Review Article | Published:

'Final common pathway' of human cancer immunotherapy: targeting random somatic mutations

Nature Immunology volume 18, pages 255262 (2017) | Download Citation

Abstract

Effective clinical cancer immunotherapies, such as administration of the cytokine IL-2, adoptive cell transfer (ACT) and the recent success of blockade of the checkpoint modulators CTLA-4 and PD-1, have been developed without clear identification of the immunogenic targets expressed by human cancers in vivo. Immunotherapy of patients with cancer through the use of ACT with autologous lymphocytes has provided an opportunity to directly investigate the antigen recognition of lymphocytes that mediate cancer regression in humans. High-throughput immunological testing of such lymphocytes in combination with improvements in deep sequencing of the autologous cancer have provided new insight into the molecular characterization and incidence of anti-tumor lymphocytes present in patients with cancer. Here we highlight evidence suggesting that T cells that target tumor neoantigens arising from cancer mutations are the main mediators of many effective cancer immunotherapies in humans.

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References

  1. 1.

    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).

  2. 2.

    et al. MAGE-A is more highly expressed than NY-ESO-1 in a systematic immunohistochemical analysis of 3668 cases. J. Immunother. 39, 181–187 (2016).

  3. 3.

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

  4. 4.

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

  5. 5.

    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).

  6. 6.

    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).

  7. 7.

    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).

  8. 8.

    , , , & Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N. Engl. J. Med. 365, 725–733 (2011).

  9. 9.

    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).

  10. 10.

    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).

  11. 11.

    et al. Immunotherapy of non-Hodgkin's lymphoma with a defined ratio of CD8+ and CD4+ CD19-specific chimeric antigen receptor-modified T cells. Sci. Transl. Med. 8, 355ra116 (2016).

  12. 12.

    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).

  13. 13.

    , & Cancer immunotherapy: moving beyond current vaccines. Nat. Med. 10, 909–915 (2004).

  14. 14.

    & Understanding and learning from the success of prophylactic human papillomavirus vaccines. Nat. Rev. Microbiol. 10, 681–692 (2012).

  15. 15.

    et al. The long-term immune response after HPV16 peptide vaccination in women with low-grade pre-malignant disorders of the uterine cervix: a placebo-controlled phase II study. Cancer Immunol. Immunother. 63, 147–160 (2014).

  16. 16.

    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).

  17. 17.

    et al. Immunogenic (tum-) variants of mouse tumor P815: cloning of the gene of tum- antigen P91A and identification of the tum- mutation. Proc. Natl. Acad. Sci. USA 85, 2274–2278 (1988).

  18. 18.

    et al. Structure of the gene of tum- transplantation antigen P198: a point mutation generates a new antigenic peptide. J. Exp. Med. 172, 35–45 (1990).

  19. 19.

    et al. Tum- antigens, TSTA, and T cell immune surveillance. Ann. NY Acad. Sci. 636, 43–51 (1991).

  20. 20.

    , , & A unique tumor antigen produced by a single amino acid substitution. Immunity 2, 45–59 (1995).

  21. 21.

    et al. The immunodominant antigen of an ultraviolet-induced regressor tumor is generated by a somatic point mutation in the DEAD box helicase p68. J. Exp. Med. 185, 695–705 (1997).

  22. 22.

    et al. Point mutation in essential genes with loss or mutation of the second allele: relevance to the retention of tumor-specific antigens. J. Exp. Med. 194, 285–300 (2001).

  23. 23.

    et al. Cancer exome analysis reveals a T-cell-dependent mechanism of cancer immunoediting. Nature 482, 400–404 (2012).

  24. 24.

    et al. Exploiting the mutanome for tumor vaccination. Cancer Res. 72, 1081–1091 (2012).

  25. 25.

    et al. Mutant MHC class II epitopes drive therapeutic immune responses to cancer. Nature 520, 692–696 (2015).

  26. 26.

    et al. Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens. Nature 515, 577–581 (2014).

  27. 27.

    et al. Predicting immunogenic tumour mutations by combining mass spectrometry and exome sequencing. Nature 515, 572–576 (2014).

  28. 28.

    et al. Nivolumab for metastatic renal cell carcinoma: results of a randomized phase II trial. J. Clin. Oncol. 33, 1430–1437 (2015).

  29. 29.

    et al. Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. N. Engl. J. Med. 373, 1803–1813 (2015).

  30. 30.

    et al. PD-1 blockade with Pembrolizumab in advanced Merkel-cell carcinoma. N. Engl. J. Med. 374, 2542–2552 (2016).

  31. 31.

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

  32. 32.

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

  33. 33.

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

  34. 34.

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

  35. 35.

    et al. Genomic and transcriptomic features of response to anti-PD-1 therapy in metastatic melanoma. Cell 165, 35–44 (2016).

  36. 36.

    et al. Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial. Lancet Oncol. 16, 257–265 (2015).

  37. 37.

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

  38. 38.

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

  39. 39.

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

  40. 40.

    et al. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science 351, 1463–1469 (2016).

  41. 41.

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

  42. 42.

    et al. Randomized, prospective evaluation comparing intensity of lymphodepletion before adoptive transfer of tumor-infiltrating lymphocytes for patients with metastatic melanoma. J. Clin. Oncol. 34, 2389–2397 (2016).

  43. 43.

    et al. A mutated β-catenin gene encodes a melanoma-specific antigen recognized by tumor infiltrating lymphocytes. J. Exp. Med. 183, 1185–1192 (1996).

  44. 44.

    et al. T cells associated with tumor regression recognize frameshifted products of the CDKN2A tumor suppressor gene locus and a mutated HLA class I gene product. J. Immunol. 172, 6057–6064 (2004).

  45. 45.

    , , & 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).

  46. 46.

    et al. Mutated PPP1R3B is recognized by T cells used to treat a melanoma patient who experienced a durable complete tumor regression. J. Immunol. 190, 6034–6042 (2013).

  47. 47.

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

  48. 48.

    et al. Durable complete response from metastatic melanoma after transfer of autologous T cells recognizing 10 mutated tumor antigens. Cancer Immunol. Res. 4, 669–678 (2016).

  49. 49.

    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).

  50. 50.

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

  51. 51.

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

  52. 52.

    et al. Use of HLA peptidomics and whole exome sequencing to identify human immunogenic neo-antigens. Oncotarget 7, 5110–5117 (2016).

  53. 53.

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

  54. 54.

    et al. Prospective identification of neoantigen-specific lymphocytes in the peripheral blood of melanoma patients. Nat. Med. 22, 433–438 (2016).

  55. 55.

    et al. Isolation of T cell receptors reactive with tumor neoantigens from tumor infiltrating lymphocytes based on CD137 expression. Clin. Cancer Res. (8 November 2016).

  56. 56.

    et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature 499, 214–218 (2013).

  57. 57.

    et al. The peptide recognized by HLA-A68.2-restricted, squamous cell carcinoma of the lung-specific cytotoxic T lymphocytes is derived from a mutated elongation factor 2 gene. Cancer Res. 58, 5144–5150 (1998).

  58. 58.

    et al. High frequency of cytolytic T lymphocytes directed against a tumor-specific mutated antigen detectable with HLA tetramers in the blood of a lung carcinoma patient with long survival. Cancer Res. 61, 3718–3724 (2001).

  59. 59.

    et al. A point mutation in the α-actinin-4 gene generates an antigenic peptide recognized by autologous cytolytic T lymphocytes on a human lung carcinoma. Cancer Res. 61, 4078–4083 (2001).

  60. 60.

    et al. A point mutation in the NFYC gene generates an antigenic peptide recognized by autologous cytolytic T lymphocytes on a human squamous cell lung carcinoma. Int. J. Cancer 118, 1992–1997 (2006).

  61. 61.

    et al. An antigen recognized by autologous CTLs on a human bladder carcinoma. J. Immunol. 160, 6188–6194 (1998).

  62. 62.

    , , , & A CASP-8 mutation recognized by cytolytic T lymphocytes on a human head and neck carcinoma. J. Exp. Med. 186, 785–793 (1997).

  63. 63.

    et al. Immunological characterization of missense mutations occurring within cytotoxic T cell-defined p53 epitopes in HLA-A*0201+ squamous cell carcinomas of the head and neck. Int. J. Cancer 120, 2618–2624 (2007).

  64. 64.

    et al. Surveillance of the tumor mutanome by T cells during progression from primary to recurrent ovarian cancer. Clin. Cancer Res. 20, 1125–1134 (2014).

  65. 65.

    , , , & Cytotoxic CD4+ and CD8+ T lymphocytes, generated by mutant p21-ras (12Val) peptide vaccination of a patient, recognize 12Val-dependent nested epitopes present within the vaccine peptide and kill autologous tumour cells carrying this mutation. Int. J. Cancer 72, 784–790 (1997).

  66. 66.

    & The immune biology of microsatellite-unstable cancer. Trends in Cancer 2, 121–133 (2016).

  67. 67.

    et al. Immunogenicity of somatic mutations in human gastrointestinal cancers. Science 350, 1387–1390 (2015).

  68. 68.

    et al. T-cell transfer therapy targeting mutated KRAS in cancer. N. Engl. J. Med. 375, 2255–2262 (2016).

  69. 69.

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

  70. 70.

    , & Paths to stemness: building the ultimate antitumour T cell. Nat. Rev. Cancer 12, 671–684 (2012).

  71. 71.

    et al. Akt inhibition enhances expansion of potent tumor-specific lymphocytes with memory cell characteristics. Cancer Res. 75, 296–305 (2015).

  72. 72.

    et al. Protein kinase B controls transcriptional programs that direct cytotoxic T cell fate but is dispensable for T cell metabolism. Immunity 34, 224–236 (2011).

  73. 73.

    , & IL-21 influences the frequency, phenotype, and affinity of the antigen-specific CD8 T cell response. J. Immunol. 175, 2261–2269 (2005).

  74. 74.

    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).

  75. 75.

    et al. Clinical scale zinc finger nuclease-mediated gene editing of PD-1 in Tumor infiltrating lymphocytes for the treatment of metastatic melanoma. Mol. Ther. 23, 1380–1390 (2015).

  76. 76.

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

  77. 77.

    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).

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Affiliations

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

    • Eric Tran
    • , Paul F Robbins
    •  & Steven A Rosenberg

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The authors declare no competing financial interests.

Corresponding author

Correspondence to Steven A Rosenberg.

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DOI

https://doi.org/10.1038/ni.3682

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