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Prospects for gene-engineered T cell immunotherapy for solid cancers

Nature Medicine volume 22, pages 26–36 (2016)Cite this article

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Abstract

Adoptive transfer of receptor-engineered T cells has produced impressive results in treating patients with B cell leukemias and lymphomas. This success has captured public imagination and driven academic and industrial researchers to develop similar 'off-the-shelf' receptors targeting shared antigens on epithelial cancers, the leading cause of cancer-related deaths. However, the successful treatment of large numbers of people with solid cancers using this strategy is unlikely to be straightforward. Receptor-engineered T cells have the potential to cause lethal toxicity from on-target recognition of normal tissues, and there is a paucity of truly tumor-specific antigens shared across tumor types. Here we offer our perspective on how expanding the use of genetically redirected T cells to treat the majority of patients with solid cancers will require major technical, manufacturing and regulatory innovations centered around the development of autologous gene therapies targeting private somatic mutations.

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Figure 1: CAR and TCR clinical trials for oncology indications in the US between 1994 and 2014.
Figure 2: Safety and tissue-selectivity mechanisms that may be inserted into gene-engineered T cells.
Figure 3: A pathway for generating autologous TCR gene therapies targeting neoantigens for patients with advanced epithelial cancers.

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References

  1. Hodi, F.S. et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363, 711–723 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Topalian, S.L. et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N. Engl. J. Med. 366, 2443–2454 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Motzer, R.J. et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N. Engl. J. Med. 373, 1803–1813 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Brahmer, J. et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N. Engl. J. Med. 373, 123–135 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Powles, T. et al. MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature 515, 558–562 (2014).

    Article  CAS  PubMed  Google Scholar 

  6. Hamanishi, J. et al. Safety and antitumor activity of anti-PD-1 antibody, nivolumab, in patients with platinum-resistant ovarian cancer. J. Clin. Oncol. 33, 4015–4022 (2015).

    Article  CAS  PubMed  Google Scholar 

  7. Ansell, S.M. et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma. N. Engl. J. Med. 372, 311–319 (2015).

    Article  CAS  PubMed  Google Scholar 

  8. Le, D.T. et al. PD-1 blockade in tumors with mismatch-repair deficiency. N. Engl. J. Med. 372, 2509–2520 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. van Rooij, N. et al. Tumor exome analysis reveals neoantigen-specific T-cell reactivity in an ipilimumab-responsive melanoma. J. Clin. Oncol. 31, e439–e442 (2013).

    Article  PubMed  Google Scholar 

  10. Snyder, A. et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N. Engl. J. Med. 371, 2189–2199 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Rizvi, N.A. et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 348, 124–128 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Tumeh, P.C. et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515, 568–571 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Rosenberg, S.A. & Restifo, N.P. Adoptive cell transfer as personalized immunotherapy for human cancer. Science 348, 62–68 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. 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).

    Article  CAS  PubMed  Google Scholar 

  16. Robbins, P.F. et al. Mining exomic sequencing data to identify mutated antigens recognized by adoptively transferred tumor-reactive T cells. Nat. Med. 19, 747–752 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Tran, E. et al. Cancer immunotherapy based on mutation-specific CD4+ T cells in a patient with epithelial cancer. Science 344, 641–645 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Tran, E. et al. Immunogenicity of somatic mutations in human gastrointestinal cancers. Science http://dx.doi.org/10.1126/science.aad1253 (2015).

  20. Djenidi, F. et al. CD8+CD103+ tumor-infiltrating lymphocytes are tumor-specific tissue-resident memory T cells and a prognostic factor for survival in lung cancer patients. J. Immunol. 194, 3475–3486 (2015).

    Article  CAS  PubMed  Google Scholar 

  21. Stevanović, S. et al. Complete regression of metastatic cervical cancer after treatment with human papillomavirus-targeted tumor-infiltrating T cells. J. Clin. Oncol. 33, 1543–1550 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Singh, H., Huls, H., Kebriaei, P. & Cooper, L.J. A new approach to gene therapy using Sleeping Beauty to genetically modify clinical-grade T cells to target CD19. Immunol. Rev. 257, 181–190 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Kantoff, P.W. et al. IMPACT Study Investigators. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N. Engl. J. Med. 363, 411–422 (2010).

    Article  CAS  PubMed  Google Scholar 

  24. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Scholler, J. et al. Decade-long safety and function of retroviral-modified chimeric antigen receptor T cells. Sci. Transl. Med. 4, 132ra53 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  26. Siegel, R.L., Miller, K.D. & Jemal, A. Cancer statistics, 2015. CA Cancer J. Clin. 65, 5–29 (2015).

    Article  PubMed  Google Scholar 

  27. Ahmadi, M. et al. CD3 limits the efficacy of TCR gene therapy in vivo. Blood 118, 3528–3537 (2011).

    Article  CAS  PubMed  Google Scholar 

  28. Abate-Daga, D. et al. Expression profiling of TCR-engineered T cells demonstrates overexpression of multiple inhibitory receptors in persisting lymphocytes. Blood 122, 1399–1410 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Palmer, D.C. et al. Cish actively silences TCR signaling in CD8+ T cells to maintain tumor tolerance. J. Exp. Med. 212, 2095–2113 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Eshhar, Z., Waks, T., Gross, G. & Schindler, D.G. Specific activation and targeting of cytotoxic lymphocytes through chimeric single chains consisting of antibody-binding domains and the gamma or zeta subunits of the immunoglobulin and T-cell receptors. Proc. Natl. Acad. Sci. USA 90, 720–724 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Khong, H.T. & Restifo, N.P. Natural selection of tumor variants in the generation of 'tumor escape' phenotypes. Nat. Immunol. 3, 999–1005 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Frigault, M.J. et al. Identification of chimeric antigen receptors that mediate constitutive or inducible proliferation of T cells. Cancer Immunol. Res. 3, 356–367 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. 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).

    Article  CAS  PubMed  Google Scholar 

  35. Recombinant DNA Advisory Committee Meeting Workshop on Cytokine Release Syndrome after T Cell Immunotherapy. June 10th, 2015. https://auth.osp.od.nih.gov/sites/default/files/resources/RAC_Agenda_Day2%28CRS%29_UPDATED.pdf. 6–15–2015.

  36. Robbins, P.F. et al. A pilot trial using lymphocytes genetically engineered with an NY-ESO-1–reactive T-cell receptor: long-term follow-up and correlates with response. Clin. Cancer Res. 21, 1019–1027 (2015).

    Article  CAS  PubMed  Google Scholar 

  37. Caballero, O.L. & Chen, Y.T. Cancer/testis (CT) antigens: potential targets for immunotherapy. Cancer Sci. 100, 2014–2021 (2009).

    Article  CAS  PubMed  Google Scholar 

  38. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  39. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. 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).

    Article  CAS  PubMed  Google Scholar 

  42. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. 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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Kershaw, M.H. et al. A phase I study on adoptive immunotherapy using gene-modified T cells for ovarian cancer. Clin. Cancer Res. 12, 6106–6115 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Lamers, C.H. 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).

    Article  PubMed  Google Scholar 

  53. Rettig, W.J. & Old, L.J. Immunogenetics of human cell surface differentiation. Annu. Rev. Immunol. 7, 481–511 (1989).

    Article  CAS  PubMed  Google Scholar 

  54. Köhler, G. & Milstein, C. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 256, 495–497 (1975).

    Article  PubMed  Google Scholar 

  55. Redman, J.M., Hill, E.M., AlDeghaither, D. & Weiner, L.M. Mechanisms of action of therapeutic antibodies for cancer. Mol. Immunol. 67, 2 Pt A, 28–45 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Stashenko, P., Nadler, L.M., Hardy, R. & Schlossman, S.F. Characterization of a human B lymphocyte-specific antigen. J. Immunol. 125, 1678–1685 (1980).

    CAS  PubMed  Google Scholar 

  57. Ellis, T.M., Simms, P.E., Slivnick, D.J., Jäck, H.M. & Fisher, R.I. CD30 is a signal-transducing molecule that defines a subset of human activated CD45RO+ T cells. J. Immunol. 151, 2380–2389 (1993).

    CAS  PubMed  Google Scholar 

  58. Andrews, R.G., Torok-Storb, B. & Bernstein, I.D. Myeloid-associated differentiation antigens on stem cells and their progeny identified by monoclonal antibodies. Blood 62, 124–132 (1983).

    Article  CAS  PubMed  Google Scholar 

  59. Malavasi, F. et al. Human CD38: a glycoprotein in search of a function. Immunol. Today 15, 95–97 (1994).

    Article  CAS  PubMed  Google Scholar 

  60. Rao, S.P. et al. Human peripheral blood mononuclear cells exhibit heterogeneous CD52 expression levels and show differential sensitivity to alemtuzumab mediated cytolysis. PLoS One 7, e39416 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Miettinen, P.J. et al. Epithelial immaturity and multiorgan failure in mice lacking epidermal growth factor receptor. Nature 376, 337–341 (1995).

    Article  CAS  PubMed  Google Scholar 

  62. Crone, S.A. et al. ErbB2 is essential in the prevention of dilated cardiomyopathy. Nat. Med. 8, 459–465 (2002).

    Article  CAS  PubMed  Google Scholar 

  63. Yu, A.L. et al. Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma. N. Engl. J. Med. 363, 1324–1334 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  65. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Pastan, I. & Hassan, R. Discovery of mesothelin and exploiting it as a target for immunotherapy. Cancer Res. 74, 2907–2912 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Tanyi, J.L. et al. Abstract CT105: Safety and feasibility of chimeric antigen receptor modified T cells directed against mesothelin (CART-meso) in patients with mesothelin expressing cancers. Proceedings of AACR Annual Meeting 2015. Cancer Res. http://dx.doi.org/10.1158/1538-7445.AM2015-CT105 (2015).

  68. Koneru, M., O'Cearbhaill, R., Pendharkar, S., Spriggs, D.R. & Brentjens, R.J. A phase I clinical trial of adoptive T cell therapy using IL-12 secreting MUC-16(ecto) directed chimeric antigen receptors for recurrent ovarian cancer. J. Transl. Med. 13, 102 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Haridas, D. et al. MUC16: molecular analysis and its functional implications in benign and malignant conditions. FASEB J. 28, 4183–4199 (2014).

    Article  CAS  PubMed  Google Scholar 

  70. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Press, M.F., Cordon-Cardo, C. & Slamon, D.J. Expression of the HER-2/neu proto-oncogene in normal human adult and fetal tissues. Oncogene 5, 953–962 (1990).

    CAS  PubMed  Google Scholar 

  72. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. 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).

    Article  CAS  PubMed  Google Scholar 

  77. Martincorena, I. & Campbell, P.J. Somatic mutation in cancer and normal cells. Science 349, 1483–1489 (2015).

    Article  CAS  PubMed  Google Scholar 

  78. Wong, A.J. et al. Structural alterations of the epidermal growth factor receptor gene in human gliomas. Proc. Natl. Acad. Sci. USA 89, 2965–2969 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Morgan, R.A. et al. Recognition of glioma stem cells by genetically modified T cells targeting EGFRvIII and development of adoptive cell therapy for glioma. Hum. Gene Ther. 23, 1043–1053 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Draper, L.M. et al. Targeting of HPV-16+ epithelial cancer cells by TCR gene engineered T cells directed against E6. Clin. Cancer Res. 21, 4431–4439 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Rosenberg, S.A. Cell transfer immunotherapy for metastatic solid cancer--what clinicians need to know. Nat. Rev. Clin. Oncol. 8, 577–585 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Jungbluth, A.A. et al. Immunohistochemical analysis of NY-ESO-1 antigen expression in normal and malignant human tissues. Int. J. Cancer 92, 856–860 (2001).

    Article  CAS  PubMed  Google Scholar 

  84. Chen, Y.T. et al. Serological analysis of Melan-A(MART-1), a melanocyte-specific protein homogeneously expressed in human melanomas. Proc. Natl. Acad. Sci. USA 93, 5915–5919 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Hunder, N.N. et al. Treatment of metastatic melanoma with autologous CD4+ T cells against NY-ESO-1. N. Engl. J. Med. 358, 2698–2703 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Ikeda, H. et al. Characterization of an antigen that is recognized on a melanoma showing partial HLA loss by CTL expressing an NK inhibitory receptor. Immunity 6, 199–208 (1997).

    Article  CAS  PubMed  Google Scholar 

  89. Chinnasamy, N. et al. A TCR targeting the HLA-A*0201-restricted epitope of MAGE-A3 recognizes multiple epitopes of the MAGE-A antigen superfamily in several types of cancer. J. Immunol. 186, 685–696 (2011).

    Article  CAS  PubMed  Google Scholar 

  90. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Gonzalez-Galarza, F.F., Christmas, S., Middleton, D. & Jones, A.R. Allele frequency net: a database and online repository for immune gene frequencies in worldwide populations. Nucleic Acids Res. 39, D913–D919 (2011).

    Article  CAS  PubMed  Google Scholar 

  93. Klebanoff, C.A., Acquavella, N., Yu, Z. & Restifo, N.P. Therapeutic cancer vaccines: are we there yet? Immunol. Rev. 239, 27–44 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  95. Andersen, R.S. et al. Dissection of T-cell antigen specificity in human melanoma. Cancer Res. 72, 1642–1650 (2012).

    Article  CAS  PubMed  Google Scholar 

  96. Van Allen, E.M. et al. Genomic correlates of response to CTLA-4 blockade in metastatic melanoma. Science 350, 207–211 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Lohr, J.G. et al. Whole-exome sequencing of circulating tumor cells provides a window into metastatic prostate cancer. Nat. Biotechnol. 32, 479–484 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Murtaza, M. et al. Non-invasive analysis of acquired resistance to cancer therapy by sequencing of plasma DNA. Nature 497, 108–112 (2013).

    Article  CAS  PubMed  Google Scholar 

  99. Gros, A. et al. PD-1 identifies the patient-specific CD8 tumor-reactive repertoire infiltrating human tumors. J. Clin. Invest. 124, 2246–2259 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Linnemann, C. et al. High-throughput identification of antigen-specific TCRs by TCR gene capture. Nat. Med. 19, 1534–1541 (2013).

    Article  CAS  PubMed  Google Scholar 

  101. Ye, Q. et al. CD137 accurately identifies and enriches for naturally occurring tumor-reactive T cells in tumor. Clin. Cancer Res. 20, 44–55 (2014).

    Article  CAS  PubMed  Google Scholar 

  102. Cohen, C.J. et al. Isolation of neoantigen-specific T cells from tumor and peripheral lymphocytes. J. Clin. Invest. 125, 3981–3991 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  103. Rodenko, B. et al. Generation of peptide-MHC class I complexes through UV-mediated ligand exchange. Nat. Protoc. 1, 1120–1132 (2006).

    Article  CAS  PubMed  Google Scholar 

  104. Gattinoni, L., Klebanoff, C.A. & Restifo, N.P. Paths to stemness: building the ultimate antitumour T cell. Nat. Rev. Cancer 12, 671–684 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Crompton, J.G., Clever, D., Vizcardo, R., Rao, M. & Restifo, N.P. Reprogramming antitumor immunity. Trends Immunol. 35, 178–185 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. 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).

    Article  CAS  PubMed  Google Scholar 

  107. Nishimura, T. et al. Generation of rejuvenated antigen-specific T cells by reprogramming to pluripotency and redifferentiation. Cell Stem Cell 12, 114–126 (2013).

    Article  CAS  PubMed  Google Scholar 

  108. Zhao, T., Zhang, Z.N., Rong, Z. & Xu, Y. Immunogenicity of induced pluripotent stem cells. Nature 474, 212–215 (2011).

    Article  CAS  PubMed  Google Scholar 

  109. Araki, R. et al. Negligible immunogenicity of terminally differentiated cells derived from induced pluripotent or embryonic stem cells. Nature 494, 100–104 (2013).

    Article  CAS  PubMed  Google Scholar 

  110. Guha, P., Morgan, J.W., Mostoslavsky, G., Rodrigues, N.P. & Boyd, A.S. Lack of immune response to differentiated cells derived from syngeneic induced pluripotent stem cells. Cell Stem Cell 12, 407–412 (2013).

    Article  CAS  PubMed  Google Scholar 

  111. Hanna, J.H., Saha, K. & Jaenisch, R. Pluripotency and cellular reprogramming: facts, hypotheses, unresolved issues. Cell 143, 508–525 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Lee, A.S., Tang, C., Rao, M.S., Weissman, I.L. & Wu, J.C. Tumorigenicity as a clinical hurdle for pluripotent stem cell therapies. Nat. Med. 19, 998–1004 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Wang, G.C., Dash, P., McCullers, J.A., Doherty, P.C. & Thomas, P.G. T cell receptor αβ diversity inversely correlates with pathogen-specific antibody levels in human cytomegalovirus infection. Sci. Transl. Med. 4, 128ra42 (2012).

    PubMed  PubMed Central  Google Scholar 

  115. Howie, B. et al. High-throughput pairing of T cell receptor α and β sequences. Sci. Transl. Med. 7, 301ra131 (2015).

    Article  CAS  PubMed  Google Scholar 

  116. Feldman, S.A. et al. Rapid production of clinical-grade gammaretroviral vectors in expanded surface roller bottles using a 'modified' step-filtration process for clearance of packaging cells. Hum. Gene Ther. 22, 107–115 (2011).

    Article  CAS  PubMed  Google Scholar 

  117. Bear, A.S. et al. Replication-competent retroviruses in gene-modified T cells used in clinical trials: is it time to revise the testing requirements? Mol. Ther. 20, 246–249 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Singh, H. et al. Redirecting specificity of T-cell populations for CD19 using the Sleeping Beauty system. Cancer Res. 68, 2961–2971 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Cox, D.B., Platt, R.J. & Zhang, F. Therapeutic genome editing: prospects and challenges. Nat. Med. 21, 121–131 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Kacherovsky, N., Liu, G.W., Jensen, M.C. & Pun, S.H. Multiplexed gene transfer to a human T-cell line by combining Sleeping Beauty transposon system with methotrexate selection. Biotechnol. Bioeng. 112, 1429–1436 (2015).

    Article  CAS  PubMed  Google Scholar 

  121. Field, A.C. et al. Comparison of lentiviral and sleeping beauty mediated αβ T cell receptor gene transfer. PLoS One 8, e68201 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Rushworth, D. et al. Universal artificial antigen presenting cells to selectively propagate T cells expressing chimeric antigen receptor independent of specificity. J. Immunother. 37, 204–213 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Klebanoff, C.A. et al. Determinants of successful CD8+ T-cell adoptive immunotherapy for large established tumors in mice. Clin. Cancer Res. 17, 5343–5352 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Casati, A. et al. Clinical-scale selection and viral transduction of human naïve and central memory CD8+ T cells for adoptive cell therapy of cancer patients. Cancer Immunol. Immunother. 62, 1563–1573 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Stemberger, C. et al. Novel serial positive enrichment technology enables clinical multiparameter cell sorting. PLoS One 7, e35798 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Gerlinger, M. et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N. Engl. J. Med. 366, 883–892 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Yachida, S. et al. Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature 467, 1114–1117 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

  130. Spiotto, M.T., Rowley, D.A. & Schreiber, H. Bystander elimination of antigen loss variants in established tumors. Nat. Med. 10, 294–298 (2004).

    Article  CAS  PubMed  Google Scholar 

  131. Breart, B., Lemaître, F., Celli, S. & Bousso, P. Two-photon imaging of intratumoral CD8+ T cell cytotoxic activity during adoptive T cell therapy in mice. J. Clin. Invest. 118, 1390–1397 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Kerkar, S.P. et al. IL-12 triggers a programmatic change in dysfunctional myeloid-derived cells within mouse tumors. J. Clin. Invest. 121, 4746–4757 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Bollard, C.M. et al. Sustained complete responses in patients with lymphoma receiving autologous cytotoxic T lymphocytes targeting Epstein-Barr virus latent membrane proteins. J. Clin. Oncol. 32, 798–808 (2014).

    Article  CAS  PubMed  Google Scholar 

  134. Corbière, V. et al. Antigen spreading contributes to MAGE vaccination-induced regression of melanoma metastases. Cancer Res. 71, 1253–1262 (2011).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  136. Riddell, S.R. et al. T-cell mediated rejection of gene-modified HIV-specific cytotoxic T lymphocytes in HIV-infected patients. Nat. Med. 2, 216–223 (1996).

    Article  CAS  PubMed  Google Scholar 

  137. Straathof, K.C. et al. An inducible caspase-9 safety switch for T-cell therapy. Blood 105, 4247–4254 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Zhou, X. et al. Long-term outcome after haploidentical stem cell transplant and infusion of T cells expressing the inducible caspase-9 safety transgene. Blood 123, 3895–3905 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Zhao, Y. et al. Multiple injections of electroporated autologous T cells expressing a chimeric antigen receptor mediate regression of human disseminated tumor. Cancer Res. 70, 9053–9061 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. 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).

    Article  CAS  PubMed  Google Scholar 

  143. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Desnoyers, L.R. et al. Tumor-specific activation of an EGFR-targeting probody enhances therapeutic index. Sci. Transl. Med. 5, 207ra144 (2013).

    Article  CAS  PubMed  Google Scholar 

  145. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by the Intramural Research Program of the National Cancer Institute, Center for Cancer Research of the US National Institutes of Health (NIH) (ZIA BC011586 and ZIA BC010763) and the NIH Center for Regenerative Medicine. Additional support was provided by generous gifts from L. Jinyuan of the Tiens Charitable Foundation and the Milstein Family Foundation.

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  1. Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA

    Christopher A Klebanoff, Steven A Rosenberg & Nicholas P Restifo

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  1. Christopher A Klebanoff
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C.A.K., S.A.R. and N.P.R. wrote and revised the manuscript.

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Correspondence to Christopher A Klebanoff or Nicholas P Restifo.

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S.A.R. reports receiving research support in the form of Cooperative Research and Development Agreements (CRADAs) with KITE Pharma, Lion Biotechnologies and Intrexon; C.A.K. and N.P.R. report no conflicts of interest.

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Klebanoff, C., Rosenberg, S. & Restifo, N. Prospects for gene-engineered T cell immunotherapy for solid cancers. Nat Med 22, 26–36 (2016). https://doi.org/10.1038/nm.4015

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