Review Article | Published:

Programming CAR-T cells to kill cancer

Nature Biomedical Engineeringvolume 2pages377391 (2018) | Download Citation

Abstract

T cells engineered to express chimeric antigen receptors (CARs) that are specific for tumour antigens have led to high complete response rates in patients with haematologic malignancies. Despite this early success, major challenges to the broad application of CAR-T cells as cancer therapies remain, including treatment-associated toxicities and cancer relapse with antigen-negative tumours. Targeting solid tumours with CAR-T cells poses additional obstacles because of the paucity of tumour-specific antigens and the immunosuppressive effects of the tumour microenvironment. To overcome these challenges, T cells can be programmed with genetic modules that increase their therapeutic potency and specificity. In this Review Article, we survey major advances in the engineering of next-generation CAR-T therapies for haematologic cancers and solid cancers, with particular emphasis on strategies for the control of CAR specificity and activity and on approaches for improving CAR-T-cell persistence and overcoming immunosuppression. We also lay out a roadmap for the development of off-the-shelf CAR-T cells.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

References

  1. 1.

    Rosenberg, S. A. et al. Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clin. Cancer Res. 17, 4550–4557 (2011).

  2. 2.

    Bethune, M. T. & Joglekar, A. V. Personalized T cell-mediated cancer immunotherapy: progress and challenges. Curr. Opin. Biotechnol. 48, 142–152 (2017).

  3. 3.

    Rapoport, A. P. et al. NY-ESO-1–specific TCR–engineered T cells mediate sustained antigen-specific antitumor effects in myeloma. Nat. Med. 21, 914–921 (2015).

  4. 4.

    Robbins, P. F. et al. Tumor regression in patients with metastatic synovial cell sarcoma and melanoma using genetically engineered lymphocytes reactive with NY-ESO-1. J. Clin. Oncol. 29, 917–924 (2011).

  5. 5.

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

  6. 6.

    Brentjens, R. J. et al. CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci. Transl. Med. 5, 177ra38 (2013).

  7. 7.

    Grupp, S. A. et al. Chimeric antigen receptor–modified T cells for acute lymphoid leukemia. N. Engl. J. Med. 368, 1509–1518 (2013).

  8. 8.

    Kochenderfer, J. N. 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. 33, 540–549 (2015).

  9. 9.

    Schuster, S. J. et al. Sustained remissions following chimeric antigen receptor modified T cells directed against CD19 (CTL019) in patients with relapsed or refractory CD19+ lymphomas. Blood 126, 183 (2015).

  10. 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).

  11. 11.

    Gardner, R. A. et al. Intent-to-treat leukemia remission by CD19 CAR T cells of defined formulation and dose in children and young adults. Blood 129, 3322–3331 (2017).

  12. 12.

    Turtle, C. J. et al. CD19 CAR–T cells of defined CD4+:CD8+ composition in adult B cell ALL patients. J. Clin. Invest. 1, 2123–2138 (2016).

  13. 13.

    Turtle, C. J. et al. Immunotherapy of non-Hodgkins lymphoma with a defined ratio of CD8+ and CD4+ CD19-specific chimeric antigen receptor-modified T cells. Sci. Transl. Med. 8, 355ra116 (2016).

  14. 14.

    CAR T-cells: an exciting frontier in cancer therapy. Lancet 390, 1006 (2017).

  15. 15.

    FDA approves CAR-T cell therapy to treat adults with certain types of large B-cell lymphoma. US Food and Drug Administration go.nature.com/2jqgcKX (18 October 2017).

  16. 16.

    Lerner, R. A. Combinatorial antibody libraries: new advances, new immunological insights. Nat. Rev. Immunol. 16, 498–508 (2016).

  17. 17.

    Long, A. H. et al. 4-1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of chimeric antigen receptors. Nat. Med. 21, 581–590 (2015).

  18. 18.

    Lynch, A. et al. Adoptive transfer of murine T cells expressing a chimeric-PD1-Dap10 receptor as an immunotherapy for lymphoma. Immunology 152, 472–483 (2017).

  19. 19.

    Niederman, T. M. J. et al. Antitumor activity of cytotoxic T lymphocytes engineered to target vascular endothelial growth factor receptors. Proc. Natl Acad. Sci. USA 99, 7009–7014 (2002).

  20. 20.

    Kahlon, K. S. et al. Specific recognition and killing of glioblastoma multiforme by interleukin 13-zetakine redirected cytolytic T cells. Cancer Res. 64, 9160–9166 (2004).

  21. 21.

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

  22. 22.

    Hammill, J. A. et al. Designed ankyrin repeat proteins are effective targeting elements for chimeric antigen receptors. J. Immunother. Cancer 3, 55 (2015).

  23. 23.

    Han, X. et al. Adnectin-based design of chimeric antigen receptor for T cell engineering. Mol. Ther. 25, 2466–2476 (2017).

  24. 24.

    Kudo, K. et al. T lymphocytes expressing a CD16 signaling receptor exert antibody-dependent cancer cell killing. Cancer Res. 74, 93–102 (2014).

  25. 25.

    Jamnani, F. R. et al. T cells expressing VHH-directed oligoclonal chimeric HER2 antigen receptors: towards tumor-directed oligoclonal T cell therapy. Biochim. Biophys. Acta 1840, 378–386 (2014).

  26. 26.

    Thayaparan, T. et al. CAR T-cell immunotherapy of MET-expressing malignant mesothelioma. OncoImmunology 6, e1363137 (2017).

  27. 27.

    Moot, R. et al. Genetic engineering of chimeric antigen receptors using lamprey derived variable lymphocyte receptors. Mol. Ther. Oncolytics 3, 16026 (2016).

  28. 28.

    Hudecek, M. et al. Receptor affinity and extracellular domain modifications affect tumor recognition by ROR1-specific chimeric antigen receptor T cells. Clin. Cancer Res. 19, 3153–3164 (2013).

  29. 29.

    Yang, J. et al. Therapeutic potential and challenges of targeting receptor tyrosine kinase ROR1 with monoclonal antibodies in B-cell malignancies. PLoS ONE 6, e21018 (2011).

  30. 30.

    Lynn, R. C. et al. Targeting of folate receptor β on acute myeloid leukemia blasts with chimeric antigen receptor-expressing T cells. Blood 125, 3466–3477 (2015).

  31. 31.

    Drent, E. et al. A rational strategy for reducing on-target off-tumor effects of CD38-chimeric antigen receptors by affinity optimization. Mol. Ther. 25, 1946–1958 (2017).

  32. 32.

    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).

  33. 33.

    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).

  34. 34.

    Haso, W. et al. Anti-CD22-chimeric antigen receptors targeting B-cell precursor acute lymphoblastic leukemia. Blood 121, 1165–1171 (2013).

  35. 35.

    James, S. E. et al. Antigen sensitivity of CD22-specific chimeric TCR is modulated by target epitope distance from the cell membrane. J. Immunol. 180, 7028–7038 (2008).

  36. 36.

    Walker, A. J. et al. Tumor antigen and receptor densities regulate efficacy of a chimeric antigen receptor targeting anaplastic lymphoma kinase. Mol. Ther. 25, 2189–2201 (2017).

  37. 37.

    Watanabe, K. et al. Target antigen density governs the efficacy of anti-CD20-CD28-CD3ζ chimeric antigen receptor-modified effector CD8+T cells. J. Immunol. 194, 911–920 (2015).

  38. 38.

    Arcangeli, S. et al. Balance of anti-CD123 chimeric antigen receptor binding affinity and density for the targeting of acute myeloid leukemia. Mol. Ther. 25, 1933–1945 (2017).

  39. 39.

    Savoldo, B. et al. CD28 costimulation improves expansion and persistence of chimeric antigen receptor-modified T cells in lymphoma patients. J. Clin. Invest. 121, 1822–1826 (2011).

  40. 40.

    Pule, M. A. et al. Virus-specific T cells engineered to coexpress tumor-specific receptors: persistence and antitumor activity in individuals with neuroblastoma. Nat. Med. 14, 1264–1270 (2008).

  41. 41.

    Louis, C. U. et al. Antitumor activity and long-term fate of chimeric antigen receptor-positive T cells in patients with neuroblastoma. Blood 118, 6050–6056 (2011).

  42. 42.

    Kochenderfer, J. N. et al. Eradication of B-lineage cells and regression of lymphoma in a patient treated with autologous T cells genetically engineered to recognize CD19. Blood 116, 4099–4102 (2010).

  43. 43.

    Porter, D. L., Levine, B. L., Kalos, M., Bagg, A. & June, C. H. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N. Engl. J. Med. 365, 725–733 (2011).

  44. 44.

    Kalos, M. et al. T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci. Transl. Med. 3, 95ra73 (2011).

  45. 45.

    Kawalekar, O. U. et al. Distinct signaling of coreceptors regulates specific metabolism pathways and impacts memory development in CAR T cells. Immunity 44, 380–390 (2016).

  46. 46.

    Ghosh, A. et al. Donor CD19 CAR T cells exert potent graft-versus-lymphoma activity with diminished graft-versus-host activity. Nat. Med. 23, 242–249 (2017).

  47. 47.

    Zhao, Z. et al. Structural design of engineered costimulation determines tumor rejection kinetics and persistence of CAR T Cells. Cancer Cell 28, 415–428 (2015).

  48. 48.

    van der Stegen, S. J. C., Hamieh, M. & Sadelain, M. The pharmacology of second-generation chimeric antigen receptors. Nat. Rev. Drug Discov. 14, 499–509 (2015).

  49. 49.

    Foster, A., Mahendravada, A., Shinners, N. & Chang, W. Regulated expansion and survival of chimeric antigen receptor-modified T cells using small molecule-dependent inducible MyD88/CD40. Mol. Ther. 25, 2176–2188 (2017).

  50. 50.

    Carpenito, C. et al. Control of large, established tumor xenografts with genetically retargeted human T cells containing CD28 and CD137 domains. Proc. Natl Acad. Sci. USA 106, 3360–3365 (2009).

  51. 51.

    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. 18, 413–420 (2010).

  52. 52.

    Abate-Daga, D. et al. A novel chimeric antigen receptor against prostate stem cell antigen mediates tumor destruction in a humanized mouse model of pancreatic cancer. Hum. Gene Ther. 25, 1003–1012 (2014).

  53. 53.

    Long, A. H. et al. Reduction of MDSCs with all-trans retinoic acid improves CAR therapy efficacy for sarcomas. Cancer Immunol. Res. 4, 869–880 (2016).

  54. 54.

    Kunkele, A. et al. Functional tuning of CARs reveals signaling threshold above which CD8+ CTL antitumor potency is attenuated due to cell Fas-FasL-dependent AICD. Cancer Immunol. Res. 3, 368–379 (2015).

  55. 55.

    Guest, R. D. et al. The role of extracellular spacer regions in the optimal design of chimeric immune receptors: evaluation of four different scFvs and antigens. J. Immunother. 28, 203–211 (2005).

  56. 56.

    Taylor, M. J., Husain, K., Gartner, Z. J., Mayor, S. & Vale, R. D. A DNA-based T cell receptor reveals a role for receptor clustering in ligand discrimination. Cell 169, 108–119 (2017).

  57. 57.

    Hudecek, M. et al. The nonsignaling extracellular spacer domain of chimeric antigen receptors is decisive for in vivo antitumor activity. Cancer Immunol. Res. 3, 125–135 (2015).

  58. 58.

    Alabanza, L. et al. Function of novel anti-CD19 chimeric antigen receptors with human variable regions is affected by hinge and transmembrane domains. Mol. Ther. 25, 2452–2465 (2017).

  59. 59.

    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).

  60. 60.

    Weijtens, M. E., Willemsen, R. A., Valerio, D., Stam, K. & Bolhuis, R. L. Single chain Ig/gamma gene-redirected human T lymphocytes produce cytokines, specifically lyse tumor cells, and recycle lytic capacity. J. Immunol. 157, 836–843 (1996).

  61. 61.

    Willemsen, R. A., Ronteltap, C., Chames, P., Debets, R. & Bolhuis, R. L. H. T cell retargeting with MHC class I-restricted antibodies: the CD28 costimulatory domain enhances antigen-specific cytotoxicity and cytokine production. J. Immunol. 174, 7853–7858 (2005).

  62. 62.

    Hombach, A., Hombach, A. A. & Abken, H. Adoptive immunotherapy with genetically engineered T cells: modification of the IgG1 Fc spacer domain in the extracellular moiety of chimeric antigen receptors avoids off-target activation and unintended initiation of an innate immune response. Gene Ther. 17, 1206–1213 (2010).

  63. 63.

    Jonnalagadda, M. et al. Chimeric antigen receptors with mutated IgG4 Fc spacer avoid Fc receptor binding and improve T cell persistence and antitumor efficacy. Mol. Ther. 23, 757–768 (2015).

  64. 64.

    Nolan, K. F. et al. Bypassing immunization: optimized design of ‘designer T cells’ against carcinoembryonic antigen (CEA)-expressing tumors, and lack of suppression by soluble CEA. Clin. Cancer Res. 5, 3928–3941 (1999).

  65. 65.

    Bridgeman, J. S. et al. The optimal antigen response of chimeric antigen receptors harboring the CD3 transmembrane domain is dependent upon incorporation of the receptor into the endogenous TCR/CD3 complex. J. Immunol. 184, 6938–6949 (2010).

  66. 66.

    Neelapu, S. S. et al. Chimeric antigen receptor T-cell therapy — assessment and management of toxicities. Nat. Rev. Clin. Oncol. 15, 47–62 (2017).

  67. 67.

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

  68. 68.

    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).

  69. 69.

    Diaconu, I. et al. Inducible caspase-9 selectively modulates the toxicities of CD19-specific chimeric antigen receptor-modified T cells. Mol. Ther. 25, 580–592 (2017).

  70. 70.

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

  71. 71.

    Paszkiewicz, P. J. et al. Targeted antibody-mediated depletion of murine CD19 CAR T cells permanently reverses B cell aplasia. J. Clin. Invest. 126, 4262–4272 (2016).

  72. 72.

    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).

  73. 73.

    Tasian, S. K. et al. Optimized depletion of chimeric antigen receptor T-cells in murine xenograft models of human acute myeloid leukemia. Blood 129, 2395–2407 (2017).

  74. 74.

    Philip, B. et al. A highly compact epitope-based marker/suicide gene for easier and safer T-cell therapy. Blood 124, 1277–1287 (2014).

  75. 75.

    Sakemura, R. et al. A Tet-On inducible system for controlling CD19-chimeric antigen receptor expression upon drug administration. Cancer Immunol. Res. 4, 658–668 (2016).

  76. 76.

    Wu, C.-Y., Roybal, K. T., Puchner, E. M., Onuffer, J. & Lim, W. A. Remote control of therapeutic T cells through a small molecule-gated chimeric receptor. Science 350, aab4077 (2015).

  77. 77.

    Mata, M. 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. 7, 1306–1319 (2017).

  78. 78.

    Rodgers, D. T. et al. Switch-mediated activation and retargeting of CAR-T cells for B-cell malignancies. Proc. Natl Acad. Sci. USA 113, 459–468 (2016).

  79. 79.

    Cao, Y. et al. Design of switchable chimeric antigen receptor T cells targeting breast cancer. Angew. Chem. Int. Ed. 55, 7520–7524 (2016).

  80. 80.

    Huet, H. A. et al. Targeting CD20+ relapsed refractory B cell lymphoma with ACTR087, antibody-coupled T-cell receptor (ACTR) engineered autologous T cells, in combination with rituximab. Blood 128, 3512 (2016).

  81. 81.

    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).

  82. 82.

    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).

  83. 83.

    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).

  84. 84.

    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).

  85. 85.

    Roybal, K. T. et al. Precision tumor recognition by T cells with combinatorial antigen-sensing circuits. Cell 164, 770–779 (2016).

  86. 86.

    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).

  87. 87.

    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).

  88. 88.

    Lanitis, E. et al. Chimeric antigen receptor T cells with dissociated signaling domains exhibit focused antitumor activity with reduced potential for toxicity in vivo. Cancer Immunol. Res. 1, 43–53 (2013).

  89. 89.

    Vantourout, P. & Hayday, A. Six-of-the-best: unique contributions of γδ T cells to immunology. Nat. Rev. Immunol. 13, 88–100 (2013).

  90. 90.

    Fisher, J. et al. Avoidance of on-target off-tumor activation using a co-stimulation-only chimeric antigen receptor. Mol. Ther. 25, 1234–1247 (2017).

  91. 91.

    Ahmed, N. et al. Human epidermal growth factor receptor 2 (HER2)-specific chimeric antigen receptor–modified T cells for the immunotherapy of HER2-positive sarcoma. J. Clin. Oncol. 33, 1688–1696 (2015).

  92. 92.

    Hegde, M. et al. Expansion of HER2-CAR T cells after lymphodepletion and clinical responses in patients with advanced sarcoma. J. Clin. Oncol. 35, 10508 (2017).

  93. 93.

    Han, X. et al. Masked chimeric antigen receptor for tumor-specific activation. Mol. Ther. 25, 274–284 (2017).

  94. 94.

    Mamot, C. et al. Tolerability, safety, pharmacokinetics, and efficacy of doxorubicin-loaded anti-EGFR immunoliposomes in advanced solid tumours: a phase 1 dose-escalation study. Lancet Oncol. 13, 1234–1241 (2012).

  95. 95.

    LaGory, E. L. & Giaccia, A. J. The ever-expanding role of HIF in tumour and stromal biology. Nat. Cell Biol. 18, 356–365 (2016).

  96. 96.

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

  97. 97.

    Turley, S. J., Cremasco, V. & Astarita, J. L. Immunological hallmarks of stromal cells in the tumour microenvironment. Nat. Rev. Immunol. 15, 669–682 (2015).

  98. 98.

    Joyce, J. A. & Fearon, D. T. T cell exclusion, immune privilege, and the tumor microenvironment. Science 348, 74–80 (2015).

  99. 99.

    Engels, B., Rowley, D. A. & Schreiber, H. Targeting stroma to treat cancers. Semin. Cancer Biol. 22, 41–49 (2012).

  100. 100.

    Irving, M., de Silly, R. V., Scholten, K., Dilek, N. & Coukos, G. Engineering chimeric antigen receptor T-cells for racing in solid tumors: don’t forget the fuel. Front. Immunol. 8, 267 (2017).

  101. 101.

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

  102. 102.

    Biswas, S. K. Metabolic reprogramming of immune cells in cancer progression. Immunity 43, 435–449 (2015).

  103. 103.

    Becker, J. C., Andersen, M. H., Schrama, D. & Thor Straten, P. Immune-suppressive properties of the tumor microenvironment. Cancer Immunol. Immunother. 62, 1137–1148 (2013).

  104. 104.

    Marvel, D. & Gabrilovich, D. I. Myeloid-derived suppressor cells in the tumor microenvironment: expect the unexpected. J. Clin. Invest. 125, 3356–3364 (2015).

  105. 105.

    Noy, R. & Pollard, J. W. Tumor-associated macrophages: from mechanisms to therapy. Immunity 41, 49–61 (2014).

  106. 106.

    Pardoll, D. M. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 12, 252–264 (2012).

  107. 107.

    Pauken, K. E. & Wherry, E. J. Overcoming T cell exhaustion in infection and cancer. Trends Immunol. 36, 265–276 (2015).

  108. 108.

    Vestweber, D. How leukocytes cross the vascular endothelium. Nat. Rev. Immunol. 15, 692–704 (2015).

  109. 109.

    Dirkx, A. E. M. et al. Tumor angiogenesis modulates leukocyte-vessel wall interactions in vivo by reducing endothelial adhesion molecule expression. Cancer Res. 63, 2322–2329 (2003).

  110. 110.

    Sackstein, R., Schatton, T. & Barthel, S. R. T-lymphocyte homing: an underappreciated yet critical hurdle for successful cancer immunotherapy. Lab. Invest. 97, 669–697 (2017).

  111. 111.

    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).

  112. 112.

    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).

  113. 113.

    Di Stasi, A. et al. T lymphocytes coexpressing CCR4 and a chimeric antigen receptor targeting CD30 have improved homing and antitumor activity in a Hodgkin tumor model. Blood 113, 6392–6402 (2009).

  114. 114.

    Siddiqui, I., Erreni, M., van Brakel, M., Debets, R. & Allavena, P. Enhanced recruitment of genetically modified CX3CR1-positive human T cells into fractalkine/CX3CL1 expressing tumors: importance of the chemokine gradient. J. Immunother. Cancer 4, 21 (2016).

  115. 115.

    Porter, D. L. et al. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci. Transl. Med. 7, 303ra139 (2015).

  116. 116.

    Fraietta, J. A. et al. Ibrutinib enhances chimeric antigen receptor T-cell engraftment and efficacy in leukemia. Blood 127, 1117–1127 (2016).

  117. 117.

    Pegram, H. J. et al. IL-12-secreting CD19-targeted cord blood-derived T cells for the immunotherapy of B-cell acute lymphoblastic leukemia. Leukemia 29, 415–422 (2015).

  118. 118.

    Chinnasamy, D. et al. Local delivery of interleukin-12 using T cells targeting vascular endothelial growth factor receptor-2 eradicates multiple vascularized tumors in mice. Clin. Cancer Res. 18, 1672–1683 (2012).

  119. 119.

    Krenciute, G. et al. Transgenic expression of IL15 improves antiglioma activity of IL13Rα2-CAR T cells but results in antigen loss variants. Cancer Immunol. Res. 5, 571–581 (2017).

  120. 120.

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

  121. 121.

    Markley, J. C. & Sadelain, M. IL-7 and IL-21 are superior to IL-2 and IL-15 in promoting human T cell-mediated rejection of systemic lymphoma in immunodeficient mice. Blood 115, 3508–3519 (2010).

  122. 122.

    Zhang, L. et al. Tumor-infiltrating lymphocytes genetically engineered with an inducible gene encoding interleukin-12 for the immunotherapy of metastatic melanoma. Clin. Cancer Res. 21, 2278–2288 (2015).

  123. 123.

    Spolski, R., Kim, H.-P., Zhu, W., Levy, D. E. & Leonard, W. J. IL-21 mediates suppressive effects via its induction of IL-10. J. Immunol. 182, 2859–2867 (2009).

  124. 124.

    Spolski, R. & Leonard, W. J. IL-21 is an immune activator that also mediates suppression via IL-10. Crit. Rev. Immunol. 30, 559–570 (2010).

  125. 125.

    Ahmadzadeh, M. & Rosenberg, S. A. IL-2 administration increases CD4+CD25hi Foxp3+ regulatory T cells in cancer patients. Blood 107, 2409–2414 (2005).

  126. 126.

    Whilding, L. M. et al. Targeting of aberrant αvβ6 integrin expression in solid tumors using chimeric antigen receptor-engineered T cells. Mol. Ther. 25, 259–273 (2017).

  127. 127.

    Atkins, M. B. et al. High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J. Clin. Oncol. 17, 2105–2116 (1999).

  128. 128.

    Fyfe, G. et al. Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy. J. Clin. Oncol. 13, 688–696 (1995).

  129. 129.

    Sportès, C. et al. Phase I study of recombinant human interleukin-7 administration in subjects with refractory malignancy. Clin. Cancer Res. 16, 727–735 (2010).

  130. 130.

    Conlon, K. C. et al. Redistribution, hyperproliferation, activation of natural killer cells and CD8 T cells, and cytokine production during first-in-human clinical trial of recombinant human interleukin-15 in patients with cancer. J. Clin. Oncol. 33, 74–82 (2015).

  131. 131.

    Shum, T., Omer, B., Tashiro, H., Kruse, R. & Wagner, D. Constitutive signaling from an engineered IL-7 receptor promotes durable tumor elimination by tumor redirected T-cells. Cancer Discov. 7, 1238–1247 (2017).

  132. 132.

    Zenatti, P. P. et al. Oncogenic IL7R gain-of-function mutations in childhood T-cell acute lymphoblastic leukemia. Nat. Genet. 43, 932–939 (2011).

  133. 133.

    Zhang, J. et al. The genetic basis of early T-cell precursor acute lymphoblastic leukaemia. Nature 481, 157–163 (2012).

  134. 134.

    Hurton, L. V. et al. Tethered IL-15 augments antitumor activity and promotes a stem-cell memory subset in tumor-specific T cells. Proc. Natl Acad. Sci. USA 113, 7788–7797 (2016).

  135. 135.

    Tanaka, M. et al. Vaccination targeting native receptors to enhance the function and proliferation of chimeric antigen receptor (CAR)-modified T cells. Clin. Cancer Res. 23, 3499–3509 (2017).

  136. 136.

    Cruz, C. R. Y. et al. Infusion of donor-derived CD19-redirected virus-specific T cells for B-cell malignancies relapsed after allogeneic stem cell transplant: a phase 1 study. Blood 122, 2956–2973 (2013).

  137. 137.

    Slaney, C. Y. et al. Dual-specific chimeric antigen receptor T cells and an indirect vaccine eradicate a variety of large solid tumors in an immunocompetent, self-antigen setting. Clin. Cancer Res. 23, 2478–2490 (2017).

  138. 138.

    Rossig, C. et al. Vaccination to improve the persistence of CD19CAR gene-modified T cells in relapsed pediatric acute lymphoblastic leukemia. Leukemia 31, 1087–1095 (2017).

  139. 139.

    Ahmed, N. et al. Autologous HER2 CMV bispecific CAR T cells are safe and demonstrate clinical benefit for glioblastoma in a Phase I trial. J. Immunother. Cancer 3, O11 (2015).

  140. 140.

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

  141. 141.

    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).

  142. 142.

    Ruella, M. et al. Overcoming the immunosuppressive tumor microenvironment of Hodgkin lymphoma using chimeric antigen receptor T Cells. Cancer Discov. 7, 1554–1167 (2017).

  143. 143.

    Chinnasamy, D. et al. Gene therapy using genetically modified lymphocytes targeting VEGFR-2 inhibits the growth of vascularized syngenic tumors in mice. J. Clin. Invest. 120, 3953–3968 (2010).

  144. 144.

    Perera, L. P. et al. Chimeric antigen receptor modified T cells that target chemokine receptor CCR4 as a therapeutic modality for T-cell malignancies. Am. J. Hematol. 92, 892–901 (2017).

  145. 145.

    Motz, G. T. et al. Tumor endothelium FasL establishes a selective immune barrier promoting tolerance in tumors. Nat. Med. 20, 607–615 (2014).

  146. 146.

    John, L. B. et al. Anti-PD-1 antibody therapy potently enhances the eradication of established tumors by gene-modified T cells. Clin. Cancer Res. 19, 5636–5646 (2013).

  147. 147.

    Gargett, T. et al. GD2-specific CAR T cells undergo potent activation and deletion following antigen encounter but can be protected from activation-induced cell death by PD-1 blockade. Mol. Ther. 24, 1135–1149 (2016).

  148. 148.

    Chong, E. A. et al. PD-1 blockade modulates chimeric antigen receptor (CAR)-modified T cells: refueling the CAR. Blood 129, 1039–1041 (2017).

  149. 149.

    Maude, S. L. et al. The effect of pembrolizumab in combination with CD19-targeted chimeric antigen receptor (CAR) T cells in relapsed acute lymphoblastic leukemia (ALL). J. Clin. Oncol. 35, 103–103 (2017).

  150. 150.

    Heczey, A. et al. CAR T cells administered in combination with lymphodepletion and PD-1 inhibition to patients with neuroblastoma. Mol. Ther. 25, 2214–2224 (2017).

  151. 151.

    Foster, A. E. et al. Antitumor activity of EBV-specific T lymphocytes transduced with a dominant negative TGF-β receptor. J. Immunother. 31, 500–505 (2008).

  152. 152.

    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).

  153. 153.

    Menger, L. et al. TALEN-mediated inactivation of PD-1 in tumor-reactive lymphocytes promotes intratumoral T-cell persistence and rejection of established tumors. Cancer Res. 76, 2087–2093 (2016).

  154. 154.

    Ren, J. et al. A versatile system for rapid multiplex genome-edited CAR T cell generation. Oncotarget 8, 17002–17011 (2017).

  155. 155.

    Zhang, Y. et al. CRISPR-Cas9 mediated LAG-3 disruption in CAR-T cells. Front. Med. 11, 554–562 (2017).

  156. 156.

    Ren, J. et al. Multiplex genome editing to generate universal CAR T cells resistant to PD1 inhibition. Clin. Cancer Res. 23, 2255–2266 (2017).

  157. 157.

    Wartewig, T. et al. PD-1 is a haploinsufficient suppressor of T cell lymphomagenesis. Nature 552, 121–125 (2017).

  158. 158.

    Scharping, N. E. et al. The tumor microenvironment represses T cell mitochondrial biogenesis to drive intratumoral T cell metabolic insufficiency and dysfunction. Immunity 45, 374–388 (2016).

  159. 159.

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

  160. 160.

    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).

  161. 161.

    Sotillo, E. et al. Convergence of acquired mutations and alternative splicing of CD19 enables resistance to CART-19 immunotherapy. Cancer Discov. 5, 1282–1295 (2015).

  162. 162.

    Jacoby, E. CD19 CAR immune pressure induces B-precursor acute lymphoblastic leukaemia lineage switch exposing inherent leukaemic plasticity. Nat. Commun. 7, 12320 (2016).

  163. 163.

    Gardner, R. et al. Acquisition of a CD19-negative myeloid phenotype allows immune escape of MLL-rearranged B-ALL from CD19 CAR-T-cell therapy. Blood 127, 2406–2410 (2016).

  164. 164.

    Yu, H. et al. Repeated loss of target surface antigen after immunotherapy in primary mediastinal large B cell lymphoma. Am. J. Hematol. 92, 11–13 (2017).

  165. 165.

    Curran, K. J. et al. Multi-center clinical trial of CAR T cells in pediatric/young adult patients with relapsed B-cell ALL. Blood 126, 2533 (2015).

  166. 166.

    Grupp, S. A. et al. Durable remissions in children with relapsed/refractory ALL treated with T cells engineered with a CD19-targeted chimeric antigen receptor (CTL019). Blood 126, 681 (2015).

  167. 167.

    Lee, D. W. et al. Safety and response of incorporating CD19 chimeric antigen receptor T cell therapy in typical salvage regimens for children and young adults with acute lymphoblastic leukemia. Blood 126, 684 (2015).

  168. 168.

    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).

  169. 169.

    Sampson, J. H. et al. Immunologic escape after prolonged progression-free survival with epidermal growth factor receptor variant III peptide vaccination in patients with newly diagnosed glioblastoma. J. Clin. Oncol. 28, 4722–4729 (2010).

  170. 170.

    Brown, C. E. et al. Bioactivity and safety of IL13Rα2-redirected chimeric antigen receptor CD8+ T cells in patients with recurrent glioblastoma. Clin. Cancer Res. 21, 4062–4072 (2015).

  171. 171.

    Hegde, M. et al. Combinational targeting offsets antigen escape and enhances effector functions of adoptively transferred T cells in glioblastoma. Mol. Ther. 21, 2087–2101 (2013).

  172. 172.

    Hegde, M. et al. Tandem CAR T cells targeting HER2 and IL13Rα2 mitigate tumor antigen escape. J. Clin. Invest. 126, 3036–3052 (2016).

  173. 173.

    Yee, C. et al. Adoptive T-cell therapy using antigen-specific CD8+ T-cell clones for the treatment of patients with metastatic melanoma: in vivo persistence, migration, and antitumor effect of transferred T-cells. Proc. Natl Acad. Sci. USA 99, 16168–16173 (2002).

  174. 174.

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

  175. 175.

    Grada, Z. et al. TanCAR: a novel bispecific chimeric antigen receptor for cancer immunotherapy. Mol. Ther. Nucleic Acids 2, e105 (2013).

  176. 176.

    Fry, T. J. et al. CD22-targeted CAR T cells induce remission in B-ALL that is naive or resistant to CD19-targeted CAR immunotherapy. Nat. Med 24, 20–28 (2018).

  177. 177.

    Ruella, M. et al. Dual CD19 and CD123 targeting prevents antigen-loss relapses after CD19-directed immunotherapies. J. Clin. Invest. 126, 3814–3826 (2016).

  178. 178.

    Anurathapan, U. et al. Kinetics of tumor destruction by chimeric antigen receptor-modified T cells. Mol. Ther. 22, 623–633 (2014).

  179. 179.

    Bielamowicz, K. et al. Trivalent CAR T-cells overcome interpatient antigenic variability in glioblastoma. Neuro. Oncol. 20, 506–518 (2017).

  180. 180.

    Beatty, G. L. Engineered chimeric antigen receptor-expressing T cells for the treatment of pancreatic ductal adenocarcinoma. Oncoimmunology 3, e28327 (2014).

  181. 181.

    Pilon, S. A., Kelly, C. & Wei, W.-Z. Broadening of epitope recognition during immune rejection of ErbB-2-positive tumor prevents growth of ErbB-2-negative tumor. J. Immunol. 170, 1202–1208 (2003).

  182. 182.

    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).

  183. 183.

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

  184. 184.

    Boice, M. et al. Loss of the HVEM tumor suppressor in lymphoma and restoration by modified CAR-T cells. Cell 167, 405–418 (2016).

  185. 185.

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

  186. 186.

    Rossi, R. L. et al. Distinct microRNA signatures in human lymphocyte subsets and enforcement of the naive state in CD4+ T cells by the microRNA miR-125b. Nat. Immunol. 12, 796–803 (2011).

  187. 187.

    Steiner, D. F. et al. MicroRNA-29 regulates T-box transcription factors and interferon-γ production in helper T cells. Immunity 35, 169–181 (2011).

  188. 188.

    Dooley, J., Linterman, M. A. & Liston, A. MicroRNA regulation of T-cell development. Immunol. Rev. 253, 53–64 (2013).

  189. 189.

    Okada, H., Kohanbash, G. & Lotze, M. T. MicroRNAs in immune regulation—opportunities for cancer immunotherapy. Int. J. Biochem. Cell Biol. 42, 1256–1261 (2010).

  190. 190.

    Sasaki, K. et al. miR-17-92 expression in differentiated T cells — implications for cancer immunotherapy. J. Transl. Med. 8, 17 (2010).

  191. 191.

    Ohno, M. et al. Expression of miR-17-92 enhances anti-tumor activity of T-cells transduced with the anti-EGFRvIII chimeric antigen receptor in mice bearing human GBM xenografts. J. Immunother. Cancer 1, 21 (2013).

  192. 192.

    Wong, R. S., Chen, Y. Y. & Smolke, C. D. Regulation of T cell proliferation with drug-responsive microRNA switches. Nucleic Acids Res. 46, 1541–1552 (2017).

  193. 193.

    Zheng, Y., Tang, L., Mabardi, L., Kumari, S. & Irvine, D. J. Enhancing adoptive cell therapy of cancer through targeted delivery of small-molecule immunomodulators to internalizing or noninternalizing receptors. ACS Nano 11, 3089–3100 (2017).

  194. 194.

    Park, J. et al. Combination delivery of TGF-β inhibitor and IL-2 by nanoscale liposomal polymeric gels enhances tumour immunotherapy. Nat. Mater. 11, 895–905 (2012).

  195. 195.

    Stephan, M. T., Moon, J. J., Um, S. H., Bershteyn, A. & Irvine, D. J. Therapeutic cell engineering with surface-conjugated synthetic nanoparticles. Nat. Med. 16, 1035–1041 (2010).

  196. 196.

    Jones, R. B. et al. Antigen recognition-triggered drug delivery mediated by nanocapsule-functionalized cytotoxic T-cells. Biomaterials 117, 44–53 (2017).

  197. 197.

    Stephan, S. B. et al. Biopolymer implants enhance the efficacy of adoptive T-cell therapy. Nat. Biotechnol. 33, 97–101 (2014).

  198. 198.

    Smith, T. T. et al. Biopolymers codelivering engineered T cells and STING agonists can eliminate heterogeneous tumors. J. Clin. Invest. 127, 2176–2191 (2017).

  199. 199.

    Tindera, M. Incoming Novartis CEO on $475,000 cancer therapy: ‘no question that the list price raises eyebrows’. Forbes go.nature.com/2HMNuPa (30 November 2017).

  200. 200.

    Rosenbaum, L. Tragedy, perseverance, and chance—the story of CAR-T therapy.N. Engl. J. Med. 377, 1313–1315 (2017).

  201. 201.

    Kite’s Yescarta™ (axicabtagene ciloleucel) becomes first CAR T therapy approved by the FDA for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy. Gilead go.nature.com/2wb51PE (18 October 2017).

  202. 202.

    With FDA approval for advanced lymphoma, second CAR T-cell therapy moves to the clinic. National Cancer Institute go.nature.com/2FDRTC5 (25 October 2017).

  203. 203.

    Brudno, J. N. et al. Allogeneic T cells that express an anti-CD19 chimeric antigen receptor induce remissions of B-cell malignancies that progress after allogeneic hematopoietic stem-cell transplantation without causing graft-versus-host disease. J. Clin. Oncol. 34, 1112–1121 (2016).

  204. 204.

    Cai, B. et al. Co-infusion of haplo-identical CD19-chimeric antigen receptor T cells and stem cells achieved full donor engraftment in refractory acute lymphoblastic leukemia. J. Hematol. Oncol. 9, 131 (2016).

  205. 205.

    Kochenderfer, J. N. et al. Donor-derived anti-CD19 chimeric-antigen-receptor-expressing T cells cause regression of malignancy persisting after allogeneic hematopoietic stem cell transplantation. Blood 122, 151 (2013).

  206. 206.

    Jacoby, E. et al. Murine allogeneic CD19 CAR T cells harbor potent antileukemic activity but have the potential to mediate lethal GVHD. Blood 127, 1361–1370 (2016).

  207. 207.

    Qasim, W. et al. Molecular remission of infant B-ALL after infusion of universal TALEN gene-edited CAR T cells. Sci. Transl. Med. 9, eaaj2013 (2017).

  208. 208.

    Zakrzewski, J. L. et al. Tumor immunotherapy across MHC barriers using allogeneic T-cell precursors. Nat. Biotechnol. 26, 453–461 (2008).

  209. 209.

    Yang, L. & Baltimore, D. Long-term in vivo provision of antigen-specific T cell immunity by programming hematopoietic stem cells. Proc. Natl Acad. Sci. USA 102, 4518–4523 (2005).

  210. 210.

    Larson, S. M. et al. Pre-clinical development of gene modification of haematopoietic stem cells with chimeric antigen receptors for cancer immunotherapy. Hum. Vaccin. Immunother. 13, 1094–1104 (2017).

  211. 211.

    Themeli, M. et al. Generation of tumor-targeted human T lymphocytes from induced pluripotent stem cells for cancer therapy. Nat. Biotechnol. 31, 928–933 (2013).

  212. 212.

    Vizcardo, R. et al. Regeneration of human tumor antigen-specific T cells from iPSCs derived from mature CD8+ T cells. Cell Stem Cell 12, 31–36 (2013).

  213. 213.

    Liao, N. S., Bix, M., Zijlstra, M., Jaenisch, R. & Raulet, D. MHC class I deficiency: susceptibility to natural killer (NK) cells and impaired NK activity. Science 253, 199–202 (1991).

  214. 214.

    Bix, M. et al. Rejection of class I MHC-deficient haemopoietic cells by irradiated MHC-matched mice. Nature 349, 329–331 (1991).

  215. 215.

    Torikai, H. et al. Toward eliminating HLA class I expression to generate universal cells from allogeneic donors. Blood 122, 1341–1349 (2013).

  216. 216.

    Gornalusse, G. G. et al. HLA-E-expressing pluripotent stem cells escape allogeneic responses and lysis by NK cells. Nat. Biotechnol. 35, 765–772 (2017).

  217. 217.

    Smith, T. T. et al. Regulation of T cell proliferation with drug-responsive microRNA switches regulation of T cell proliferation with drug-responsive microRNA switches. Nat. Nanotech. 46, 1541–1552 (2017).

  218. 218.

    Garfall, A. L. et al. Chimeric antigen receptor T cells against CD19 for multiple myeloma. N. Engl. J. Med. 373, 1040–1047 (2015).

  219. 219.

    Hacein-Bey-Abina, S. et al. Insertional oncogenesis in 4 patients after retrovirus-mediated gene therapy of SCID-X1. J. Clin. Invest. 118, 3132–3142 (2008).

  220. 220.

    Tsukahara, T. et al. The Tol2 transposon system mediates the genetic engineering of T-cells with CD19-specific chimeric antigen receptors for B-cell malignancies. Gene Ther. 22, 209–215 (2015).

  221. 221.

    Kebriaei, P. et al. Phase I trials using Sleeping Beauty to generate CD19-specific CAR T cells. J. Clin. Invest. 126, 3363–3376 (2016).

  222. 222.

    Nakazawa, Y. et al. PiggyBac-mediated cancer immunotherapy using EBV-specific cytotoxic T-cells expressing HER2-specific chimeric antigen receptor. Mol. Ther. 19, 2133–2143 (2011).

  223. 223.

    Soifer, H. et al. Stable integration of transgenes delivered by a retrotransposon-adenovirus hybrid vector. Hum. Gene Ther. 12, 1417–1428 (2001).

  224. 224.

    Staunstrup, N. H. et al. Hybrid lentivirus-transposon vectors with a random integration profile in human cells. Mol. Ther. 17, 1205–1214 (2009).

  225. 225.

    Yant, S. R. et al. Transposition from a gutless adeno-transposon vector stabilizes transgene expression in vivo. Nat. Biotechnol. 20, 999–1005 (2002).

  226. 226.

    Eyquem, J. et al. Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumour rejection. Nature 543, 113–117 (2017).

  227. 227.

    Wang, J. et al. Highly efficient homology-driven genome editing in human T cells by combining zinc-finger nuclease mRNA and AAV6 donor delivery. Nucleic Acids Res. 44, e30 (2016).

  228. 228.

    MacLeod, D. T. et al. Integration of a CD19 CAR into the TCR alpha chain locus streamlines production of allogeneic gene-edited CAR T cells. Mol. Ther. 25, 949–961 (2017).

  229. 229.

    Jackson, H. J., Rafiq, S. & Brentjens, R. J. Driving CAR T-cells forward. Nat. Rev. Clin. Oncol. 13, 370–383 (2016).

  230. 230.

    Fry, T. J. et al. CD22-targeted CAR T cells induce remission in B-ALL that is naive or resistant to CD19-targeted CAR immunotherapy. Nat. Med. 24, 20–28 (2018).

  231. 231.

    Shah, N. N. et al. Minimal residual disease negative complete remissions following anti-CD22 chimeric antigen receptor (CAR) in children and young adults with relapsed/refractory acute lymphoblastic leukemia (ALL). Blood 128, 650 (2016).

  232. 232.

    Shalabi, H. et al. A prospective evaluation of neurocognitive function and neurologic symptoms in pediatric and young adult patients with relapsed/refractory acute lymphoblastic leukemia (ALL) undergoing anti-CD22 chimeric antigen receptor therapy. Blood 128, 1625 (2016).

  233. 233.

    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).

  234. 234.

    Cohen, A. D. et al. B-cell maturation antigen (BCMA)-specific chimeric antigen receptor T cells (CART-BCMA) for multiple myeloma (MM): initial safety and efficacy from a phase I study. Blood 128, 1147 (2016).

  235. 235.

    Wang, Y. et al. Effective response and delayed toxicities of refractory advanced diffuse large B-cell lymphoma treated by CD20-directed chimeric antigen receptor-modified T cells. Clin. Immunol. 155, 160–175 (2014).

  236. 236.

    Till, B. G. et al. CD20-specific adoptive immunotherapy for lymphoma using a chimeric antigen receptor with both CD28 and 4-1BB domains: pilot clinical trial results. Blood 119, 3940–3950 (2012).

  237. 237.

    Ramos, C. A. et al. Clinical responses with T lymphocytes targeting malignancy-associated κ light chains. J. Clin. Invest. 126, 2588–2596 (2016).

  238. 238.

    Vera, J. et al. T lymphocytes redirected against the κ light chain of human immunoglobulin efficiently kill mature B lymphocyte-derived malignant cells. Blood 108, 3890–3897 (2006).

  239. 239.

    Hudecek, M. et al. The B-cell tumor-associated antigen ROR1 can be targeted with T cells modified to express a ROR1-specific chimeric antigen receptor. Blood 116, 4532–4541 (2010).

  240. 240.

    Berger, C. et al. Safety of targeting ROR1 in primates with chimeric antigen receptor-modified T cells. Cancer Immunol. Res. 3, 206–216 (2015).

  241. 241.

    Mackall, C. L. & Miklos, D. B. CNS endothelial cell activation emerges as a driver of CAR T cell-associated neurotoxicity. Cancer Discov. 7, 1371–1373 (2017).

  242. 242.

    Ghorashian, S. et al. A novel low affinity CD19 CAR results in durable disease remissions and prolonged CAR T cell persistence without severe CRS or neurotoxicity in patients with paediatric ALL. Blood 130, 806 (2017).

  243. 243.

    Nishio, N. et al. Armed oncolytic virus enhances immune functions of chimeric antigen receptor-modified T cells in solid tumors. Cancer Res. 74, 5195–5205 (2014).

  244. 244.

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

  245. 245.

    Maher, J., Brentjens, R. J., Gunset, G., Rivière, I. & Sadelain, M. Human T-lymphocyte cytotoxicity and proliferation directed by a single chimeric TCRζ/CD28 receptor. Nat. Biotechnol. 20, 70–75 (2002).

  246. 246.

    Pulè, M. A. et al. A chimeric T cell antigen receptor that augments cytokine release and supports clonal expansion of primary human T cells. Mol. Ther. 12, 933–941 (2005).

  247. 247.

    Hombach, A. A., Heiders, J., Foppe, M., Chmielewski, M. & Abken, H. OX40 costimulation by a chimeric antigen receptor abrogates CD28 and IL-2 induced IL-10 secretion by redirected CD4+ T cells. Oncoimmunology 1, 458–466 (2012).

  248. 248.

    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 TCR chain. J. Immunol. 172, 104–113 (2004).

  249. 249.

    Guedan, S. et al. ICOS-based chimeric antigen receptors program bipolar TH17/TH1 cells. Blood 124, 1070–1080 (2014).

  250. 250.

    Song, D. G. et al. CD27 costimulation augments the survival and antitumor activity of redirected human T cells in vivo. Blood 119, 696–706 (2012).

  251. 251.

    Shaffer, D. R. et al. T cells redirected against CD70 for the immunotherapy of CD70-positive malignancies. Blood 117, 4304–4314 (2011).

  252. 252.

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

  253. 253.

    Tanoue, K. et al. Armed oncolytic adenovirus-expressing PD-L1 mini-body enhances antitumor effects of chimeric antigen receptor T cells in solid tumors. Cancer Res. 77, 2040–2051 (2017).

  254. 254.

    Li, S. et al. Enhanced cancer immunotherapy by chimeric antigen receptor-modified T cells engineered to secrete checkpoint inhibitors. Clin. Cancer Res. 15, 6982–6992 (2017).

Download references

Acknowledgements

This work was supported by a SU2C-St. Baldrick’s Pediatric Cancer Dream Team Translational Research Grant (SU2CAACR-DT1113). C.L.M. is a member of the Parker Institute for Cancer Immunotherapy, which supports the Stanford University Cancer Immunotherapy Program. L.L. is supported by the National Science Foundation Graduate Research Fellowship, Stanford Graduate Fellowship, and Stanford EDGE Fellowship. R.G.M. is supported by a SARC Career Development Award.

Author information

Affiliations

  1. Department of Bioengineering, Stanford University, Stanford, CA, USA

    • Louai Labanieh
  2. Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA

    • Robbie G. Majzner
    •  & Crystal L. Mackall
  3. Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA

    • Crystal L. Mackall
  4. Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA

    • Crystal L. Mackall

Authors

  1. Search for Louai Labanieh in:

  2. Search for Robbie G. Majzner in:

  3. Search for Crystal L. Mackall in:

Contributions

All authors contributed to writing and editing the manuscript.

Competing interests

C.L.M. is an inventor on a patent for a CD22-directed CAR licensed by JUNO Therapeutics, receives research funding from Bluebird Bio and Obsidian Therapeutics, and serves on the advisory boards of Unum Therapeutics, GlaxoSmithKline and Vor Pharmaceuticals. L.L. and R.G.M. declare no competing interests.

Corresponding author

Correspondence to Crystal L. Mackall.

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/s41551-018-0235-9