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Advances in personalized cancer immunotherapy

  • Special Feature
  • Antitumor immunity and advances in cancer immunotherapy
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Abstract

There are currently three major approaches to T cell-based cancer immunotherapy, namely, active vaccination, adoptive cell transfer therapy and immune checkpoint blockade. Recently, this latter approach has demonstrated remarkable clinical benefits, putting cancer immunotherapy under the spotlight. Better understanding of the dynamics of anti-tumor immune responses (the “Cancer-Immunity Cycle”) is crucial for the further development of this form of treatment. Tumors employ multiple strategies to escape from anti-tumor immunity, some of which result from the selection of cancer cells with immunosuppressive activity by the process of cancer immunoediting. Apart from this selective process, anti-tumor immune responses can also be inhibited in multiple different ways which vary from patient to patient. This implies that cancer immunotherapy must be personalized to (1) identify the rate-limiting steps in any given patient, (2) identify and combine strategies to overcome these hurdles, and (3) proceed with the next round of the “Cancer-Immunity Cycle”. Cancer cells have genetic alterations which can provide the immune system with targets by which to recognize and eradicate the tumor. Mutated proteins expressed exclusively in cancer cells and recognizable by the immune system are known as neoantigens. The development of next-generation sequencing technology has made it possible to determine the genetic landscape of human cancer and facilitated the utilization of genomic information to identify such candidate neoantigens in individual cancers. Future immunotherapies will need to be personalized in terms of the identification of both patient-specific immunosuppressive mechanisms and target neoantigens.

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References

  1. Parish CR. Cancer immunotherapy: the past, the present and the future. Immunol Cell Biol. 2003;81:106–13.

    Article  CAS  PubMed  Google Scholar 

  2. Melief CJ, van Hall T, Arens R, Ossendorp F, van der Burg SH. Therapeutic cancer vaccines. J Clin Invest. 2015;125:3401–12.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Rosenberg SA, Restifo NP. Adoptive cell transfer as personalized immunotherapy for human cancer. Science. 2015;348:62–8.

    Article  CAS  PubMed  Google Scholar 

  4. Morgan RA, Dudley ME, Wunderlich JR, Hughes MS, Yang JC, Sherry RM, et al. Cancer regression in patients after transfer of genetically engineered lymphocytes. Science. 2006;314:126–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Porter DL, Levine BL, Kalos M, Bagg A, June CH. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med. 2011;365:725–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Sharma P, Allison JP. The future of immune checkpoint therapy. Science. 2015;348:56–61.

    Article  CAS  PubMed  Google Scholar 

  7. Couzin-Frankel J. Breakthrough of the year 2013. Cancer immunotherapy. Science. 2013;342:1432–3.

    Article  CAS  PubMed  Google Scholar 

  8. Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013;39:1–10.

    Article  PubMed  Google Scholar 

  9. Kroemer G, Galluzzi L, Kepp O, Zitvogel L. Immunogenic cell death in cancer therapy. Annu Rev Immunol. 2013;31:51–72.

    Article  CAS  PubMed  Google Scholar 

  10. Viaud S, Daillere R, Boneca IG, Lepage P, Langella P, Chamaillard M, et al. Gut microbiome and anticancer immune response: really hot Sh*t! Cell Death Differ. 2015;22:199–214.

    Article  CAS  PubMed  Google Scholar 

  11. Nishikawa H, Sakaguchi S. Regulatory T cells in cancer immunotherapy. Curr Opin Immunol. 2014;27:1–7.

    Article  CAS  PubMed  Google Scholar 

  12. Corbiere V, Chapiro J, Stroobant V, Ma W, Lurquin C, Lethe B, et al. Antigen spreading contributes to MAGE vaccination-induced regression of melanoma metastases. Cancer Res. 2011;71:1253–62.

    Article  CAS  PubMed  Google Scholar 

  13. Motz GT, Coukos G. Deciphering and reversing tumor immune suppression. Immunity. 2013;39:61–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science. 2011;331:1565–70.

    Article  CAS  PubMed  Google Scholar 

  15. Matsushita H, Vesely MD, Koboldt DC, Rickert CG, Uppaluri R, Magrini VJ, et al. Cancer exome analysis reveals a T-cell-dependent mechanism of cancer immunoediting. Nature. 2012;482:400–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366:2443–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Leach DR, Krummel MF, Allison JP. Enhancement of antitumor immunity by CTLA-4 blockade. Science. 1996;271:1734–6.

    Article  CAS  PubMed  Google Scholar 

  19. Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N. 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. 2002;99:12293–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Galluzzi L, Senovilla L, Zitvogel L, Kroemer G. The secret ally: immunostimulation by anticancer drugs. Nat Rev Drug Discov. 2012;11:215–33.

    Article  CAS  PubMed  Google Scholar 

  21. Schumacher TN, Schreiber RD. Neoantigens in cancer immunotherapy. Science. 2015;348:69–74.

    Article  CAS  PubMed  Google Scholar 

  22. Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SA, Behjati S, Biankin AV, et al. Signatures of mutational processes in human cancer. Nature. 2013;500:415–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Heemskerk B, Kvistborg P, Schumacher TN. The cancer antigenome. EMBO J. 2013;32:194–203.

    Article  CAS  PubMed  Google Scholar 

  24. Gilboa E. The makings of a tumor rejection antigen. Immunity. 1999;11:263–70.

    Article  CAS  PubMed  Google Scholar 

  25. Brown SD, Warren RL, Gibb EA, Martin SD, Spinelli JJ, Nelson BH, et al. Neo-antigens predicted by tumor genome meta-analysis correlate with increased patient survival. Genome Res. 2014;24:743–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Rooney MS, Shukla SA, Wu CJ, Getz G, Hacohen N. Molecular and genetic properties of tumors associated with local immune cytolytic activity. Cell. 2015;160:48–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Castle JC, Kreiter S, Diekmann J, Lower M, van de Roemer N, de Graaf J, et al. Exploiting the mutanome for tumor vaccination. Cancer Res. 2012;72:1081–91.

    Article  CAS  PubMed  Google Scholar 

  28. Gubin MM, Zhang X, Schuster H, Caron E, Ward JP, Noguchi T, et al. Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens. Nature. 2014;515:577–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. van Rooij N, van Buuren MM, Philips D, Velds A, Toebes M, Heemskerk B, et al. Tumor exome analysis reveals neoantigen-specific T-cell reactivity in an ipilimumab-responsive melanoma. J Clin Oncol. 2013;31:e439–42.

    Article  PubMed  Google Scholar 

  30. Tumeh PC, Harview CL, Yearley JH, Shintaku IP, Taylor EJ, Robert L, et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature. 2014;515:568–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Snyder A, Makarov V, Merghoub T, Yuan J, Zaretsky JM, Desrichard A, et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med. 2014;371:2189–99.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V, Havel JJ, et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015;348:124–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372:2509–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Stefansson OA, Jonasson JG, Johannsson OT, Olafsdottir K, Steinarsdottir M, Valgeirsdottir S, et al. Genomic profiling of breast tumours in relation to BRCA abnormalities and phenotypes. Breast Cancer Res. 2009;11:R47.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Robbins PF, Lu YC, El-Gamil M, Li YF, Gross C, Gartner J, et al. Mining exomic sequencing data to identify mutated antigens recognized by adoptively transferred tumor-reactive T cells. Nat Med. 2013;19:747–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Tran E, Turcotte S, Gros A, Robbins PF, Lu YC, Dudley ME, et al. Cancer immunotherapy based on mutation-specific CD4+ T cells in a patient with epithelial cancer. Science. 2014;344:641–5.

    Article  CAS  PubMed  Google Scholar 

  37. Tran E, Ahmadzadeh M, Lu YC, Gros A, Turcotte S, Robbins PF, et al. Immunogenicity of somatic mutations in human gastrointestinal cancers. Science. 2015;350:1387–90.

    Article  CAS  PubMed  Google Scholar 

  38. Kvistborg P, Shu CJ, Heemskerk B, Fankhauser M, Thrue CA, Toebes M, et al. TIL therapy broadens the tumor-reactive CD8(+) T cell compartment in melanoma patients. Oncoimmunology. 2012;1:409–18.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Gjertsen MK, Bakka A, Breivik J, Saeterdal I, Solheim BG, Soreide O, et al. Vaccination with mutant ras peptides and induction of T-cell responsiveness in pancreatic carcinoma patients carrying the corresponding RAS mutation. Lancet. 1995;346:1399–400.

    Article  CAS  PubMed  Google Scholar 

  40. Matsushita H, Enomoto Y, Kume H, Nakagawa T, Fukuhara H, Suzuki M, et al. A pilot study of autologous tumor lysate-loaded dendritic cell vaccination combined with sunitinib for metastatic renal cell carcinoma. J Immunother Cancer. 2014;2:30.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Srivastava PK. Immunotherapy of human cancer: lessons from mice. Nat Immunol. 2000;1:363–6.

    Article  CAS  PubMed  Google Scholar 

  42. Wood C, Srivastava P, Bukowski R, Lacombe L, Gorelov AI, Gorelov S, et al. An adjuvant autologous therapeutic vaccine (HSPPC-96; vitespen) versus observation alone for patients at high risk of recurrence after nephrectomy for renal cell carcinoma: a multicentre, open-label, randomised phase III trial. Lancet. 2008;372:145–54.

    Article  CAS  PubMed  Google Scholar 

  43. Bloch O, Crane CA, Fuks Y, Kaur R, Aghi MK, Berger MS, et al. Heat-shock protein peptide complex-96 vaccination for recurrent glioblastoma: a phase II, single-arm trial. Neuro Oncol. 2014;16:274–9.

    Article  CAS  PubMed  Google Scholar 

  44. van der Bruggen P, Traversari C, Chomez P, Lurquin C, De Plaen E, Van den Eynde B, et al. A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma. Science. 1991;254:1643–7.

    Article  PubMed  Google Scholar 

  45. Lennerz V, Fatho M, Gentilini C, Frye RA, Lifke A, Ferel D, et al. The response of autologous T cells to a human melanoma is dominated by mutated neoantigens. Proc Natl Acad Sci USA. 2005;102:16013–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Kawakami Y, Fujita T, Matsuzaki Y, Sakurai T, Tsukamoto M, Toda M, et al. Identification of human tumor antigens and its implications for diagnosis and treatment of cancer. Cancer Sci. 2004;95:784–91.

    Article  CAS  PubMed  Google Scholar 

  47. Nishimura Y, Tomita Y, Yuno A, Yoshitake Y, Shinohara M. Cancer immunotherapy using novel tumor-associated antigenic peptides identified by genome-wide cDNA microarray analyses. Cancer Sci. 2015;106:505–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Sjoblom T, Jones S, Wood LD, Parsons DW, Lin J, Barber TD, et al. The consensus coding sequences of human breast and colorectal cancers. Science. 2006;314:268–74.

    Article  PubMed  Google Scholar 

  49. Segal NH, Parsons DW, Peggs KS, Velculescu V, Kinzler KW, Vogelstein B, et al. Epitope landscape in breast and colorectal cancer. Cancer Res. 2008;68:889–92.

    Article  CAS  PubMed  Google Scholar 

  50. Meyerson M, Gabriel S, Getz G. Advances in understanding cancer genomes through second-generation sequencing. Nat Rev Genet. 2010;11:685–96.

    Article  CAS  PubMed  Google Scholar 

  51. Lundegaard C, Lamberth K, Harndahl M, Buus S, Lund O, Nielsen M. NetMHC-3.0: accurate web accessible predictions of human, mouse and monkey MHC class I affinities for peptides of length 8–11. Nucleic Acids Res. 2008;36:W509–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Carreno BM, Magrini V, Becker-Hapak M, Kaabinejadian S, Hundal J, Petti AA, et al. Cancer immunotherapy. A dendritic cell vaccine increases the breadth and diversity of melanoma neoantigen-specific T cells. Science. 2015;348:803–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Britten CM, Singh-Jasuja H, Flamion B, Hoos A, Huber C, Kallen KJ, et al. The regulatory landscape for actively personalized cancer immunotherapies. Nat Biotechnol. 2013;31:880–2.

    Article  CAS  PubMed  Google Scholar 

  54. De Plaen E, Lurquin C, Van Pel A, Mariame B, Szikora JP, Wolfel T, 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. 1988;85:2274–8.

    Article  PubMed  PubMed Central  Google Scholar 

  55. International Human Genome Sequencing Consortium. Finishing the euchromatic sequence of the human genome. Nature. 2004;431:931–45.

    Article  Google Scholar 

  56. Zhou J, Dudley ME, Rosenberg SA, Robbins PF. 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. 2005;28:53–62.

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

The part of this study was performed as a research program of the Project for Development of Innovative research on Cancer Therapeutics (P-Direct), Ministry of Education, Culture, Sports, Science and Technology of Japan (Kazuhiro Kakimi); this study was also supported in part by The Japanese Breast Cancer Society (Tomoharu Sugie).

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Authors and Affiliations

  1. Department of Immunotherapeutics, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-Ku, Tokyo, 113-8655, Japan

    Kazuhiro Kakimi, Takahiro Karasaki & Hirokazu Matsushita

  2. Department of Surgery, Kansai Medical University, Hirakata, Japan

    Tomoharu Sugie

Authors
  1. Kazuhiro Kakimi
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  2. Takahiro Karasaki
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  3. Hirokazu Matsushita
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  4. Tomoharu Sugie
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Correspondence to Kazuhiro Kakimi.

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Conflict of interest

Kazuhiro Kakimi received a research grant from Medinet Co. Ltd. Tomoharu Sugie received lecture fees from Astra Zeneca and Novartis Pharma. Other authors have no conflict of interest.

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Kakimi, K., Karasaki, T., Matsushita, H. et al. Advances in personalized cancer immunotherapy. Breast Cancer 24, 16–24 (2017). https://doi.org/10.1007/s12282-016-0688-1

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