, van Elzakker P, et al. Immune responses to transgene and retroviral vector in patients treated with ex vivo-engineered T cells. Blood. 2011;117(1):72–82. doi:10.1182/blood-2010-07-294520. [20889925]
   PubMed Web of Science ®Google Scholar
• Turtle CJ, Hanafi L-A, Berger C, et al. CD19 CAR–T cells of defined CD4+:CD8+ composition in adult B cell ALL patients. J Clin Invest. 2016;126(6):2123–2138. doi:10.1172/JCI85309. [27111235]
   PubMed Web of Science ®Google Scholar
• Maus MV, Haas AR, Beatty GL, et al. T cells expressing chimeric antigen receptors can cause anaphylaxis in humans. Cancer Immunol Res. 2013;1(1):26–31. doi:10.1158/2326-6066.CIR-13-0006. [24777247]
   Web of Science ®Google Scholar
• Chen W, Ma Y, Shen Z, et al. Humanized anti-CD19 CAR-T cell therapy and sequential allogeneic hematopoietic stem cell transplantation achieved long-term survival in refractory and relapsed B lymphocytic leukemia: a retrospective study of CAR-T cell therapy. Front Immunol. 2021;12:755549. doi:10.3389/fimmu.2021.755549. [34777367]
   PubMedGoogle Scholar
• Heng G, Jia J, Li S, et al. Sustained therapeutic efficacy of humanized anti-CD19 chimeric antigen receptor T cells in relapsed/refractory acute lymphoblastic leukemia. Clin Cancer Res. 2020;26(7):1606–1615. doi:10.1158/1078-0432.CCR-19-1339. [31732519]
   PubMed Web of Science ®Google Scholar
• Myers RM, Li Y, Barz Leahy A, et al. Humanized CD19-targeted chimeric antigen receptor (CAR) T cells in CAR-naive and CAR-exposed children and young adults with relapsed or refractory acute lymphoblastic leukemia. JCO. 2021;39(27):3044–3055. doi:10.1200/JCO.20.03458.
   PubMed Web of Science ®Google Scholar
• Zheng L, Ren L, Kouhi A, et al. A humanized Lym-1 CAR with novel DAP10/DAP12 signaling domains demonstrates reduced tonic signaling and increased antitumor activity in B-cell lymphoma models. Clin Cancer Res. 2020;26(14):3694–3706. doi:10.1158/1078-0432.CCR-19-3417. [32273277]
   PubMed Web of Science ®Google Scholar
• Zhao Y, Liu Z, Wang X, et al. Treatment with humanized selective CD19CAR-T cells shows efficacy in highly treated B-ALL patients who have relapsed after receiving murine-based CD19CAR-T therapies. Clin Cancer Res. 2019;25(18):5595–5607. doi:10.1158/1078-0432.CCR-19-0916. [31300451]
   PubMed Web of Science ®Google Scholar
• Hege KM, Bergsland EK, Fisher GA, et al. Safety, tumor trafficking and immunogenicity of chimeric antigen receptor (CAR)-T cells specific for TAG-72 in colorectal cancer. J Immunother Cancer. 2017;5:22. doi:10.1186/s40425-017-0222-9.
   PubMed Web of Science ®Google Scholar
• Lam N, Trinklein ND, Buelow B, et al. Anti-BCMA chimeric antigen receptors with fully human heavy-chain-only antigen recognition domains. Nat Commun. 2020;11(1):283. doi:10.1038/s41467-019-14119-9. [31941907]
   PubMed Web of Science ®Google Scholar
• Whilding LM, Parente-Pereira AC, Zabinski T, et al. Targeting of aberrant αvβ6 integrin expression in solid tumors using chimeric antigen receptor-engineered T cells. Mol Ther. 2017;25(1):259–273. doi:10.1016/j.ymthe.2016.10.012. [28129120]
   PubMed Web of Science ®Google Scholar
• Clarke SC, Ma B, Trinklein ND, et al. Multispecific antibody development platform based on human heavy chain antibodies. Front Immunol. 2018;9:3037. doi:10.3389/fimmu.2018.03037. [30666250]
   PubMed Web of Science ®Google Scholar
• Deng X, Gao F, Li N, et al. Antitumor activity of NKG2D CAR-T cells against human colorectal cancer cells in vitro and in vivo. Am J Cancer Res. 2019;9(5):945–958.
   PubMed Web of Science ®Google Scholar
• Lu P, Lu X-a, Zhang X, et al. Which is better in CD19 CAR-T treatment of r/r B-ALL, CD28 or 4-1BB? A parallel trial under the same manufacturing process. JCO. 2018;36(15_suppl):3041–3041. doi:10.1200/JCO.2018.36.15_suppl.3041.
   Web of Science ®Google Scholar
• Long AH, Haso WM, Shern JF, et al. 4-1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of chimeric antigen receptors. Nat Med. 2015;21(6):581–590. doi:10.1038/nm.3838. [25939063]
   PubMed Web of Science ®Google Scholar
• Song D-G, Ye Q, Poussin M, et al. CD27 costimulation augments the survival and antitumor activity of redirected human T cells in vivo. Blood. 2012;119(3):696–706. doi:10.1182/blood-2011-03-344275. [22117050]
   PubMed Web of Science ®Google Scholar
• Almåsbak H, Walseng E, Kristian A, et al. Inclusion of an IgG1-Fc spacer abrogates efficacy of CD19 CAR T cells in a xenograft mouse model. Gene Ther. 2015;22(5):391–403. doi:10.1038/gt.2015.4. [25652098]
   PubMed Web of Science ®Google Scholar
• Shen C-J, Yang Y-X, Han EQ, et al. Chimeric antigen receptor containing ICOS signaling domain mediates specific and efficient antitumor effect of T cells against EGFRvIII expressing glioma. J Hematol Oncol. 2013;6:33. doi:10.1186/1756-8722-6-33. [23656794]
   PubMed Web of Science ®Google Scholar
• Enblad G, Karlsson H, Gammelgård G, et al. A Phase I/IIa Trial Using CD19-targeted third-generation CAR T cells for lymphoma and leukemia. Clin Cancer Res. 2018;24(24):6185–6194. doi:10.1158/1078-0432.CCR-18-0426. [30097433]
   PubMed Web of Science ®Google Scholar
• Roselli E, Boucher JC, Li G, et al. 4-1BB and optimized CD28 co-stimulation enhances function of human mono-specific and bi-specific third-generation CAR T cells. J Immunother Cancer. 2021;9(10):e003354. doi:10.1136/jitc-2021-003354.
   PubMed Web of Science ®Google Scholar
• Konstorum A, Vella AT, Adler AJ, Laubenbacher RC. A mathematical model of combined CD8 T cell costimulation by 4-1BB (CD137) and OX40 (CD134) receptors. Sci Rep. 2019;9(1):10862. doi:10.1038/s41598-019-47333-y.
   PubMedGoogle Scholar
• Fraietta JA, Lacey SF, Orlando EJ, et al. Determinants of response and resistance to CD19 chimeric antigen receptor (CAR) T cell therapy of chronic lymphocytic leukemia. Nat Med. 2018;24(5):563–571. doi:10.1038/s41591-018-0010-1.
   PubMed Web of Science ®Google Scholar
• Klebanoff CA, Crompton JG, Leonardi AJ, et al. Inhibition of AKT signaling uncouples T cell differentiation from expansion for receptor-engineered adoptive immunotherapy. JCI Insight. 2017;2(23):e95103. doi:10.1172/jci.insight.95103.
   PubMed Web of Science ®Google Scholar
• Sakuishi K, Apetoh L, Sullivan JM, et al. Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity. J Exp Med. 2010;207(10):2187–2194. doi:10.1084/jem.20100643. [20819927]
   PubMed Web of Science ®Google Scholar
• Ren J, Liu X, Fang C, et al. Multiplex genome editing to generate universal CAR T cells resistant to PD1 inhibition. Clin Cancer Res. 2017;23(9):2255–2266. doi:10.1158/1078-0432.CCR-16-1300. [27815355]
   PubMed Web of Science ®Google Scholar
• Cooper ML, DiPersio JF. Chimeric antigen receptor T cells (CAR-T) for the treatment of T-cell malignancies. Best Pract Res Clin Haematol. 2019;32(4):101097. doi:10.1016/j.beha.2019.101097. [31779968]
   PubMed Web of Science ®Google Scholar
• Giuffrida L, et al. CRISPR/Cas9 mediated deletion of the adenosine A2A receptor enhances CAR T cell efficacy. Nat. Commun. 2021;12:3236.
   PubMed Web of Science ®Google Scholar
• Li S, Wang X, Yuan Z, et al. Eradication of T-ALL cells by CD7-targeted universal CAR-T cells and initial test of ruxolitinib-based CRS management. Clin Cancer Res. 2021;27(5):1242–1246. doi:10.1158/1078-0432.CCR-20-1271. [33234511]
   PubMed Web of Science ®Google Scholar
• Themeli M, Kloss CC, Ciriello G, et al. Generation of tumor-targeted human T lymphocytes from induced pluripotent stem cells for cancer therapy. Nat Biotechnol. 2013;31(10):928–933. doi:10.1038/nbt.2678. [23934177]
   PubMed Web of Science ®Google Scholar
• Bachanova V, Cayci Z, Lewis D, et al. Initial clinical activity of FT596, a first-in-class, multi-antigen targeted, off-the-shelf, iPSC-derived CD19 CAR NK cell therapy in relapsed/refractory B-cell lymphoma. Blood. 2020;136(Suppl. 1):8–8. doi:10.1182/blood-2020-141606.
   PubMedGoogle Scholar
• Benjamin R, Graham C, Yallop D, et al. Genome-edited, donor-derived allogeneic anti-CD19 chimeric antigen receptor T cells in paediatric and adult B-cell acute lymphoblastic leukaemia: results of two phase 1 studies. Lancet Lond. Engl. 2020;396(10266):1885–1894. doi:10.1016/S0140-6736(20)32334-5.
   PubMed Web of Science ®Google Scholar
• Li L, Hu S, Chen X. Non-viral delivery systems for CRISPR/Cas9-based genome editing: challenges and opportunities. Biomaterials. 2018;171:207–218. doi:10.1016/j.biomaterials.2018.04.031. [29704747]
   PubMed Web of Science ®Google Scholar
• Cherkassky L, Morello A, Villena-Vargas J, et al. Human CAR T cells with cell-intrinsic PD-1 checkpoint blockade resist tumor-mediated inhibition. J Clin Invest. 2016;126(8):3130–3144. doi:10.1172/JCI83092. [27454297]
   PubMed Web of Science ®Google Scholar
• Chong EA, Melenhorst JJ, Lacey SF, et al. PD-1 blockade modulates chimeric antigen receptor (CAR)–modified T cells: refueling the CAR. Blood. 2017;129(8):1039–1041. doi:10.1182/blood-2016-09-738245. [28031179]
   PubMed Web of Science ®Google Scholar
• Cao Y, Lu W, Sun R, 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. doi:10.3389/fonc.2019.00767. [31482064]
   PubMed Web of Science ®Google Scholar
• Michot JM, Bigenwald C, Champiat S, et al. Immune-related adverse events with immune checkpoint blockade: a comprehensive review. Eur J Cancer. 2016;54:139–148. doi:10.1016/j.ejca.2015.11.016. [26765102]
   PubMed Web of Science ®Google Scholar
• Rafiq S, Yeku OO, Jackson HJ, et al. Targeted delivery of a PD-1-blocking scFv by CAR-T cells enhances anti-tumor efficacy in vivo. Nat Biotechnol. 2018;36(9):847–856. doi:10.1038/nbt.4195. [30102295]
   PubMed Web of Science ®Google Scholar
• Li S, Siriwon N, Zhang X, et al. Enhanced cancer immunotherapy by chimeric antigen receptor–modified T cells engineered to secrete checkpoint inhibitors. Clin Cancer Res. 2017;23(22):6982–6992. doi:10.1158/1078-0432.CCR-17-0867. [28912137]
   PubMed Web of Science ®Google Scholar
• Rupp LJ, Schumann K, Roybal KT, et al. CRISPR/Cas9-mediated PD-1 disruption enhances anti-tumor efficacy of human chimeric antigen receptor T cells. Sci Rep. 2017;7(1):737. doi:10.1038/s41598-017-00462-8.
   PubMed Web of Science ®Google Scholar
• Zhang Y, Zhang X, Cheng C, et al. CRISPR-Cas9 mediated LAG-3 disruption in CAR-T cells. Front Med. 2017;11(4):554–562. doi:10.1007/s11684-017-0543-6. [28625015]
   PubMed Web of Science ®Google Scholar
• Greco B, Malacarne V, De Girardi F, et al. Disrupting N-glycan expression on tumor cells boosts chimeric antigen receptor T cell efficacy against solid malignancies. Sci Transl Med. 2022;14(628):eabg3072. doi:10.1126/scitranslmed.abg3072. [35044789]
   PubMed Web of Science ®Google Scholar
• Liu Y-T, Sun Z-J. Turning cold tumors into hot tumors by improving T-cell infiltration. Theranostics. 2021;11(11):5365–5386. doi:10.7150/thno.58390. [33859752]
   PubMed Web of Science ®Google Scholar
• Wang L-CS, Lo A, Scholler J, et al. Targeting fibroblast activation protein in tumor stroma with chimeric antigen receptor T cells can inhibit tumor growth and augment host immunity without severe toxicity. Cancer Immunol Res. 2014;2(2):154–166. doi:10.1158/2326-6066.CIR-13-0027. [24778279]
   PubMed Web of Science ®Google Scholar
• Rodriguez-Garcia A, Lynn RC, Poussin M, et al. CAR-T cell-mediated depletion of immunosuppressive tumor-associated macrophages promotes endogenous antitumor immunity and augments adoptive immunotherapy. Nat Commun. 2021;12(1):877. doi:10.1038/s41467-021-20893-2.
   PubMed Web of Science ®Google Scholar
• Priceman SJ, Tilakawardane D, Jeang B, et al. Regional delivery of chimeric antigen receptor-engineered T cells effectively targets HER2+ breast cancer metastasis to the brain. Clin Cancer Res. 2018;24(1):95–105. doi:10.1158/1078-0432.CCR-17-2041. [29061641]
   PubMed Web of Science ®Google Scholar
• Donovan LK, Delaidelli A, Joseph SK, et al. Locoregional delivery of CAR T cells to the cerebrospinal fluid for treatment of metastatic medulloblastoma and ependymoma. Nat Med. 2020;26(5):720–731. doi:10.1038/s41591-020-0827-2. [32341580]
   PubMed Web of Science ®Google Scholar
• Theruvath J, Sotillo E, Mount CW, et al. Locoregionally administered B7-H3-targeted CAR T cells for treatment of atypical teratoid/rhabdoid tumors. Nat Med. 2020;26(5):712–719. doi:10.1038/s41591-020-0821-8. [32341579]
   PubMed Web of Science ®Google Scholar
• Tang X, Wang Y, Huang J, et al. Administration of B7-H3 targeted chimeric antigen receptor-T cells induce regression of glioblastoma. Signal Transduct Target Ther. 2021;6(1):125. doi:10.1038/s41392-021-00505-7.
   PubMed Web of Science ®Google Scholar
• Wang Y, Wang L, Zeng Y, et al. Successful BCMA CAR-T therapy for multiple myeloma with central nervous system involvement manifesting as cauda equina syndrome-A wandering road to remission. Front Oncol. 2021;11:755584. doi:10.3389/fonc.2021.755584. [34868965]
   PubMed Web of Science ®Google Scholar
• Wang Y, et al. BCMA CAR-T therapy is safe and effective for refractory/relapsed multiple myeloma with central nervous system involvement. J. Immunother. 2021;45(1):25–34. doi:10.1097/CJI.0000000000000391.
   Web of Science ®Google Scholar
• Adusumilli PS, Cherkassky L, Villena-Vargas J, et al. Regional delivery of mesothelin-targeted CAR T cell therapy generates potent and long-lasting CD4-dependent tumor immunity. Sci Transl Med. 2014;6(261):261ra151. doi:10.1126/scitranslmed.3010162. [25378643]
   PubMed Web of Science ®Google Scholar
• Ghosn M, Cheema W, Zhu A, et al. Image-guided interventional radiological delivery of chimeric antigen receptor (CAR) T cells for pleural malignancies in a phase I/II clinical trial. Lung Cancer. 2022;165:1–9. doi:10.1016/j.lungcan.2022.01.003. [35045358]
   PubMed Web of Science ®Google Scholar
• Wang X, Walter M, Urak R, et al. Lenalidomide enhances the function of CS1 chimeric antigen receptor–redirected T cells against multiple myeloma. Clin Cancer Res. 2018;24(1):106–119. doi:10.1158/1078-0432.CCR-17-0344. [29061640]
   PubMed Web of Science ®Google Scholar
• Wang Z, Zhou G, Risu N, et al. Lenalidomide enhances CAR-T cell activity against solid tumor cells. Cell Transplant. 2020;29:963689720920825. doi:10.1177/0963689720920825. [32967454]
   PubMed Web of Science ®Google Scholar
• Quach H, Ritchie D, Stewart AK, et al. Mechanism of action of immunomodulatory drugs (IMiDS) in multiple myeloma. Leukemia. 2010;24(1):22–32. doi:10.1038/leu.2009.236. [19907437]
   PubMed Web of Science ®Google Scholar
• Wang Y, et al. Low-dose decitabine priming endows CAR T cells with enhanced and persistent antitumour potential via epigenetic reprogramming. Nat. Commun. 2021;12:409.
   PubMed Web of Science ®Google Scholar
• Caruso HG, Hurton LV, Najjar A, et al. Tuning sensitivity of CAR to EGFR density limits recognition of normal tissue while maintaining potent antitumor activity. Cancer Res. 2015;75(17):3505–3518. doi:10.1158/0008-5472.CAN-15-0139. [26330164]
   PubMed Web of Science ®Google Scholar
• Davenport AJ, Jenkins MR, Cross RS, et al. CAR-T cells inflict sequential killing of multiple tumor target cells. Cancer Immunol Res. 2015;3(5):483–494. doi:10.1158/2326-6066.CIR-15-0048. [25711536]
   PubMed Web of Science ®Google Scholar
• Eyquem J, Mansilla-Soto J, Giavridis T, et al. Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumour rejection. Nature. 2017;543(7643):113–117. doi:10.1038/nature21405. [28225754]
   PubMed Web of Science ®Google Scholar
• Walker AJ, Majzner RG, Zhang L, et al. Tumor antigen and receptor densities regulate efficacy of a chimeric antigen receptor targeting anaplastic lymphoma kinase. Mol Ther. 2017;25(9):2189–2201. doi:10.1016/j.ymthe.2017.06.008. [28676342]
   PubMed Web of Science ®Google Scholar
• Hamieh M, Dobrin A, Cabriolu A, et al. CAR T cell trogocytosis and cooperative killing regulate tumour antigen escape. Nature. 2019;568(7750):112–116. doi:10.1038/s41586-019-1054-1. [30918399]
   PubMed Web of Science ®Google Scholar
• Li W, Qiu S, Chen J, et al. Chimeric antigen receptor designed to prevent ubiquitination and downregulation showed durable antitumor efficacy. Immunity. 2020;53(2):456–470.e6. doi:10.1016/j.immuni.2020.07.011. [32758419]
   PubMed Web of Science ®Google Scholar
• Li W, Yang H, Li L, Wang H. CAR trafficking does matter: prospects of ‘Chimeric antigen receptor designed to prevent ubiquitination and downregulation showed durable antitumor efficacy. J Mol Cell Biol. 2020;12(9):745–746. doi:10.1093/jmcb/mjaa045. [33340406]
   PubMed Web of Science ®Google Scholar
• Larson RC, Maus MV. Recent advances and discoveries in the mechanisms and functions of CAR T cells. Nat Rev Cancer. 2021;21(3):145–161. doi:10.1038/s41568-020-00323-z. [33483715]
   PubMed Web of Science ®Google Scholar
• Maude SL, Frey N, Shaw PA, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014;371(16):1507–1517. doi:10.1056/NEJMoa1407222. [25317870]
   PubMed Web of Science ®Google Scholar
• Hines MR, Keenan C, Maron Alfaro G, et al. Hemophagocytic lymphohistiocytosis-like toxicity (carHLH) after CD19-specific CAR T-cell therapy. Br J Haematol. 2021;194(4):701–707. doi:10.1111/bjh.17662.
   PubMed Web of Science ®Google Scholar
• Lichtenstein DA, Schischlik F, Shao L, et al. Characterization of HLH-like manifestations as a CRS variant in patients receiving CD22 CAR T-cells. Blood Blood. 2021;138(24):2469–2484. doi:10.1182/blood.2021011898.
   PubMed Web of Science ®Google Scholar
• Gust J, Hay KA, Hanafi L-A, et al. Endothelial activation and blood–brain barrier disruption in neurotoxicity after adoptive immunotherapy with CD19 CAR-T cells. Cancer Discov. 2017;7(12):1404–1419. doi:10.1158/2159-8290.CD-17-0698. [29025771]
   PubMed Web of Science ®Google Scholar
• Teachey DT, Lacey SF, Shaw PA, et al. Identification of predictive biomarkers for cytokine release syndrome after chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia. Cancer Discov. 2016;6(6):664–679. doi:10.1158/2159-8290.CD-16-0040.
   PubMed Web of Science ®Google Scholar
• Sadelain M, Brentjens R, Rivière I. The basic principles of chimeric antigen receptor design. Cancer Discov. 2013;3(4):388–398. doi:10.1158/2159-8290.CD-12-0548. [23550147]
   PubMed Web of Science ®Google Scholar
• Maus MV, June CH. Making better chimeric antigen receptors for adoptive T-cell therapy. Clin Cancer Res. 2016;22(8):1875–1884. doi:10.1158/1078-0432.CCR-15-1433.
   PubMed Web of Science ®Google Scholar
• Kochenderfer JN, Dudley ME, Kassim SH, et al. Chemotherapy-refractory diffuse large B-cell lymphoma and indolent B-cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor. J Clin Oncol. 2015;33(6):540–549. doi:10.1200/JCO.2014.56.2025. [25154820]
   PubMed Web of Science ®Google Scholar
• Parker KR, Migliorini D, Perkey E, et al. Single-cell analyses identify brain mural cells expressing CD19 as potential off-tumor targets for CAR-T immunotherapies. Cell. 2020;183(1):126–142.e17. doi:10.1016/j.cell.2020.08.022. [32961131]
   PubMed Web of Science ®Google Scholar
• Morgan RA, Yang JC, Kitano M, et al. Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2. Mol Ther. 2010;18(4):843–851. doi:10.1038/mt.2010.24. [20179677]
   PubMed Web of Science ®Google Scholar
• Jones BS, Lamb LS, Goldman F, Di Stasi A. Improving the safety of cell therapy products by suicide gene transfer. Front Pharmacol. 2014;5:254. doi:10.3389/fphar.2014.00254. [25505885]
   PubMedGoogle Scholar
• Gargett T, Brown MP. The inducible caspase-9 suicide gene system as a ‘safety switch’ to limit on-target, off-tumor toxicities of chimeric antigen receptor T cells. Front Pharmacol. 2014;5:235. doi:10.3389/fphar.2014.00235. [25389405]
   PubMed Web of Science ®Google Scholar
• Wang X, Chang W-C, Wong CW, et al. A transgene-encoded cell surface polypeptide for selection, in vivo tracking, and ablation of engineered cells. Blood. 2011;118(5):1255–1263. doi:10.1182/blood-2011-02-337360. [21653320]
   PubMed Web of Science ®Google Scholar
• Hong M, Clubb JD, Chen YY. Engineering CAR-T cells for next-generation cancer therapy. Cancer Cell. 2020;38(4):473–488. doi:10.1016/j.ccell.2020.07.005. [32735779]
   PubMed Web of Science ®Google Scholar
• Fedorov VD, Themeli M, Sadelain M. PD-1- and CTLA-4-based inhibitory chimeric antigen receptors (iCARs) divert off-target immunotherapy responses. Sci Transl Med. 2013;5(215):215ra172. doi:10.1126/scitranslmed.3006597. [24337479]
   PubMed Web of Science ®Google Scholar
• Pfeiffer A, et al. In vivo generation of human CD19-CAR T cells results in B-cell depletion and signs of cytokine release syndrome. EMBO Mol. Med. 2018;10:e9158.
   PubMed Web of Science ®Google Scholar
• Agarwal S, Weidner T, Thalheimer FB, Buchholz CJ. In vivo generated human CAR T cells eradicate tumor cells. Oncoimmunology. 2019;8(12):e1671761. doi:10.1080/2162402X.2019.1671761. [31741773]
   PubMed Web of Science ®Google Scholar
• Smith TT, Stephan SB, Moffett HF, et al. In situ programming of leukaemia-specific T cells using synthetic DNA nanocarriers. Nat Nanotechnol. 2017;12(8):813–820. doi:10.1038/nnano.2017.57. [28416815]
   PubMed Web of Science ®Google Scholar
• Agarwalla P, et al. Bioinstructive implantable scaffolds for rapid in vivo manufacture and release of CAR-T cells. Nat. Biotechnol. 2022. doi:10.1038/s41587-022-01245-x.
   PubMed Web of Science ®Google Scholar