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Navigating CAR-T cells through the solid-tumour microenvironment

Nature Reviews Drug Discovery volume 20, pages 531–550 (2021)Cite this article

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Abstract

The adoptive transfer of T cells that are engineered to express chimeric antigen receptors (CARs) has shown remarkable success in treating B cell malignancies but only limited efficacy against other cancer types, especially solid tumours. Compared with haematological diseases, solid tumours present a unique set of challenges, including a lack of robustly expressed, tumour-exclusive antigen targets as well as highly immunosuppressive and metabolically challenging tumour microenvironments that limit treatment safety and efficacy. Here, we review protein- and cell-engineering strategies that seek to overcome these obstacles and produce next-generation T cells with enhanced tumour specificity and sustained effector function for the treatment of solid malignancies.

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Fig. 1: CARs are synthetic modular receptors with programmable antigen recognition.
Fig. 2: T cell-extrinsic factors limiting treatment efficacy against solid tumours.
Fig. 3: CAR-T cells face intrinsic and extrinsic metabolic challenges in the tumour microenvironment.
Fig. 4: CAR-T cell safety and control can be managed through genetic or pharmacological strategies.

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References

  1. Sadelain, M., Brentjens, R. & Rivière, I. The basic principles of chimeric antigen receptor design. Cancer Discov. 3, 388–398 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Finney, H. M., Lawson, A. D. G., Bebbington, C. R. & Weir, A. N. C. Chimeric receptors providing both primary and costimulatory signaling in T cells from a single gene product. J. Immunol. 161, 2791–2797 (1998).

    CAS  PubMed  Google Scholar 

  3. Finney, H. M., Akbar, A. N. & Lawson, A. D. G. Activation of resting human primary T cells with chimeric receptors: costimulation from CD28, inducible costimulator, CD134, and CD137 in series with signals from the TCRζ chain. J. Immunol. 172, 104–113 (2004).

    CAS  PubMed  Google Scholar 

  4. Imai, C. et al. Chimeric receptors with 4-1BB signaling capacity provoke potent cytotoxicity against acute lymphoblastic leukemia. Leukemia 18, 676–684 (2004).

    CAS  PubMed  Google Scholar 

  5. Maude, S. L. et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N. Engl. J. Med. 371, 1507–1517 (2014).

    PubMed  PubMed Central  Google Scholar 

  6. Hinrichs, C. S. & Restifo, N. P. Reassessing target antigens for adoptive T cell therapy. Nat. Biotechnol. 31, 999–1008 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Rosenberg, S. A. Finding suitable targets is the major obstacle to cancer gene therapy. Cancer Gene Ther. 21, 45–47 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Yu, J. X., Upadhaya, S., Tatake, R., Barkalow, F. & Hubbard-Lucey, V. M. Cancer cell therapies: the clinical trial landscape. Nat. Rev. Drug Discov. 19, 583–584 (2020).

    CAS  PubMed  Google Scholar 

  9. Davila, M. L. et al. Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci. Transl. Med. 6, 224ra25 (2014).

    PubMed  PubMed Central  Google Scholar 

  10. Lee, D. W. et al. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. Lancet 385, 517–528 (2015).

    CAS  PubMed  Google Scholar 

  11. Sadelain, M., Brentjens, R., Rivière, I. & Park, J. CD19 CAR therapy for acute lymphoblastic leukemia. Am. Soc. Clin. Oncol. Educ. Book https://doi.org/10.14694/EdBook_AM.2015.35.e360 (2015).

    Article  PubMed  Google Scholar 

  12. Johnson, L. A. et al. Gene therapy with human and mouse T-cell receptors mediates cancer regression and targets normal tissues expressing cognate antigen. Blood 114, 535–546 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Parkhurst, M. R. et al. T cells targeting carcinoembryonic antigen can mediate regression of metastatic colorectal cancer but induce severe transient colitis. Mol. Ther. 19, 620–626 (2011).

    CAS  PubMed  Google Scholar 

  14. Lamers, C. H. J. et al. Treatment of metastatic renal cell carcinoma with autologous T-lymphocytes genetically retargeted against carbonic anhydrase IX: first clinical experience. J. Clin. Oncol. 24, e20–e22 (2006).

    PubMed  Google Scholar 

  15. Morgan, R. A. et al. Cancer regression and neurologic toxicity following anti-MAGE-A3 TCR gene therapy. J. Immunother. 36, 133–151 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Linette, G. P. et al. Cardiovascular toxicity and titin cross-reactivity of affinity-enhanced T cells in myeloma and melanoma. Blood 122, 863–871 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Cameron, B. J. et al. Identification of a titin-derived HLA-A1–presented peptide as a cross-reactive target for engineered MAGE A3–directed T cells. Sci. Transl. Med. 5, 197ra103 (2013).

    PubMed  PubMed Central  Google Scholar 

  18. Morgan, R. A. 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. 18, 843–851 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Chang, K., Pai, L. H., Batra, J. K., Pastan, I. & Willingham, M. C. Characterization of the antigen (CAK1) recognized by monoclonal antibody K1 present on ovarian cancers and normal mesothelium. Cancer Res. 52, 181–186 (1992).

    CAS  PubMed  Google Scholar 

  20. Morello, A., Sadelain, M. & Adusumilli, P. S. Mesothelin-targeted CARs: driving T cells to solid tumors. Cancer Discov. 6, 133–146 (2016).

    CAS  PubMed  Google Scholar 

  21. Maus, M. V. et al. T cells expressing chimeric antigen receptors can cause anaphylaxis in humans. Cancer Immunol. Res. 1, 26–31 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Beatty, G. L. et al. Mesothelin-specific chimeric antigen receptor mRNA-engineered T cells induce antitumor activity in solid malignancies. Cancer Immunol. Res. 2, 112–120 (2014).

    CAS  PubMed  Google Scholar 

  23. Haas, A. R. et al. Phase I study of lentiviral-transduced chimeric antigen receptor-modified T cells recognizing mesothelin in advanced solid cancers. Mol. Ther. 27, 1919–1929 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Adusumilli, P. S. et al. Regional delivery of mesothelin-targeted CAR T cells for pleural cancers: safety and preliminary efficacy in combination with anti-PD-1 agent. J. Clin. Oncol. 37, 2511 (2019).

    Google Scholar 

  25. Annunziata, C. M. et al. Feasibility and preliminary safety and efficacy of first-in-human intraperitoneal delivery of MCY-M11, anti-human-mesothelin CAR mRNA transfected into peripheral blood mononuclear cells, for ovarian cancer and malignant peritoneal mesothelioma. J. Clin. Oncol. 38, 3014 (2020).

    Google Scholar 

  26. Chmielewski, M., Hombach, A., Heuser, C., Adams, G. P. & Abken, H. T cell activation by antibody-like immunoreceptors: increase in affinity of the single-chain fragment domain above threshold does not increase T cell activation against antigen-positive target cells but decreases selectivity. J. Immunol. 173, 7647–7653 (2004).

    CAS  PubMed  Google Scholar 

  27. Liu, X. et al. Affinity-tuned ErbB2 or EGFR chimeric antigen receptor T cells exhibit an increased therapeutic index against tumors in mice. Cancer Res. 75, 3596–3607 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Caruso, H. G. et al. Tuning sensitivity of CAR to EGFR density limits recognition of normal tissue while maintaining potent antitumor activity. Cancer Res. 75, 3505–3518 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Stone, J. D., Aggen, D. H., Schietinger, A., Schreiber, H. & Kranz, D. M. A sensitivity scale for targeting T cells with chimeric antigen receptors (CARs) and bispecific T-cell Engagers (BiTEs). OncoImmunology 1, 863–873 (2012).

    PubMed  PubMed Central  Google Scholar 

  30. Posey, A. D. et al. Engineered CAR T cells targeting the cancer-associated Tn-glycoform of the membrane Mucin MUC1 control adenocarcinoma. Immunity 44, 1444–1454 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. He, Y. et al. Multiple cancer-specific antigens are targeted by a chimeric antigen receptor on a single cancer cell. JCI Insight 4, e130416 (2019).

    PubMed Central  Google Scholar 

  32. Sharma, P. et al. Structure-guided engineering of the affinity and specificity of CARs against Tn-glycopeptides. Proc. Natl Acad. Sci. USA 117, 15148–15159 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Kloss, C. C., Condomines, M., Cartellieri, M., Bachmann, M. & Sadelain, M. Combinatorial antigen recognition with balanced signaling promotes selective tumor eradication by engineered T cells. Nat. Biotechnol. 31, 71–75 (2013).

    CAS  PubMed  Google Scholar 

  34. Roybal, K. T. et al. Engineering T cells with customized therapeutic response programs using synthetic notch receptors. Cell 167, 419–432.e16 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Srivastava, S. et al. Logic-gated ROR1 chimeric antigen receptor expression rescues T cell-mediated toxicity to normal tissues and enables selective tumor targeting. Cancer Cell 35, 489–503.e8 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Joseph, H. et al. SynNotch-CAR T cells overcome challenges of specificity, heterogeneity, and persistence in treating glioblastoma. Sci. Transl Med. 13, eabe7378 (2021).

    Google Scholar 

  37. Fedorov, V. D., Themeli, M. & Sadelain, M. PD-1– and CTLA-4–based inhibitory chimeric antigen receptors (iCARs) divert off-target immunotherapy responses. Sci. Transl. Med. 5, 215ra172 (2013).

    PubMed  PubMed Central  Google Scholar 

  38. Cho, J. H., Collins, J. J. & Wong, W. W. Universal chimeric antigen receptors for multiplexed and logical control of T cell responses. Cell 173, 1426–1438.e11 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Chowdhury, D. & Lieberman, J. Death by a thousand cuts: granzyme pathways of programmed cell death. Annu. Rev. Immunol. 26, 389–420 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Ho, P., Ede, C. & Chen, Y. Y. Modularly constructed synthetic granzyme B molecule enables interrogation of intracellular proteases for targeted cytotoxicity. ACS Synth. Biol. 6, 1484–1495 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Höckel, M. & Vaupel, P. Tumor hypoxia: definitions and current clinical, biologic, and molecular aspects. J. Natl Cancer Inst. 93, 266–276 (2001).

    PubMed  Google Scholar 

  42. Ede, C., Chen, X., Lin, M.-Y. & Chen, Y. Y. Quantitative analyses of core promoters enable precise engineering of regulated gene expression in mammalian cells. ACS Synth. Biol. 5, 395–404 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Juillerat, A. et al. An oxygen sensitive self-decision making engineered CAR T-cell. Sci. Rep. 7, 39833 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Brennan, C. W. et al. The somatic genomic landscape of glioblastoma. Cell 155, 462–477 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Johnson, L. A. et al. Rational development and characterization of humanized anti–EGFR variant III chimeric antigen receptor T cells for glioblastoma. Sci. Transl. Med. 7, 275ra22 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Nathanson, D. A. et al. Targeted therapy resistance mediated by dynamic regulation of extrachromosomal mutant EGFR DNA. Science 343, 72–76 (2014).

    CAS  PubMed  Google Scholar 

  47. Snuderl, M. et al. Mosaic amplification of multiple receptor tyrosine kinase genes in glioblastoma. Cancer Cell 20, 810–817 (2011).

    CAS  PubMed  Google Scholar 

  48. Majzner, R. G. & Mackall, C. L. Tumor antigen escape from CAR T-cell therapy. Cancer Discov. 8, 1219–1226 (2018).

    CAS  PubMed  Google Scholar 

  49. Zah, E., Lin, M.-Y., Silva-Benedict, A., Jensen, M. C. & Chen, Y. Y. T cells expressing CD19/CD20 bispecific chimeric antigen receptors prevent antigen escape by malignant B cells. Cancer Immunol. Res. 4, 498–508 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Qin, H. et al. Preclinical development of bivalent chimeric antigen receptors targeting both CD19 and CD22. Mol. Ther.Oncolytics 11, 127–137 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Zah, E. et al. Systematically optimized BCMA/CS1 bispecific CAR-T cells robustly control heterogeneous multiple myeloma. Nat. Commun. 11, 2283 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Bielamowicz, K. et al. Trivalent CAR T cells overcome interpatient antigenic variability in glioblastoma. Neuro Oncol. 20, 506–518 (2018).

    CAS  PubMed  Google Scholar 

  53. Bos, T. J., De Bruyne, E., Van Lint, S., Heirman, C. & Vanderkerken, K. Large double copy vectors are functional but show a size-dependent decline in transduction efficiency. J. Biotechnol. 150, 37–40 (2010).

    CAS  PubMed  Google Scholar 

  54. Zhang, T., Lemoi, B. A. & Sentman, C. L. Chimeric NK-receptor–bearing T cells mediate antitumor immunotherapy. Blood 106, 1544–1551 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Lyons, S. A., O’Neal, J. & Sontheimer, H. Chlorotoxin, a scorpion-derived peptide, specifically binds to gliomas and tumors of neuroectodermal origin. Glia 39, 162–173 (2002).

    PubMed  Google Scholar 

  56. Wang, D. et al. Chlorotoxin-directed CAR T cells for specific and effective targeting of glioblastoma. Sci. Transl. Med. 12, eaaw2672 (2020). This study demonstrates efficient eradication of heterogeneous GBM tumours using T cells engineered with CARs that have a single, rather than multiple, ligand-binding domain.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Wing, A. et al. Improving CART-cell therapy of solid tumors with oncolytic virus–driven production of a bispecific T-cell engager. Cancer Immunol. Res. 6, 605–616 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Choi, B. D. et al. CAR-T cells secreting BiTEs circumvent antigen escape without detectable toxicity. Nat. Biotechnol. 37, 1049–1058 (2019).

    CAS  PubMed  Google Scholar 

  59. Park, A. K. et al. Effective combination immunotherapy using oncolytic viruses to deliver CAR targets to solid tumors. Sci. Transl. Med. 12, eaaz1863 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Chapuis, A. G. et al. Transferred WT1-reactive CD8+ T cells can mediate antileukemic activity and persist in post-transplant patients. Sci. Transl. Med. 5, 174ra27 (2013).

    PubMed  PubMed Central  Google Scholar 

  61. Chapuis, A. G. et al. T cell receptor gene therapy targeting WT1 prevents acute myeloid leukemia relapse post-transplant. Nat. Med. 25, 1064–1072 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Kageyama, S. et al. Adoptive transfer of MAGE-A4 T-cell receptor gene-transduced lymphocytes in patients with recurrent esophageal cancer. Clin. Cancer Res. 21, 2268–2277 (2015).

    CAS  PubMed  Google Scholar 

  63. Maus, M. V. et al. An MHC-restricted antibody-based chimeric antigen receptor requires TCR-like affinity to maintain antigen specificity. Mol. Ther. Oncolytics 3, 1–9 (2016).

    PubMed  Google Scholar 

  64. Akahori, Y. et al. Antitumor activity of CAR-T cells targeting the intracellular oncoprotein WT1 can be enhanced by vaccination. Blood 132, 1134–1145 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Schumacher, T. N. & Schreiber, R. D. Neoantigens in cancer immunotherapy. Science 348, 69–74 (2015).

    CAS  PubMed  Google Scholar 

  66. Nielsen, M. et al. NetMHCpan, a method for quantitative predictions of peptide binding to any HLA-A and -B locus protein of known sequence. PLoS ONE 2, e796 (2007).

    PubMed  PubMed Central  Google Scholar 

  67. Fritsch, E. F. et al. HLA-binding properties of tumor neoepitopes in humans. Cancer Immunol. Res. 2, 522–529 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Peng, S. et al. Sensitive detection and analysis of neoantigen-specific T cell populations from tumors and blood. Cell Rep. 28, 2728–2738.e7 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Carreno, B. M. et al. A dendritic cell vaccine increases the breadth and diversity of melanoma neoantigen-specific T cells. Science 348, 803–808 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Ott, P. A. et al. An immunogenic personal neoantigen vaccine for patients with melanoma. Nature 547, 217–221 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Ahmadzadeh, M. et al. Tumor antigen–specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired. Blood 114, 1537–1544 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Klebanoff, C. A., Gattinoni, L. & Restifo, N. P. Sorting through subsets: which T-cell populations mediate highly effective adoptive immunotherapy? J. Immunother. 35, 651–660 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Yamamoto, T. N., Kishton, R. J. & Restifo, N. P. Developing neoantigen-targeted T cell–based treatments for solid tumors. Nat. Med. 25, 1488–1499 (2019).

    CAS  PubMed  Google Scholar 

  74. Alexandrov, L. B. et al. Signatures of mutational processes in human cancer. Nature 500, 415–421 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Lu, Y.-C. et al. Efficient identification of mutated cancer antigens recognized by T cells associated with durable tumor regressions. Clin. Cancer Res. 20, 3401–3410 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Linnemann, C. et al. High-throughput epitope discovery reveals frequent recognition of neo-antigens by CD4+ T cells in human melanoma. Nat. Med. 21, 81–85 (2015).

    CAS  PubMed  Google Scholar 

  77. Nagarsheth, N., Wicha, M. S. & Zou, W. Chemokines in the cancer microenvironment and their relevance in cancer immunotherapy. Nat. Rev. Immunol. 17, 559–572 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Valkenburg, K. C., de Groot, A. E. & Pienta, K. J. Targeting the tumour stroma to improve cancer therapy. Nat. Rev. Clin. Oncol. 15, 366–381 (2018).

    PubMed  PubMed Central  Google Scholar 

  79. Lanitis, E., Irving, M. & Coukos, G. Targeting the tumor vasculature to enhance T cell activity. Curr. Opin. Immunol. 33, 55–63 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Huang, Y. et al. Improving immune–vascular crosstalk for cancer immunotherapy. Nat. Rev. Immunol. 18, 195–203 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Craddock, J. A. et al. Enhanced tumor trafficking of GD2 chimeric antigen receptor T cells by expression of the chemokine receptor CCR2b. J. Immunother. 33, 780–788 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Moon, E. K. et al. Expression of a functional CCR2 receptor enhances tumor localization and tumor eradication by retargeted human T cells expressing a mesothelin-specific chimeric antibody receptor. Clin. Cancer Res. 17, 4719–4730 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Adachi, K. 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. 36, 346–351 (2018).

    CAS  PubMed  Google Scholar 

  84. Gunderson, A. J. et al. TGFβ suppresses CD8+ T cell expression of CXCR3 and tumor trafficking. Nat. Commun. 11, 1749 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Mariathasan, S. et al. TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature 554, 544–548 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Tauriello, D. V. F. et al. TGFβ drives immune evasion in genetically reconstituted colon cancer metastasis. Nature 554, 538–543 (2018).

    CAS  PubMed  Google Scholar 

  87. Chakravarthy, A., Khan, L., Bensler, N. P., Bose, P. & De Carvalho, D. D. TGF-β-associated extracellular matrix genes link cancer-associated fibroblasts to immune evasion and immunotherapy failure. Nat. Commun. 9, 4692 (2018).

    PubMed  PubMed Central  Google Scholar 

  88. Kakarla, S. et al. Antitumor effects of chimeric receptor engineered human T cells directed to tumor stroma. Mol. Ther. 21, 1611–1620 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Wang, L.-C. S. 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. 2, 154–166 (2014).

    CAS  PubMed  Google Scholar 

  90. Tran, E. et al. Immune targeting of fibroblast activation protein triggers recognition of multipotent bone marrow stromal cells and cachexia. J. Exp. Med. 210, 1125–1135 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Anderton, M. J. et al. Induction of heart valve lesions by small-molecule ALK5 inhibitors. Toxicol. Pathol. 39, 916–924 (2011).

    CAS  PubMed  Google Scholar 

  92. Hanley, C. J. et al. Targeting the myofibroblastic cancer-associated fibroblast phenotype through inhibition of NOX4. J. Natl Cancer Inst. 110, 109–120 (2018).

    CAS  Google Scholar 

  93. Ford, K. et al. NOX4 inhibition potentiates immunotherapy by overcoming cancer-associated fibroblast-mediated CD8 T-cell exclusion from tumours. Cancer Res. 80, 1846–1860 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Caruana, I. et al. Heparanase promotes tumor infiltration and antitumor activity of CAR-redirected T lymphocytes. Nat. Med. 21, 524–529 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Newick, K. et al. Augmentation of CAR T-cell trafficking and antitumor efficacy by blocking protein kinase A localization. Cancer Immunol. Res. 4, 541–551 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Muller, W. A. Mechanisms of leukocyte transendothelial migration. Annu. Rev. Pathol. 6, 323–344 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Adusumilli, P. S. et al. Regional delivery of mesothelin-targeted CAR T cell therapy generates potent and long-lasting CD4-dependent tumor immunity. Sci. Transl. Med. 6, 261ra151 (2014).

    PubMed  PubMed Central  Google Scholar 

  98. Saied, A. et al. Neutrophil:lymphocyte ratios and serum cytokine changes after hepatic artery chimeric antigen receptor-modified T-cell infusions for liver metastases. Cancer Gene Ther. 21, 457–462 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Katz, S. C. et al. Phase I hepatic immunotherapy for metastases study of intra-arterial chimeric antigen receptor–modified T-cell therapy for CEA+ liver metastases. Clin. Cancer Res. 21, 3149–3159 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Katz, S. C. et al. HITM-SIR: phase Ib trial of intraarterial chimeric antigen receptor T-cell therapy and selective internal radiation therapy for CEA+ liver metastases. Cancer Gene Ther. 27, 341–355 (2020).

    CAS  PubMed  Google Scholar 

  101. Brown, C. E. et al. Optimization of IL13Rα2-targeted chimeric antigen receptor T cells for improved anti-tumor efficacy against glioblastoma. Mol. Ther. 26, 31–44 (2018).

    CAS  PubMed  Google Scholar 

  102. Theruvath, J. et al. Locoregionally administered B7-H3-targeted CAR T cells for treatment of atypical teratoid/rhabdoid tumors. Nat. Med. 26, 712–719 (2020). This study systematically compares various CAR-T cell delivery routes to demonstrate that locoregional administration produces an optimal therapeutic response.

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Stephan, S. B. et al. Biopolymer implants enhance the efficacy of adoptive T-cell therapy. Nat. Biotechnol. 33, 97–101 (2015).

    CAS  PubMed  Google Scholar 

  104. Smith, T. T. et al. Biopolymers codelivering engineered T cells and STING agonists can eliminate heterogeneous tumors. J. Clin. Invest. 127, 2176–2191 (2017). This study takes a multi-pronged, interdisciplinary approach to effectively deliver CAR T cells with enhanced potency against solid tumours by co-administration with STING agonists in a biopolymer scaffold.

    PubMed  PubMed Central  Google Scholar 

  105. Coon, M. E., Stephan, S. B., Gupta, V., Kealey, C. P. & Stephan, M. T. Nitinol thin films functionalized with CAR-T cells for the treatment of solid tumours. Nat. Biomed. Eng. 4, 195–206 (2020).

    CAS  PubMed  Google Scholar 

  106. Gabrilovich, D. I., Ostrand-Rosenberg, S. & Bronte, V. Coordinated regulation of myeloid cells by tumours. Nat. Rev. Immunol. 12, 253–268 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Quail, D. F. & Joyce, J. A. Microenvironmental regulation of tumor progression and metastasis. Nat. Med. 19, 1423–1437 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Binnewies, M. et al. Understanding the tumor immune microenvironment (TIME) for effective therapy. Nat. Med. 24, 541–550 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Bollard, C. M. et al. Adapting a transforming growth factor β-related tumor protection strategy to enhance antitumor immunity. Blood 99, 3179–3187 (2002).

    CAS  PubMed  Google Scholar 

  110. Roth, T. L. et al. Pooled knockin targeting for genome engineering of cellular immunotherapies. Cell 181, 728–744.e21 (2020). This study employs a transgene knock-in, library-screening approach to identify synthetic receptors that confer enhanced T cell function against solid tumours.

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Chang, Z. L. et al. Rewiring T-cell responses to soluble factors with chimeric antigen receptors. Nat. Chem. Biol. 14, 317–324 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Hou, A. J., Chang, Z. L., Lorenzini, M. H., Zah, E. & Chen, Y. Y. TGF-β–responsive CAR-T cells promote anti-tumor immune function. Bioeng. Transl. Med. 3, 75–86 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Chang, Z. L., Hou, A. J. & Chen, Y. Y. Engineering primary T cells with chimeric antigen receptors for rewired responses to soluble ligands. Nat. Protoc. 15, 1507–1524 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Kloss, C. C. et al. Dominant-negative TGF-β receptor enhances PSMA-targeted human CAR T cell proliferation and augments prostate cancer eradication. Mol. Ther. 26, 1855–1866 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Wilkie, S. et al. Selective expansion of chimeric antigen receptor-targeted T-cells with potent effector function using interleukin-4. J. Biol. Chem. 285, 25538–25544 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Leen, A. M. et al. Reversal of tumor immune inhibition using a chimeric cytokine receptor. Mol. Ther. 22, 1211–1220 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Mohammed, S. et al. Improving chimeric antigen receptor-modified T cell function by reversing the immunosuppressive tumor microenvironment of pancreatic cancer. Mol. Ther. 25, 249–258 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Sukumaran, S. et al. Enhancing the potency and specificity of engineered T cells for cancer treatment. Cancer Discov. 8, 972–987 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Cherkassky, L. et al. Human CAR T cells with cell-intrinsic PD-1 checkpoint blockade resist tumor-mediated inhibition. J. Clin. Invest. 126, 3130–3144 (2016).

    PubMed  PubMed Central  Google Scholar 

  120. Prosser, M. E., Brown, C. E., Shami, A. F., Forman, S. J. & Jensen, M. C. Tumor PD-L1 co-stimulates primary human CD8+ cytotoxic T cells modified to express a PD1:CD28 chimeric receptor. Mol. Immunol. 51, 263–272 (2012).

    CAS  PubMed  Google Scholar 

  121. Liu, X. et al. A chimeric switch-receptor targeting PD1 augments the efficacy of second generation CAR T-cells in advanced solid tumors. Cancer Res. 76, 1578–1590 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Yamamoto, T. N. et al. T cells genetically engineered to overcome death signaling enhance adoptive cancer immunotherapy. J. Clin. Invest. 129, 1551–1565 (2019).

    PubMed  PubMed Central  Google Scholar 

  123. Chmielewski, M., Kopecky, C., Hombach, A. A. & Abken, H. IL-12 release by engineered T cells expressing chimeric antigen receptors can effectively muster an antigen-independent macrophage response on tumor cells that have shut down tumor antigen expression. Cancer Res. 71, 5697–5706 (2011).

    CAS  PubMed  Google Scholar 

  124. Pegram, H. J. et al. Tumor-targeted T cells modified to secrete IL-12 eradicate systemic tumors without need for prior conditioning. Blood 119, 4133–4141 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Hu, B. et al. Augmentation of antitumor immunity by human and mouse CAR T cells secreting IL-18. Cell Rep. 20, 3025–3033 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Avanzi, M. P. et al. Engineered tumor-targeted T cells mediate enhanced anti-tumor efficacy both directly and through activation of the endogenous immune system. Cell Rep. 23, 2130–2141 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Ma, X. et al. Interleukin-23 engineering improves CAR T cell function in solid tumors. Nat. Biotechnol. 38, 448–459 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Cassetta, L. & Kitamura, T. Targeting tumor-associated macrophages as a potential strategy to enhance the response to immune checkpoint inhibitors. Front. Cell Dev. Biol. 6, 38 (2018).

    PubMed  PubMed Central  Google Scholar 

  129. Strauss, L. et al. Targeted deletion of PD-1 in myeloid cells induces antitumor immunity. Sci. Immunol. 5, eaay1863 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Stromnes, I. M. et al. Differential effects of depleting versus programming tumor-associated macrophages on engineered T cells in pancreatic ductal adenocarcinoma. Cancer Immunol. Res. 7, 977–989 (2019). This study demonstrates the advantage of myeloid-cell reprogramming over depletion in combination with adoptive T cell transfer.

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Parihar, R. et al. NK cells expressing a chimeric activating receptor eliminate MDSCs and rescue impaired CAR-T cell activity against solid tumors. Cancer Immunol. Res. 7, 363–375 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Parisi, G. et al. Persistence of adoptively transferred T cells with a kinetically engineered IL-2 receptor agonist. Nat. Commun. 11, 660 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Sun, Z. et al. A next-generation tumor-targeting IL-2 preferentially promotes tumor-infiltrating CD8+ T-cell response and effective tumor control. Nat. Commun. 10, 3874 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Sockolosky, J. T. et al. Selective targeting of engineered T cells using orthogonal IL-2 cytokine-receptor complexes. Science 359, 1037–1042 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Neubert, N. J. et al. T cell-induced CSF1 promotes melanoma resistance to PD1 blockade. Sci. Transl. Med. 10, eaan3311 (2018).

    PubMed  PubMed Central  Google Scholar 

  136. O’Rourke, D. M. 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. 9, eaaa0984 (2017).

    PubMed  PubMed Central  Google Scholar 

  137. Sampson, J. H. et al. EGFRvIII mCAR-modified T-cell therapy cures mice with established intracerebral glioma and generates host immunity against tumor-antigen loss. Clin. Cancer Res. 20, 972–984 (2014).

    CAS  PubMed  Google Scholar 

  138. Pituch, K. C. et al. Adoptive transfer of IL13Rα2-specific chimeric antigen receptor T cells creates a pro-inflammatory environment in glioblastoma. Mol. Ther. 26, 986–995 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Ma, L. et al. Enhanced CAR-T cell activity against solid tumors by vaccine boosting through the chimeric receptor. Science 365, 162–168 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Lai, J. et al. Adoptive cellular therapy with T cells expressing the dendritic cell growth factor Flt3L drives epitope spreading and antitumor immunity. Nat. Immunol. 21, 914–926 (2020). This study presents a novel strategy to engineer CAR T cells that recruit DCs to stimulate endogenous antitumour immunity.

    CAS  PubMed  Google Scholar 

  141. Liu, Y. et al. Gasdermin E-mediated target cell pyroptosis by CAR T cells triggers cytokine release syndrome. Sci. Immunol. 5, eaax7969 (2020). This study demonstrates that CAR T cells can induce pyroptosis in target tumour cells, and that pyroptosis is directly correlated with CRS-related toxicities and may contribute to the recruitment of an endogenous antitumour immune response.

    CAS  PubMed  Google Scholar 

  142. Zhou, Z. et al. Granzyme A from cytotoxic lymphocytes cleaves GSDMB to trigger pyroptosis in target cells. Science 368, eaaz7548 (2020).

    CAS  PubMed  Google Scholar 

  143. Wang, Y. et al. Chemotherapy drugs induce pyroptosis through caspase-3 cleavage of a gasdermin. Nature 547, 99–103 (2017).

    CAS  PubMed  Google Scholar 

  144. Wang, Q. et al. A bioorthogonal system reveals antitumour immune function of pyroptosis. Nature 579, 421–426 (2020).

    CAS  PubMed  Google Scholar 

  145. Pavlova, N. N. & Thompson, C. B. The emerging hallmarks of cancer metabolism. Cell Metab. 23, 27–47 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. Heiden, M. G. V., Cantley, L. C. & Thompson, C. B. Understanding the warburg effect: the metabolic requirements of cell proliferation. Science 324, 1029–1033 (2009).

    Google Scholar 

  147. Chang, C.-H. et al. Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell 162, 1229–1241 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Menk, A. V. et al. Early TCR signaling induces rapid aerobic glycolysis enabling distinct acute T cell effector functions. Cell Rep. 22, 1509–1521 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Chang, C.-H. et al. Posttranscriptional control of T cell effector function by aerobic glycolysis. Cell 153, 1239–1251 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Ho, P.-C. et al. Phosphoenolpyruvate is a metabolic checkpoint of anti-tumor T cell responses. Cell 162, 1217–1228 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  151. Qiu, J. et al. Acetate promotes T cell effector function during glucose restriction. Cell Rep. 27, 2063–2074.e5 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Renner, K. et al. Restricting glycolysis preserves T cell effector functions and augments checkpoint therapy. Cell Rep. 29, 135–150.e9 (2019).

    CAS  PubMed  Google Scholar 

  153. Cascone, T. et al. Increased tumor glycolysis characterizes immune resistance to adoptive T cell therapy. Cell Metab. 27, 977–987.e4 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Bengsch, B. et al. Bioenergetic insufficiencies due to metabolic alterations regulated by the inhibitory receptor PD-1 are an early driver of CD8+ T cell exhaustion. Immunity 45, 358–373 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  155. Fisicaro, P. et al. Targeting mitochondrial dysfunction can restore antiviral activity of exhausted HBV-specific CD8 T cells in chronic hepatitis B. Nat. Med. 23, 327–336 (2017).

    CAS  PubMed  Google Scholar 

  156. Dumauthioz, N. et al. Enforced PGC-1α expression promotes CD8 T cell fitness, memory formation and antitumor immunity. Cell. Mol. Immunol. https://doi.org/10.1038/s41423-020-0365-3 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  157. Ligtenberg, M. A. et al. Coexpressed catalase protects chimeric antigen receptor–redirected t cells as well as bystander cells from oxidative stress–induced loss of antitumor activity. J. Immunol. 196, 759–766 (2016).

    CAS  PubMed  Google Scholar 

  158. Vardhana, S. A. et al. Impaired mitochondrial oxidative phosphorylation limits the self-renewal of T cells exposed to persistent antigen. Nat. Immunol. 21, 1022–1033 (2020). This study highlights the mechanisms underlying mitochondrial metabolic stresses caused by chronic T cell stimulation and provides a solution to remedy the metabolic and effector T cell dysfunction.

    CAS  PubMed  PubMed Central  Google Scholar 

  159. Gemta, L. F. et al. Impaired enolase 1 glycolytic activity restrains effector functions of tumor-infiltrating CD8+ T cells. Sci. Immunol. 4, eaap9520 (2019). This study pinpoints enolase 1 as a key mediator of glycolytic repression in CD8+ TILs, providing a novel mechanism towards understanding metabolic dysfunction in TILs and an accompanying solution.

    CAS  PubMed  PubMed Central  Google Scholar 

  160. Chakraborty, P. et al. Pro-survival lipid sphingosine-1-phosphate metabolically programs T cells to limit anti-tumor activity. Cell Rep. 28, 1879–1893.e7 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  161. O’Sullivan, D. et al. Memory CD8+ T cells use cell-intrinsic lipolysis to support the metabolic programming necessary for development. Immunity 41, 75–88 (2014).

    PubMed  PubMed Central  Google Scholar 

  162. Mellor, A. L. & Munn, D. H. Ido expression by dendritic cells: tolerance and tryptophan catabolism. Nat. Rev. Immunol. 4, 762–774 (2004).

    CAS  PubMed  Google Scholar 

  163. Li, H. et al. Metabolomic adaptations and correlates of survival to immune checkpoint blockade. Nat. Commun. 10, 4346 (2019).

    PubMed  PubMed Central  Google Scholar 

  164. Long, G. V. et al. Epacadostat plus pembrolizumab versus placebo plus pembrolizumab in patients with unresectable or metastatic melanoma (ECHO-301/KEYNOTE-252): a phase 3, randomised, double-blind study. Lancet Oncol. 20, 1083–1097 (2019).

    CAS  PubMed  Google Scholar 

  165. Triplett, T. A. et al. Reversal of indoleamine 2,3-dioxygenase–mediated cancer immune suppression by systemic kynurenine depletion with a therapeutic enzyme. Nat. Biotechnol. 36, 758–764 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  166. Beavis, P. A., Stagg, J., Darcy, P. K. & Smyth, M. J. CD73: a potent suppressor of antitumor immune responses. Trends Immunol. 33, 231–237 (2012).

    CAS  PubMed  Google Scholar 

  167. Zhang, B. et al. High expression of CD39/ENTPD1 in malignant epithelial cells of human rectal adenocarcinoma. Tumor Biol. 36, 9411–9419 (2015).

    CAS  Google Scholar 

  168. Leone, R. D. & Emens, L. A. Targeting adenosine for cancer immunotherapy. J. Immunother. Cancer 6, 57 (2018).

    PubMed  PubMed Central  Google Scholar 

  169. Beavis, P. A. et al. Targeting the adenosine 2A receptor enhances chimeric antigen receptor T cell efficacy. J. Clin. Invest. 127, 929–941 (2017).

    PubMed  PubMed Central  Google Scholar 

  170. Fischer, K. et al. Inhibitory effect of tumor cell-derived lactic acid on human T cells. Blood 109, 3812–3819 (2007).

    CAS  PubMed  Google Scholar 

  171. Brand, A. et al. LDHA-associated lactic acid production blunts tumor immunosurveillance by T and NK cells. Cell Metab. 24, 657–671 (2016).

    CAS  PubMed  Google Scholar 

  172. Angelin, A. et al. Foxp3 reprograms T cell metabolism to function in low-glucose, high-lactate environments. Cell Metab. 25, 1282–1293.e7 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  173. Colegio, O. R. et al. Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature 513, 559–563 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  174. Calcinotto, A. et al. Modulation of microenvironment acidity reverses anergy in human and murine tumor-infiltrating T lymphocytes. Cancer Res. 72, 2746–2756 (2012).

    CAS  PubMed  Google Scholar 

  175. Pilon-Thomas, S. et al. Neutralization of tumor acidity improves antitumor responses to immunotherapy. Cancer Res. 76, 1381–1390 (2016).

    CAS  PubMed  Google Scholar 

  176. Yang, W. et al. Potentiating the antitumour response of CD8+ T cells by modulating cholesterol metabolism. Nature 531, 651–655 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  177. Patel, C. H. & Powell, J. D. Targeting T cell metabolism to regulate T cell activation, differentiation and function in disease. Curr. Opin. Immunol. 46, 82–88 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  178. McLane, L. M., Abdel-Hakeem, M. S. & Wherry, E. J. CD8 T cell exhaustion during chronic viral infection and cancer. Annu. Rev. Immunol. 37, 457–495 (2019).

    CAS  PubMed  Google Scholar 

  179. Pauken, K. E. et al. Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade. Science 354, 1160–1165 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  180. Satpathy, A. T. et al. Massively parallel single-cell chromatin landscapes of human immune cell development and intratumoral T cell exhaustion. Nat. Biotechnol. 37, 925–936 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  181. Khan, O. et al. TOX transcriptionally and epigenetically programs CD8+ T cell exhaustion. Nature 571, 211–218 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  182. Scott, A. C. et al. TOX is a critical regulator of tumour-specific T cell differentiation. Nature 571, 270–274 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  183. Yao, C. et al. Single-cell RNA-seq reveals TOX as a key regulator of CD8+ T cell persistence in chronic infection. Nat. Immunol. 20, 890–901 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  184. Alfei, F. et al. TOX reinforces the phenotype and longevity of exhausted T cells in chronic viral infection. Nature 571, 265–269 (2019).

    CAS  PubMed  Google Scholar 

  185. Chen, J. et al. NR4A transcription factors limit CAR T cell function in solid tumours. Nature 567, 530–534 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  186. LaFleur, M. W. et al. PTPN2 regulates the generation of exhausted CD8+ T cell subpopulations and restrains tumor immunity. Nat. Immunol. 20, 1335–1347 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  187. Wiede, F. et al. PTPN2 phosphatase deletion in T cells promotes anti-tumour immunity and CAR T-cell efficacy in solid tumours. EMBO J. 39, e103637 (2020).

    CAS  PubMed  Google Scholar 

  188. Chen, Z. et al. TCF-1-centered transcriptional network drives an effector versus exhausted CD8 T cell-fate decision. Immunity 51, 840–855.e5 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  189. Siddiqui, I. et al. Intratumoral Tcf1+PD-1+CD8+ T cells with stem-like properties promote tumor control in response to vaccination and checkpoint blockade immunotherapy. Immunity 50, 195–211.e10 (2019).

    CAS  PubMed  Google Scholar 

  190. Beltra, J.-C. et al. Developmental relationships of four exhausted CD8+ T cell subsets reveals underlying transcriptional and epigenetic landscape control mechanisms. Immunity 52, 825–841.e8 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  191. Lynn, R. C. et al. c-Jun overexpression in CAR T cells induces exhaustion resistance. Nature 576, 293–300 (2019). This study identifies novel epigenetic and genetic features of CAR-T cell exhaustion and provides a CAR-T cell engineering solution that increases CAR-T cell resistance to exhaustion.

    CAS  PubMed  PubMed Central  Google Scholar 

  192. Feucht, J. et al. Calibration of CAR activation potential directs alternative T cell fates and therapeutic potency. Nat. Med. 25, 82–88 (2019). This study provides an elegant engineering strategy, through rational modulation of CD3ζ signalling, to balance strong antitumour responses with CAR-T cell longevity.

    CAS  PubMed  Google Scholar 

  193. Rafiq, S. et al. Targeted delivery of a PD-1-blocking scFv by CAR-T cells enhances anti-tumor efficacy in vivo. Nat. Biotechnol. 36, 847–856 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  194. Grosser, R., Cherkassky, L., Chintala, N. & Adusumilli, P. S. Combination immunotherapy with CAR T cells and checkpoint blockade for the treatment of solid tumors. Cancer Cell 36, 471–482 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  195. Brentjens, R. J. et al. Safety and persistence of adoptively transferred autologous CD19-targeted T cells in patients with relapsed or chemotherapy refractory B-cell leukemias. Blood 118, 4817–4828 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  196. Kochenderfer, J. N. et al. B-cell depletion and remissions of malignancy along with cytokine-associated toxicity in a clinical trial of anti-CD19 chimeric-antigen-receptor-transduced T cells. Blood 119, 2709–2720 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  197. Locke, F. L. et al. Phase 1 results of ZUMA-1: a multicenter study of KTE-C19 anti-CD19 CAR T cell therapy in refractory aggressive lymphoma. Mol. Ther. 25, 285–295 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  198. Ali, S. A. et al. T cells expressing an anti-B-cell maturation antigen chimeric antigen receptor cause remissions of multiple myeloma. Blood 128, 1688–1700 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  199. Cohen, A. D. et al. Safety and efficacy of B-cell maturation antigen (BCMA)-specific chimeric antigen receptor T cells (CART-BCMA) with cyclophosphamide conditioning for refractory multiple myeloma (MM). Blood 130, 505 (2017).

    Google Scholar 

  200. Brudno, J. N. et al. T cells genetically modified to express an anti-B-cell maturation antigen chimeric antigen receptor cause remissions of poor-prognosis relapsed multiple myeloma. J. Clin. Oncol. 36, 2267–2280 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  201. Raje, N. et al. Anti-BCMA CAR T-cell therapy bb2121 in relapsed or refractory multiple myeloma. N. Engl. J. Med. 380, 1726–1737 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  202. Lee, D. W. et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood 124, 188–195 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  203. Sterner, R. M. et al. GM-CSF inhibition reduces cytokine release syndrome and neuroinflammation but enhances CAR-T cell function in xenografts. Blood 133, 697–709 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  204. Giavridis, T. et al. CAR T cell-induced cytokine release syndrome is mediated by macrophages and abated by IL-1 blockade. Nat. Med. 24, 731–738 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  205. Norelli, M. et al. Monocyte-derived IL-1 and IL-6 are differentially required for cytokine-release syndrome and neurotoxicity due to CAR T cells. Nat. Med. 24, 739–748 (2018).

    CAS  PubMed  Google Scholar 

  206. Tan, A. H. J., Vinanica, N. & Campana, D. Chimeric antigen receptor–T cells with cytokine neutralizing capacity. Blood Adv. 4, 1419–1431 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  207. Brown, C. E. et al. Regression of glioblastoma after chimeric antigen receptor T-cell therapy. N. Engl. J. Med. 375, 2561–2569 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  208. Mount, C. W. et al. Potent antitumor efficacy of anti-GD2 CAR T cells in H3-K27M+ diffuse midline gliomas. Nat. Med. 24, 572–579 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  209. Gust, J. et al. Endothelial activation and blood–brain barrier disruption in neurotoxicity after adoptive immunotherapy with CD19 CAR-T cells. Cancer Discov. 7, 1404–1419 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  210. Neelapu, S. S. et al. Chimeric antigen receptor T-cell therapy — assessment and management of toxicities. Nat. Rev. Clin. Oncol. 15, 47–62 (2018).

    CAS  PubMed  Google Scholar 

  211. Parker, K. R. et al. Single-cell analyses identify brain mural cells expressing CD19 as potential off-tumor targets for CAR-T immunotherapies. Cell 183, 126–142.e17 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  212. Di Stasi, A. et al. Inducible apoptosis as a safety switch for adoptive cell therapy. N. Engl. J. Med. 365, 1673–1683 (2011).

    PubMed  PubMed Central  Google Scholar 

  213. Bonini, C. et al. HSV-TK gene transfer into donor lymphocytes for control of allogeneic graft-versus-leukemia. Science 276, 1719–1724 (1997).

    CAS  PubMed  Google Scholar 

  214. Berger, C., Flowers, M. E., Warren, E. H. & Riddell, S. R. Analysis of transgene-specific immune responses that limit the in vivo persistence of adoptively transferred HSV-TK-modified donor T cells after allogeneic hematopoietic cell transplantation. Blood 107, 2294–2302 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  215. Ciceri, F. et al. Infusion of suicide-gene-engineered donor lymphocytes after family haploidentical haemopoietic stem-cell transplantation for leukaemia (the TK007 trial): a non-randomised phase I–II study. Lancet Oncol. 10, 489–500 (2009).

    PubMed  Google Scholar 

  216. Griffioen, M. et al. Retroviral transfer of human CD20 as a suicide gene for adoptive T-cell therapy. Haematologica 94, 1316–1320 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  217. Wang, X. et al. A transgene-encoded cell surface polypeptide for selection, in vivo tracking, and ablation of engineered cells. Blood 118, 1255–1263 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  218. Mestermann, K. et al. The tyrosine kinase inhibitor dasatinib acts as a pharmacologic on/off switch for CAR T cells. Sci. Transl. Med. 11, eaau5907 (2019). This study introduces a novel method to rapidly and reversibly inhibit CAR-T cell activity without the need to introduce additional genetic components.

    PubMed  PubMed Central  Google Scholar 

  219. Juillerat, A. et al. Modulation of chimeric antigen receptor surface expression by a small molecule switch. BMC Biotechnol. 19, 44 (2019).

    PubMed  PubMed Central  Google Scholar 

  220. Weber, E. W. et al. Transient “rest” induces functional reinvigoration and epigenetic remodeling in exhausted CAR-T cells. Preprint at bioRxiv https://doi.org/10.1101/2020.01.26.920496 (2020).

    Article  Google Scholar 

  221. Giordano-Attianese, G. et al. A computationally designed chimeric antigen receptor provides a small-molecule safety switch for T-cell therapy. Nat. Biotechnol. 38, 426–432 (2020).

    CAS  PubMed  Google Scholar 

  222. Foster, A. E. et al. Regulated expansion and survival of chimeric antigen receptor-modified T cells using small molecule-dependent inducible MyD88/CD40. Mol. Ther. 25, 2176–2188 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  223. Narayanan, P. et al. A composite MyD88/CD40 switch synergistically activates mouse and human dendritic cells for enhanced antitumor efficacy. J. Clin. Invest. 121, 1524–1534 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  224. Harris, D. T. & Kranz, D. M. Adoptive T cell therapies: a comparison of T cell receptors and chimeric antigen receptors. Trends Pharmacol. Sci. 37, 220–230 (2016).

    CAS  PubMed  Google Scholar 

  225. Wu, L., Wei, Q., Brzostek, J. & Gascoigne, N. R. J. Signaling from T cell receptors (TCRs) and chimeric antigen receptors (CARs) on T cells. Cell. Mol. Immunol. 17, 600–612 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  226. Harris, D. T. et al. Comparison of T cell activities mediated by human TCRs and CARs that use the same recognition domains. J. Immunol. 200, 1088–1100 (2018).

    CAS  PubMed  Google Scholar 

  227. Oren, R. et al. Functional comparison of engineered T cells carrying a native TCR versus TCR-like antibody-based chimeric antigen receptors indicates affinity/avidity thresholds. J. Immunol. 193, 5733–5743 (2014).

    CAS  PubMed  Google Scholar 

  228. Xu, Y. et al. A novel antibody-TCR (AbTCR) platform combines Fab-based antigen recognition with gamma/delta-TCR signaling to facilitate T-cell cytotoxicity with low cytokine release. Cell Discov. 4, 1–13 (2018).

    Google Scholar 

  229. Baeuerle, P. A. et al. Synthetic TRuC receptors engaging the complete T cell receptor for potent anti-tumor response. Nat. Commun. 10, 2087 (2019).

    PubMed  PubMed Central  Google Scholar 

  230. Helsen, C. W. et al. The chimeric TAC receptor co-opts the T cell receptor yielding robust anti-tumor activity without toxicity. Nat. Commun. 9, 3049 (2018).

    PubMed  PubMed Central  Google Scholar 

  231. Seo, H. et al. TOX and TOX2 transcription factors cooperate with NR4A transcription factors to impose CD8+ T cell exhaustion. Proc. Natl. Acad. Sci. USA 116, 12410–12415 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  232. Stadtmauer, E. A. et al. CRISPR-engineered T cells in patients with refractory cancer. Science 367, eaba7365 (2020).

    CAS  PubMed  Google Scholar 

  233. Wei, J. et al. Targeting REGNASE-1 programs long-lived effector T cells for cancer therapy. Nature 576, 471–476 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  234. Gurusamy, D. et al. Multi-phenotype CRISPR-Cas9 screen identifies p38 kinase as a target for adoptive immunotherapies. Cancer Cell 37, 818–833.e9 (2020).

    CAS  PubMed  Google Scholar 

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Acknowledgements

A.J.H. was supported by the Mark Foundation (grant to Y.Y.C.) and L.C.C. was supported by the National Science Foundation (grant to Y.Y.C.).

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Authors and Affiliations

  1. Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, Los Angeles, CA, USA

    Andrew J. Hou, Laurence C. Chen & Yvonne Y. Chen

  2. Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA

    Yvonne Y. Chen

  3. Parker Institute for Cancer Immunotherapy Center at UCLA, Los Angeles, CA, USA

    Yvonne Y. Chen

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Correspondence to Yvonne Y. Chen.

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Y.Y.C. and A.J.H. declare competing financial interests in the form of patent applications whose value may be affected by the publication of this work. L.C.C. declares no competing interests.

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Glossary

T cell exhaustion

An evolving term that broadly describes a state of T cell hypofunctionality, characterized by distinct epigenetic, metabolic and phenotypic signatures, as a consequence of chronic stimulation.

B cell aplasia

Depletion of healthy B cells in a patient receiving CAR-T cells targeting pan-B cell markers.

Mesothelial cells

Cells that line internal body cavities, including organs such as the heart and lungs.

Boolean AND-gate logic

A logical computation in which both condition ‘A’ AND condition ‘B’ must be met for the outcome to be true.

Boolean AND-NOT-gate

A logical computation in which condition ‘A’ must be true AND condition ‘B’ must NOT be true for the outcome to be true.

Bispecific T cell engager

(BiTE). A bispecific antibody consisting of a tumour-targeting antibody and a T cell-stimulating, anti-CD3 antibody.

Immunoreceptor tyrosine-based activation motifs

Conserved sequences found in the cytoplasmic region of CD3 T cell receptor chains that when phosphorylated serve as docking sites for downstream signalling molecules.

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Hou, A.J., Chen, L.C. & Chen, Y.Y. Navigating CAR-T cells through the solid-tumour microenvironment. Nat Rev Drug Discov 20, 531–550 (2021). https://doi.org/10.1038/s41573-021-00189-2

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