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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References
Hodi, F.S. et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363, 711–723 (2010).
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).
Motzer, R.J. et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N. Engl. J. Med. 373, 1803–1813 (2015).
Brahmer, J. et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N. Engl. J. Med. 373, 123–135 (2015).
Powles, T. et al. MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature 515, 558–562 (2014).
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).
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).
Le, D.T. et al. PD-1 blockade in tumors with mismatch-repair deficiency. N. Engl. J. Med. 372, 2509–2520 (2015).
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).
Snyder, A. et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N. Engl. J. Med. 371, 2189–2199 (2014).
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).
Tumeh, P.C. et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515, 568–571 (2014).
Rosenberg, S.A. & Restifo, N.P. Adoptive cell transfer as personalized immunotherapy for human cancer. Science 348, 62–68 (2015).
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).
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).
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).
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).
Tran, E. et al. Cancer immunotherapy based on mutation-specific CD4+ T cells in a patient with epithelial cancer. Science 344, 641–645 (2014).
Tran, E. et al. Immunogenicity of somatic mutations in human gastrointestinal cancers. Science http://dx.doi.org/10.1126/science.aad1253 (2015).
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).
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).
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).
Kantoff, P.W. et al. IMPACT Study Investigators. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N. Engl. J. Med. 363, 411–422 (2010).
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).
Scholler, J. et al. Decade-long safety and function of retroviral-modified chimeric antigen receptor T cells. Sci. Transl. Med. 4, 132ra53 (2012).
Siegel, R.L., Miller, K.D. & Jemal, A. Cancer statistics, 2015. CA Cancer J. Clin. 65, 5–29 (2015).
Ahmadi, M. et al. CD3 limits the efficacy of TCR gene therapy in vivo. Blood 118, 3528–3537 (2011).
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).
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).
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).
Khong, H.T. & Restifo, N.P. Natural selection of tumor variants in the generation of 'tumor escape' phenotypes. Nat. Immunol. 3, 999–1005 (2002).
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).
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).
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).
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.
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).
Caballero, O.L. & Chen, Y.T. Cancer/testis (CT) antigens: potential targets for immunotherapy. Cancer Sci. 100, 2014–2021 (2009).
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).
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).
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).
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).
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).
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).
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).
Grupp, S.A. et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N. Engl. J. Med. 368, 1509–1518 (2013).
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).
Maude, S.L. et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N. Engl. J. Med. 371, 1507–1517 (2014).
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).
Garfall, A.L. et al. Chimeric antigen receptor T cells against CD19 for multiple myeloma. N. Engl. J. Med. 373, 1040–1047 (2015).
Lee, D.W. et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood 124, 188–195 (2014).
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).
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).
Rettig, W.J. & Old, L.J. Immunogenetics of human cell surface differentiation. Annu. Rev. Immunol. 7, 481–511 (1989).
Köhler, G. & Milstein, C. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 256, 495–497 (1975).
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).
Stashenko, P., Nadler, L.M., Hardy, R. & Schlossman, S.F. Characterization of a human B lymphocyte-specific antigen. J. Immunol. 125, 1678–1685 (1980).
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).
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).
Malavasi, F. et al. Human CD38: a glycoprotein in search of a function. Immunol. Today 15, 95–97 (1994).
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).
Miettinen, P.J. et al. Epithelial immaturity and multiorgan failure in mice lacking epidermal growth factor receptor. Nature 376, 337–341 (1995).
Crone, S.A. et al. ErbB2 is essential in the prevention of dilated cardiomyopathy. Nat. Med. 8, 459–465 (2002).
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).
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).
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).
Pastan, I. & Hassan, R. Discovery of mesothelin and exploiting it as a target for immunotherapy. Cancer Res. 74, 2907–2912 (2014).
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).
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).
Haridas, D. et al. MUC16: molecular analysis and its functional implications in benign and malignant conditions. FASEB J. 28, 4183–4199 (2014).
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).
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).
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).
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).
Hinrichs, C.S. & Restifo, N.P. Reassessing target antigens for adoptive T-cell therapy. Nat. Biotechnol. 31, 999–1008 (2013).
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).
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).
Martincorena, I. & Campbell, P.J. Somatic mutation in cancer and normal cells. Science 349, 1483–1489 (2015).
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).
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).
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).
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).
Rosenberg, S.A. Cell transfer immunotherapy for metastatic solid cancer--what clinicians need to know. Nat. Rev. Clin. Oncol. 8, 577–585 (2011).
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).
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).
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).
Morgan, R.A. et al. Cancer regression and neurological toxicity following anti-MAGE-A3 TCR gene therapy. J. Immunother. 36, 133–151 (2013).
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).
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).
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).
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).
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).
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).
Klebanoff, C.A., Acquavella, N., Yu, Z. & Restifo, N.P. Therapeutic cancer vaccines: are we there yet? Immunol. Rev. 239, 27–44 (2011).
Schumacher, T.N. & Schreiber, R.D. Neoantigens in cancer immunotherapy. Science 348, 69–74 (2015).
Andersen, R.S. et al. Dissection of T-cell antigen specificity in human melanoma. Cancer Res. 72, 1642–1650 (2012).
Van Allen, E.M. et al. Genomic correlates of response to CTLA-4 blockade in metastatic melanoma. Science 350, 207–211 (2015).
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).
Murtaza, M. et al. Non-invasive analysis of acquired resistance to cancer therapy by sequencing of plasma DNA. Nature 497, 108–112 (2013).
Gros, A. et al. PD-1 identifies the patient-specific CD8 tumor-reactive repertoire infiltrating human tumors. J. Clin. Invest. 124, 2246–2259 (2014).
Linnemann, C. et al. High-throughput identification of antigen-specific TCRs by TCR gene capture. Nat. Med. 19, 1534–1541 (2013).
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).
Cohen, C.J. et al. Isolation of neoantigen-specific T cells from tumor and peripheral lymphocytes. J. Clin. Invest. 125, 3981–3991 (2015).
Rodenko, B. et al. Generation of peptide-MHC class I complexes through UV-mediated ligand exchange. Nat. Protoc. 1, 1120–1132 (2006).
Gattinoni, L., Klebanoff, C.A. & Restifo, N.P. Paths to stemness: building the ultimate antitumour T cell. Nat. Rev. Cancer 12, 671–684 (2012).
Crompton, J.G., Clever, D., Vizcardo, R., Rao, M. & Restifo, N.P. Reprogramming antitumor immunity. Trends Immunol. 35, 178–185 (2014).
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).
Nishimura, T. et al. Generation of rejuvenated antigen-specific T cells by reprogramming to pluripotency and redifferentiation. Cell Stem Cell 12, 114–126 (2013).
Zhao, T., Zhang, Z.N., Rong, Z. & Xu, Y. Immunogenicity of induced pluripotent stem cells. Nature 474, 212–215 (2011).
Araki, R. et al. Negligible immunogenicity of terminally differentiated cells derived from induced pluripotent or embryonic stem cells. Nature 494, 100–104 (2013).
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).
Hanna, J.H., Saha, K. & Jaenisch, R. Pluripotency and cellular reprogramming: facts, hypotheses, unresolved issues. Cell 143, 508–525 (2010).
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).
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).
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).
Howie, B. et al. High-throughput pairing of T cell receptor α and β sequences. Sci. Transl. Med. 7, 301ra131 (2015).
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).
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).
Singh, H. et al. Redirecting specificity of T-cell populations for CD19 using the Sleeping Beauty system. Cancer Res. 68, 2961–2971 (2008).
Cox, D.B., Platt, R.J. & Zhang, F. Therapeutic genome editing: prospects and challenges. Nat. Med. 21, 121–131 (2015).
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).
Field, A.C. et al. Comparison of lentiviral and sleeping beauty mediated αβ T cell receptor gene transfer. PLoS One 8, e68201 (2013).
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).
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).
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).
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).
Stemberger, C. et al. Novel serial positive enrichment technology enables clinical multiparameter cell sorting. PLoS One 7, e35798 (2012).
Gerlinger, M. et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N. Engl. J. Med. 366, 883–892 (2012).
Yachida, S. et al. Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature 467, 1114–1117 (2010).
Sotillo, E. et al. Convergence of acquired mutations and alternative splicing of CD19 enables resistance to CART-19 immunotherapy. Cancer Discov. (2015).
Spiotto, M.T., Rowley, D.A. & Schreiber, H. Bystander elimination of antigen loss variants in established tumors. Nat. Med. 10, 294–298 (2004).
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).
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).
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).
Corbière, V. et al. Antigen spreading contributes to MAGE vaccination-induced regression of melanoma metastases. Cancer Res. 71, 1253–1262 (2011).
Bonini, C. et al. HSV-TK gene transfer into donor lymphocytes for control of allogeneic graft-versus-leukemia. Science 276, 1719–1724 (1997).
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).
Straathof, K.C. et al. An inducible caspase-9 safety switch for T-cell therapy. Blood 105, 4247–4254 (2005).
Di Stasi, A. et al. Inducible apoptosis as a safety switch for adoptive cell therapy. N. Engl. J. Med. 365, 1673–1683 (2011).
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).
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).
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).
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).
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).
Desnoyers, L.R. et al. Tumor-specific activation of an EGFR-targeting probody enhances therapeutic index. Sci. Transl. Med. 5, 207ra144 (2013).
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).
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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C.A.K., S.A.R. and N.P.R. wrote and revised the manuscript.
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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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DOI: https://doi.org/10.1038/nm.4015
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