Key Points
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Somatic mutations can cause tumours to express mutant proteins that are tumour specific and not expressed on normal cells (neoantigens). In the subset of human tumours with a viral aetiology, the proteins encoded by viral genes are another type of neoantigen.
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Neoantigens are an attractive immune target because their selective expression on tumours may minimize immune tolerance as well as the risk of autoimmunity. Therefore, neoantigen-specific therapies may be more effective and less toxic than therapies targeting tumour-associated antigens.
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Neoantigens serve a crucial role in the naturally occurring antitumour T cell response, and are also the most important tumour antigens in certain cancers for which immune checkpoint inhibitors have shown clinical efficacy.
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As neoantigens are unique and not shared between different patients, neoantigen-targeted therapy will probably need to be on an individual basis. A personalized approach to targeting neoantigens has only recently been possible as a result of major advances in genomics and bioinformatics, including massively parallel sequencing and epitope prediction algorithms.
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Two therapeutic platforms that could be used to target neoantigens are adoptive cell therapy (ACT) using neoantigen-specific T cell products, and personalized vaccines encoding predicted neoantigens.
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Neoantigen-specific therapies will probably need to be combined with other therapies such as immune checkpoint inhibitors to overcome immunosuppressive mechanisms in the tumour microenvironment that inhibit neoantigen-specific immune responses.
Abstract
The past decade of cancer research has been marked by a growing appreciation of the role of immunity in cancer. Mutations in the tumour genome can cause tumours to express mutant proteins that are tumour specific and not expressed on normal cells (neoantigens). These neoantigens are an attractive immune target because their selective expression on tumours may minimize immune tolerance as well as the risk of autoimmunity. In this Review we discuss the emerging evidence that neoantigens are recognized by the immune system and can be targeted to increase antitumour immunity. We also provide a framework for personalized cancer immunotherapy through the identification and selective targeting of individual tumour neoantigens, and present the potential benefits and obstacles to this approach of targeted immunotherapy.
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Change history
24 August 2017
In the legend of Figure 2 of this article there was an error in the formula for the objective response rate (ORR). The formula should read ORR (%) = 8 x ln(x) + 9. This has now been corrected in the online version.
References
Garraway, L. A. & Lander, E. S. Lessons from the cancer genome. Cell 153, 17–37 (2013).
Vogelstein, B. et al. Cancer genome landscapes. Science 339, 1546–1558 (2013).
Segal, N. H. et al. Epitope landscape in breast and colorectal cancer. Cancer Res. 68, 889–892 (2008).
Wood, L. D. et al. The genomic landscapes of human breast and colorectal cancers. Science 318, 1108–1113 (2007).
O'Brien, S. G. et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N. Engl. J. Med. 348, 994–1004 (2003).
Sledge, G. W. The challenge and promise of the genomic era. J. Clin. Oncol. 30, 203–209 (2012).
Lu, Y.-C. & Robbins, P. F. Cancer immunotherapy targeting neoantigens. Semin. Immunol. 28, 22–27 (2016).
Gubin, M. M. et al. Tumor neoantigens: building a framework for personalized cancer immunotherapy. J. Clin. Invest. 125, 3413–3421 (2015).
Ward, J. P., Gubin, M. M. & Schreiber, R. D. The role of neoantigens in naturally occurring and therapeutically induced immune responses to cancer. Adv. Immunol. 130, 25–74 (2016).
Feng, H., Shuda, M., Chang, Y. & Moore, P. S. Clonal integration of a polyomavirus in human Merkel cell carcinoma. Science 319, 1096–1100 (2008).
Gillison, M. L. Evidence for a causal association between human papillomavirus and a subset of head and neck cancers. J. Natl Cancer Inst. 92, 709–720 (2000).
Walboomers, J. M. M. et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J. Pathol. 189, 12–19 (1999).
Coulie, P. G., Van den Eynde, B. J., van der Bruggen, P. & Boon, T. Tumour antigens recognized by T lymphocytes: at the core of cancer immunotherapy. Nat. Rev. Cancer 14, 135–146 (2014).
Simpson, A. J. G., Caballero, O. L., Jungbluth, A., Chen, Y.-T. & Old, L. J. Cancer/testis antigens, gametogenesis and cancer. Nat. Rev. Cancer 5, 615–625 (2005).
Trimble, C. L. et al. Safety, efficacy, and immunogenicity of VGX-3100, a therapeutic synthetic DNA vaccine targeting human papillomavirus 16 and 18 E6 and E7 proteins for cervical intraepithelial neoplasia 2/3: a randomised, double-blind, placebo-controlled phase 2b trial. Lancet 386, 2078–2088 (2015).
Nedergaard, M. K., Hedegaard, C. J. & Poulsen, H. S. Targeting the epidermal growth factor receptor in solid tumor malignancies. BioDrugs 26, 83–99 (2012).
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).
Tran, E. et al. T-cell transfer therapy targeting mutant KRAS in cancer. N. Engl. J. Med. 375, 2255–2262 (2016).
Wedén, S. et al. Long-term follow-up of patients with resected pancreatic cancer following vaccination against mutant K-ras. Int. J. Cancer 128, 1120–1128 (2011).
Brahmer, J. R. et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N. Engl. J. Med. 366, 2455–2465 (2012).
Chen, L. et al. Anti-PD-1/PD-L1 therapy of human cancer: past, present, and future. J. Clin. Invest. 125, 3384–3391 (2015).
Melero, I. et al. Therapeutic vaccines for cancer: an overview of clinical trials. Nat. Rev. Clin. Oncol. 11, 509–524 (2014).
Stone, J. D., Harris, D. T. & Kranz, D. M. TCR affinity for p/MHC formed by tumor antigens that are self-proteins: impact on efficacy and toxicity. Curr. Opin. Immunol. 33, 16–22 (2015).
Aleksic, M. et al. Different affinity windows for virus and cancer-specific T-cell receptors: implications for therapeutic strategies. Eur. J. Immunol. 42, 3174–3179 (2012).
Tian, S., Maile, R., Collins, E. J. & Frelinger, J. A. CD8+ T cell activation is governed by TCR-peptide/MHC affinity, not dissociation rate. J. Immunol. 179, 2952–2960 (2007).
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).
Grupp, S. A. et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N. Engl. J. Med. 368, 1509–1518 (2013).
Maude, S. L. et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N. Engl. J. Med. 371, 1507–1517 (2014).
Lamers, C. H. et al. Treatment of metastatic renal cell carcinoma with CAIX CAR-engineered T cells: clinical evaluation and management of on-target toxicity. Mol. Ther. 21, 904–912 (2013).
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).
Morgan, R. A. et al. Cancer regression and neurological toxicity following anti-MAGE-A3 TCR gene therapy. J. Immunother. 36, 133–151 (2013).
Germeau, C. et al. High frequency of antitumor T cells in the blood of melanoma patients before and after vaccination with tumor antigens. J. Exp. Med. 201, 241–248 (2005).
Joseph, C. G. et al. Association of the autoimmune disease scleroderma with an immunologic response to cancer. Science 343, 152–157 (2014). This study showed that even neoantigen-specific T cells against a mutated tumour protein can be cross-reactive with the non-mutated version of the antigen and can induce autoimmunity.
Gross, L. Intradermal immunization of C3H mice against a sarcoma that originated in an animal of the same line. Cancer Res. 3, 326–333 (1943).
De Plaen, E. et al. Immunogenic (tum−) variants of mouse tumor P815: cloning of the gene of tum-antigen P91A and identification of the tum-mutation. Immunology 85, 2274–2278 (1988). This study demonstrated that antitumour T cells can recognize aberrant peptides derived from tumour-specific mutations.
Lurquin, C. et al. Structure of the gene of tum− transplantation antigen P91A: the mutated exon encodes a peptide recognized with Ld by cytolytic T cells. Cell 58, 293–303 (1989).
Monach, P. A., Meredith, S. C., Siegel, C. T. & Schreiber, H. A unique tumor antigen produced by a single amino acid substitution. Immunity 2, 45–59 (1995).
Coulie, P. G. et al. A mutated intron sequence codes for an antigenic peptide recognized by cytolytic T lymphocytes on a human melanoma. Proc. Natl Acad. Sci. USA 92, 7976–7980 (1995).
Wölfel, T. et al. A p16INK4a-insensitive CDK4 mutant targeted by cytolytic T lymphocytes in a human melanoma. Science 269, 1281–1284 (1995). This study analysed the naturally occurring antitumour T cell response against melanoma in a patient to demonstrate that immunoreactivity against neoantigens predominates over the response to TAAs.
Zhou, X. et al. Diverse CD8+ T-cell responses to renal cell carcinoma antigens in patients treated with an autologous granulocyte–macrophage colony-stimulating factor gene-transduced renal tumor cell vaccine. Cancer Res. 65, 1079–1088 (2005).
Lennerz, V. et al. The response of autologous T cells to a human melanoma is dominated by mutated neoantigens. Proc. Natl Acad. Sci. USA 102, 16013–16018 (2005).
Zhou, J., Dudley, M. E., Rosenberg, S. A. & Robbins, P. F. Persistence of multiple tumor-specific T-cell clones is associated with complete tumor regression in a melanoma patient receiving adoptive cell transfer therapy. J. Immunother. 28, 53–62 (2005).
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. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 348, 124–128 (2015).
Gubin, M. M. et al. Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens. Nature 515, 577–581 (2014).
Gros, A. et al. Prospective identification of neoantigen-specific lymphocytes in the peripheral blood of melanoma patients. Nat. Med. 22, 433–438 (2016).
Dummer, R. et al. A randomized controlled comparison of pembrolizumab and chemotherapy in patients with ipilimumab-refractory melanoma. J. Transl Med. 13, O5 (2015).
Robert, C. et al. Nivolumab in previously untreated melanoma without BRAF mutation. N. Engl. J. Med. 372, 320–330 (2014).
Robert, C. et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N. Engl. J. Med. 364, 2517–2526 (2011).
Hodi, F. S. et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363, 711–723 (2010).
Larkin, J. et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N. Engl. J. Med. 373, 23–34 (2015).
Borghaei, H. et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N. Engl. J. Med. 373, 1627–1639 (2015).
Sundar, R., Cho, B.-C., Brahmer, J. R. & Soo, R. A. Nivolumab in NSCLC: latest evidence and clinical potential. Ther. Adv. Med. Oncol. 7, 85–96 (2015).
Garon, E. B. et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N. Engl. J. Med. 372, 2018–2028 (2015).
Alexandrov, L. B. et al. Signatures of mutational processes in human cancer. Nature 500, 415–421 (2013).
Abdul-Hassan Tawbi, H. et al. Safety and efficacy of PD-1 blockade using pembrolizumab in patients with advanced soft tissue (STS) and bone sarcomas (BS): results of SARC028 — a multicenter phase II study. J. Clin. Oncol. 34, abstr. 11006 (2016).
Kwon, E. D. et al. Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol. 15, 700–712 (2014).
Le, D. T. et al. PD-1 blockade in tumors with mismatch-repair deficiency. N. Engl. J. Med. 372, 2509–2520 (2015). This paper provided support for the role of somatic mutations in the response to immune checkpoint inhibitors.
McGranahan, N. et al. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science 351, 1463–1469 (2016).
Hugo, W. et al. Genomic and transcriptomic features of response to anti-PD-1 therapy in metastatic melanoma. Cell 165, 35–44 (2016).
Sivan, A. et al. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science 350, 1084–1089 (2015).
Rosenberg, S. A. Interleukin 2 for patients with renal cancer. Nat. Clin. Pract. Oncol. 4, 497 (2007).
Rosenberg, S. A. IL-2: the first effective immunotherapy for human cancer. J. Immunol. 192, 5451–5458 (2014).
Motzer, R. J. et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N. Engl. J. Med. 373, 1803–1813 (2015).
Goh, G. et al. Mutational landscape of MCPyV-positive and MCPyV-negative Merkel cell carcinomas with implications for immunotherapy. Oncotarget 7, 3403–3415 (2016). This study showed that in a subset of MCCs with a viral aetiology, neoantigens derived from viral proteins can serve as strong immune stimulants and may be an attractive target for cancer immunotherapy.
Nghiem, P. T. et al. PD-1 blockade with pembrolizumab in advanced Merkel-cell carcinoma. N. Engl. J. Med. 374, 2542–2552 (2016).
Lipson, E. J. et al. PD-L1 expression in the Merkel cell carcinoma microenvironment: association with inflammation, Merkel cell polyomavirus and overall survival. Cancer Immunol. Res. 1, 54–63 (2013).
Lawrence, M. S. et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature 499, 214–218 (2013).
Folgiero, V. et al. IDO1 involvement in mTOR pathway: a molecular mechanism of resistance to mTOR targeting in medulloblastoma. Oncotarget 7, 52900–52911 (2016).
Zhang, L., Gajewski, T. F. & Kline, J. PD-1/PD-L1 interactions inhibit antitumor immune responses in a murine acute myeloid leukemia model. Blood 114, 1545–1552 (2009).
Fukuno, K. et al. Expression of indoleamine 2,3-dioxygenase in leukemic cells indicates an unfavorable prognosis in acute myeloid leukemia patients with intermediate-risk cytogenetics. Leuk. Lymphoma 56, 1398–1405 (2015).
Mussai, F. et al. Acute myeloid leukemia creates an arginase-dependent immunosuppressive microenvironment. Blood 122, 749–758 (2013).
Stone, R. M. et al. Low dose interleukin-2 following intensification therapy with high dose cytarabine for acute myelogenous leukemia in first complete remission. Am. J. Hematol. 83, 771–777 (2008).
Meloni, G. et al. Interleukin-2 may induce prolonged remissions in advanced acute myelogenous leukemia. Blood 84, 2158–2163 (1994).
Tran, E. et al. Immunogenicity of somatic mutations in human gastrointestinal cancers. Science 350, 1387–1390 (2015). This study supports the idea that most tumours have neoantigens that are recognizable by the immune system and are potentially susceptible to immune-targeting interventions.
Parsons, D. W. et al. The genetic landscape of the childhood cancer medulloblastoma. Science 331, 435–439 (2011).
Dunn, G. P., Bruce, A. T., Ikeda, H., Old, L. J. & Schreiber, R. D. Cancer immunoediting: from immunosurveillance to tumor escape. Nat. Immunol. 3, 991–998 (2002).
Schreiber, R. D., Old, L. J. & Smyth, M. J. Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion. Science 331, 1565–1570 (2011).
Shankaran, V. et al. IFNγ and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature 410, 1107–1111 (2001).
Diamond, M. S. et al. Type I interferon is selectively required by dendritic cells for immune rejection of tumors. J. Exp. Med. 208, 1989–2003 (2011).
Screpanti, V., Wallin, R. P. A., Grandien, A. & Ljunggren, H.-G. Impact of FASL-induced apoptosis in the elimination of tumor cells by NK cells. Mol. Immunol. 42, 495–499 (2005).
Champsaur, M. & Lanier, L. L. Effect of NKG2D ligand expression on host immune responses. Immunol. Rev. 235, 267–285 (2010).
Diefenbach, A., Jensen, E. R., Jamieson, A. M. & Raulet, D. H. Rae1 and H60 ligands of the NKG2D receptor stimulate tumour immunity. Nature 413, 165–171 (2001).
Mittal, D., Gubin, M. M., Schreiber, R. D. & Smyth, M. J. New insights into cancer immunoediting and its three component phases — elimination, equilibrium and escape. Curr. Opin. Immunol. 27, 16–25 (2014).
MacKie, R. M., Reid, R. & Junor, B. Fatal melanoma transferred in a donated kidney 16 years after melanoma surgery. N. Engl. J. Med. 348, 567–568 (2003).
Koebel, C. M. et al. Adaptive immunity maintains occult cancer in an equilibrium state. Nature 450, 903–917 (2007).
Khong, H. T. & Restifo, N. P. Natural selection of tumor variants in the generation of “tumor escape” phenotypes. Nat. Immunol. 3, 999–1005 (2002).
Zaretsky, J. M. et al. Mutations associated with acquired resistance to PD-1 blockade in melanoma. N. Engl. J. Med. 375, 819–829 (2016).
Yannakou, C. K., Came, N., Bajel, A. R. & Juneja, S. CD19 negative relapse in B-ALL treated with blinatumomab therapy: avoiding the trap. Blood 126, 4983–4983 (2015).
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).
Uyttenhove, B. C., Maryanski, J. & Boon, T. Escape of mouse mastocytoma. J. Exp. Med. 157, 1040–1052 (1983). This work showed for the first time that as tumours progress, they lose immunogenicity and antigenicity through the immunoselection of clones expressing weaker antigens, a process that has been termed immunoediting.
Matsushita, H. et al. Cancer exome analysis reveals a T-cell-dependent mechanism of cancer immunoediting. Nature 482, 400–404 (2012).
Uyttenhove, C. et al. Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase. Nat. Med. 9, 1269–1274 (2003).
Iwai, Y. et al. Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc. Natl Acad. Sci. USA 99, 12293–12297 (2002).
Mellman, I., Coukos, G. & Dranoff, G. Cancer immunotherapy comes of age. Nature 480, 480–489 (2011).
Tseng, D. et al. Anti-CD47 antibody-mediated phagocytosis of cancer by macrophages primes an effective antitumor T-cell response. Proc. Natl Acad. Sci. USA 110, 11103–11108 (2013).
Pardoll, D. Cancer and the immune system: basic concepts and targets for intervention. Semin. Oncol. 42, 523–538 (2015).
Singer, K., Gottfried, E., Kreutz, M. & Mackensen, A. Suppression of T-cell responses by tumor metabolites. Cancer Immunol. Immunother. 60, 425–431 (2011).
Chang, C.-H. et al. Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell 162, 1229–1241 (2015).
Sharma, M. D. et al. Plasmacytoid dendritic cells from mouse tumor-draining lymph nodes directly activate mature Tregs via indoleamine 2,3-dioxygenase. J. Clin. Invest. 117, 2570–2582 (2007).
Serafini, P., Borrello, I. & Bronte, V. Myeloid suppressor cells in cancer: recruitment, phenotype, properties, and mechanisms of immune suppression. Semin. Cancer Biol. 16, 53–65 (2006).
Munn, D. H. et al. Expression of indoleamine 2,3-dioxygenase by plasmacytoid dendritic cells in tumor-draining lymph nodes. J. Clin. Invest. 114, 280–290 (2004).
Mao, Y., Poschke, I. & Kiessling, R. Tumour-induced immune suppression: role of inflammatory mediators released by myelomonocytic cells. J. Intern. Med. 276, 154–170 (2014).
Corzo, C. A. et al. Mechanism regulating reactive oxygen species in tumor-induced myeloid-derived suppressor cells. J. Immunol. 182, 5693–5701 (2009).
Munn, D. H. et al. GCN2 kinase in T cells mediates proliferative arrest and anergy induction in response to indoleamine 2,3-dioxygenase. Immunity 22, 633–642 (2005).
Willimsky, G. et al. Immunogenicity of premalignant lesions is the primary cause of general cytotoxic T lymphocyte unresponsiveness. J. Exp. Med. 205, 1687–1700 (2008).
Kammertoens, T., Qin, Z., Briesemeister, D., Bendelac, A. & Blankenstein, T. B-cells and IL-4 promote methylcholanthrene-induced carcinogenesis but there is no evidence for a role of T/NKT-cells and their effector molecules (Fas-ligand, TNF-α, perforin). Int. J. Cancer 131, 1499–1508 (2012).
Choi, M. et al. Genetic diagnosis by whole exome capture and massively parallel DNA sequencing. Proc. Natl Acad. Sci. USA 106, 19096–19101 (2009).
Ng, S. B. et al. Targeted capture and massively parallel sequencing of 12 human exomes. Nature 461, 272–276 (2009).
Nielsen, M., Lundegaard, C., Lund, O. & Kes¸mir, C. The role of the proteasome in generating cytotoxic T-cell epitopes: insights obtained from improved predictions of proteasomal cleavage. Immunogenetics 57, 33–41 (2005).
Larsen, M. V. et al. Large-scale validation of methods for cytotoxic T-lymphocyte epitope prediction. BMC Bioinformatics 8, 424 (2007).
Peters, B., Bulik, S., Tampe, R., Van Endert, P. M. & Holzhütter, H.-G. Identifying MHC class I epitopes by predicting the TAP transport efficiency of epitope precursors. J. Immunol. 171, 1741–1749 (2003).
Nielsen, M. & Andreatta, M. NetMHCpan-3.0; improved prediction of binding to MHC class I molecules integrating information from multiple receptor and peptide length datasets. Genome Med. 8, 33 (2016).
Nielsen, M. et al. NetMHCpan, a method for quantitative predictions of peptide binding to any HLA-A and -B locus protein of known sequence. PLoS ONE 2, e796 (2007).
Rammensee, H.-G., Bachmann, J., Emmerich, N. P. N., Bachor, O. A. & Stevanovic´, S. SYFPEITHI: database for MHC ligands and peptide motifs. Immunogenetics 50, 213–219 (1999).
Biesecker, L. G. & Green, R. C. Diagnostic clinical genome and exome sequencing. N. Engl. J. Med. 370, 2418–2425 (2014).
Bjorkman, P. J. et al. Structure of the human class I histocompatibility antigen, HLA-A2. Nature 329, 506–512 (1987).
Babbitt, B. P., Allen, P. M., Matsueda, G., Haber, E. & Unanue, E. R. Binding of immunogenic peptides to Ia histocompatibility molecules. Nature 317, 359–361 (1985).
Nielsen, M., Lund, O., Buus, S. & Lundegaard, C. MHC class II epitope predictive algorithms. Immunology 130, 319–328 (2010).
Kreiter, S. et al. Mutant MHC class II epitopes drive therapeutic immune responses to cancer. Nature 520, 692–696 (2015).
Tran, E. et al. Cancer immunotherapy based on mutation-specific CD4+ T cells in a patient with epithelial cancer. Science 9, 641–645 (2014). This case report demonstrated proof of principle for treating cancer with neoantigen-directed immunotherapy.
Yadav, M. et al. Predicting immunogenic tumour mutations by combining mass spectrometry and exome sequencing. Nature 515, 572–576 (2014).
Carreno, B. M. et al. A dendritic cell vaccine increases the breadth and diversity of melanoma neoantigen-specific T cells. Science 348, 803–808 (2015). This study demonstrated that vaccination can induce neoantigen-specific T cell responses that are not naturally occurring.
Robbins, P. F. et al. Mining exomic sequencing data to identify mutaded antigens recognized by adoptively transferred tumor-reactive cells. Nat. Med. 19, 747–752 (2013).
Fritsch, E. F. et al. HLA-binding properties of tumor neoepitopes in humans. Cancer Immunol. Res. 2, 522–529 (2014).
Van Buuren, M. M., Calis, J. J. & Schumacher, T. N. High sensitivity of cancer exome-based CD8 T cell neo-antigen identification. Oncoimmunology 3, e28836 (2014).
Duan, F. et al. Genomic and bioinformatic profiling of mutational neoepitopes reveals new rules to predict anticancer immunogenicity. J. Exp. Med. 211, 2231–2248 (2014).
Bargou, R. et al. Tumor regression in cancer patients by very low doses of a T cell-engaging antibody. Science 321, 974–977 (2008).
Baeuerle, P. A. & Reinhardt, C. Bispecific T-cell engaging antibodies for cancer therapy. Cancer Res. 69, 4941–4944 (2009).
Topp, M. S. et al. Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study. Lancet Oncol. 16, 57–66 (2015).
Gross, G., Waks, T. & Eshhar, Z. Expression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibody-type specificity. Proc. Natl Acad. Sci. USA 86, 10024–10028 (1989).
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).
Dao, T. et al. Therapeutic bispecific T-cell engager antibody targeting the intracellular oncoprotein WT1. Nat. Biotechnol. 33, 1079–1086 (2015).
Strønen, E. et al. Targeting of cancer neoantigens with donor-derived T cell receptor repertoires. Science 352, 1337–1341 (2016).
Kantoff, P. W. et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N. Engl. J. Med. 363, 411–422 (2010).
Cheever, M. A. et al. The prioritization of cancer antigens: a National Cancer Institute pilot project for the acceleration of translational research. Clin. Cancer Res. 15, 5323–5337 (2009).
Krieg, A. M. Therapeutic potential of Toll-like receptor 9 activation. Nat. Rev. Drug Discov. 5, 471–484 (2006).
Baird, J. R. et al. Radiotherapy combined with novel STING-targeting oligonucleotides results in regression of established tumors. Cancer Res. 76, 50–61 (2016).
Lutz, E. R. et al. Immunotherapy converts nonimmunogenic pancreatic tumors into immunogenic foci of immune regulation. Cancer Immunol. Res. 2, 616–631 (2014).
Taube, J. M. et al. Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy. Clin. Cancer Res. 20, 5064–5074 (2014).
Soares, K. C. et al. PD-1/PD-L1 blockade together with vaccine therapy facilitates effector T-cell infiltration into pancreatic tumors. J. Immunother. 38, 1–11 (2015).
Li, B. et al. Anti-programmed death-1 synergizes with granulocyte macrophage colony-stimulating factor-secreting tumor cell immunotherapy providing therapeutic benefit to mice with established tumors. Clin. Cancer Res. 15, 1623–1634 (2009).
Fu, J. et al. STING agonist formulated cancer vaccines can cure established tumors resistant to PD-1 blockade. Sci. Transl Med. 7, 283ra52 (2015).
Duraiswamy, J., Kaluza, K. M., Freeman, G. J. & Coukos, G. Dual blockade of PD-1 and CTLA-4 combined with tumor vaccine effectively restores T-cell rejection function in tumors. Cancer Res. 73, 3591–3603 (2013).
Topalian, S. L., Drake, C. G. & Pardoll, D. M. Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell 27, 450–461 (2015).
Spranger, S. et al. Mechanism of tumor rejection with doublets of CTLA-4, PD-1/PD-L1, or IDO blockade involves restored IL-2 production and proliferation of CD8+ T cells directly within the tumor microenvironment. J. Immunother. Cancer 2, 3 (2014).
Leone, R. D., Lo, Y.-C. & Powell, J. D. A2aR antagonists: next generation checkpoint blockade for cancer immunotherapy. Comput. Struct. Biotechnol. J. 13, 265–272 (2015).
Provenzano, P. P. et al. Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell 21, 418–429 (2012).
Ebert, P. J. R. et al. MAP kinase inhibition promotes T cell and anti-tumor activity in combination with PD-L1 checkpoint blockade. Immunity 44, 609–621 (2016).
Patel, S. P. & Kurzrock, R. PD-L1 expression as a predictive biomarker in cancer immunotherapy. Mol. Cancer Ther. 14, 847–856 (2015).
Bach, P. B. & Pearson, S. D. Payer and policy maker steps to support value-based pricing for drugs. JAMA 314, 2503–2504 (2015).
Gerlinger, M. et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N. Engl. J. Med. 366, 883–892 (2012).
Ali, S. & Coombes, R. C. Endocrine-responsive breast cancer and strategies for combating resistance. Nat. Rev. Cancer 2, 101–112 (2002).
Quintás-Cardama, A. et al. Molecular biology of bcr-abl1-positive chronic myeloid leukemia. Blood 113, 1619–1630 (2009).
Turner, N. C. et al. Palbociclib in hormone-receptor-positive advanced breast cancer. N. Engl. J. Med. 373, 209–219 (2015).
Larkin, J. et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N. Engl. J. Med. 371, 1867–1876 (2014).
Eisenhauer, E. A. et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur. J. Cancer 45, 228–247 (2009).
Slamon, D. J. et al. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 244, 707–712 (1989).
Le, D. T. et al. A live-attenuated Listeria vaccine (ANZ-100) and a live-attenuated Listeria vaccine expressing mesothelin (CRS-207) for advanced cancers: phase I studies of safety and immune induction. Clin. Cancer Res. 18, 858–868 (2012).
Argani, P. et al. Mesothelin is overexpressed in the vast majority of ductal adenocarcinomas of the pancreas: identification of a new pancreatic cancer marker by serial analysis of gene expression (SAGE). Clin. Cancer Res. 7, 3862–3868 (2001).
Thomas, A. M. et al. Mesothelin-specific CD8+ T cell responses provide evidence of in vivo cross-priming by antigen-presenting cells in vaccinated pancreatic cancer patients. J. Exp. Med. 200, 297–306 (2004).
Chomez, P. et al. An overview of the MAGE gene family with the identification of all human members of the family. Cancer Res. 61, 5544–5551 (2001).
Gnjatic, S. et al. NY-ESO-1: review of an immunogenic tumor antigen. Adv. Cancer Res. 95, 1–30 (2006).
Acknowledgements
The authors gratefully acknowledge support from the Bloomberg–Kimmel Institute for Cancer Immunotherapy and the Skip Viragh Center for Pancreatic Cancer Research and Clinical Care at Johns Hopkins University, Baltimore, Maryland, USA.
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Under a licensing agreement between Aduro BioTech, Inc. and the Johns Hopkins University and E.M.J., the University is entitled to milestone payments and royalty on sales of certain cancer vaccine products (E.M.J.). The other authors have no conflict to disclose.
Glossary
- Passenger mutations
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Mutations that have no effect on the fitness of the cell, and are therefore not implicated in oncogenesis.
- Driver mutations
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Mutations that cause a selective advantage to a cell clone and are therefore causally implicated in oncogenesis.
- Nonsynonymous mutations
-
Point mutations and missense mutations that alter the amino acid sequence of proteins.
- Major histocompatibility complex
-
(MHC). Cell surface proteins that bind to short sequences of amino acids (epitopes) and display them on the cell surface for recognition by the immune system. MHC class I is present on the surface of virtually all nucleated cells including tumour cells and presents intracellular antigens to CD8+ T cells; MHC class II is present on antigen presenting cells and presents exogenous antigens to CD4+ T helper cells.
- Neoantigens
-
Mutations in the tumour genome can cause tumours to express mutant proteins that are tumour specific and not expressed on normal cells — referred to as neoantigens.
- Objective response rates
-
(ORRs). ORR is a common efficacy end point used in clinical trials of cancer therapies in solid tumours, usually defined as the percentage of patients who experience at least a 30% decrease in tumour diameter on an imaging scan.
- Central and peripheral tolerance
-
A state in which immune cells are unresponsive to antigens as a result of clonal deletion of autoreactive B cells and T cells, as well as the dampening of potentially autoreactive B cells and T cells through regulatory immune cells and subsequent downregulation of costimulatory molecules.
- Chimeric antigen receptor (CAR) T cells
-
T cells that are modified to express an antigen recognition domain of a specific antibody fused to an intracellular signalling domain.
- Adoptive cell therapy
-
(ACT). An immunotherapy treatment in which antitumour lymphocytes are identified, expanded in vitro and then infused into a patient with cancer. The administered antitumour lymphocytes can be autologous (patient's own) or allogeneic (donor).
- Microsatellite instability
-
(MSI). Increased propensity for changes in microsatellite (short tandem repeat) sequences resulting from defects in DNA mismatch repair.
- Immunogenic
-
The ability to induce an immune response.
- Adjuvant
-
An immunostimulatory agent designed to enhance the immune response to a vaccine.
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Yarchoan, M., Johnson, B., Lutz, E. et al. Targeting neoantigens to augment antitumour immunity. Nat Rev Cancer 17, 209–222 (2017). https://doi.org/10.1038/nrc.2016.154
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DOI: https://doi.org/10.1038/nrc.2016.154
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