Immunologic Research

, Volume 58, Issue 2–3, pp 292–299 | Cite as

Tumor antigen discovery through translation of the cancer genome

IMMUNOLOGY AT STANFORD UNIVERSITY

Abstract

Cancer cells harbor unique mutations that theoretically create corresponding unique tumor-specific antigens. This class of mutated antigens represents an attractive target for cancer immunotherapy, but their identification has been cumbersome. By combining cancer genome sequencing with computational analysis of MHC binding, it is possible to predict and rank all of the possible mutated tumor antigens. This form of antigen screen is being combined with high throughput methods to measure the immune response to each candidate mutated antigen. Using these techniques, it is possible to systematically test each mutated tumor antigens for an associated immune response. Only a small fraction of the putative mutated antigens tested in this manner have been found to elicit an immune response, yet these responses appear to be both robust and durable. It is becoming increasingly clear that these mutated tumor antigens are an important target in the antitumor response. Studies incorporating this approach promise to improve our understanding of the inherent immunogenicity of individual cancers, potentially providing an explanation for the varying clinical responses to novel immunotherapeutic agents.

Keywords

Neoantigen Antigenome Mutated antigen Immunome Cancer immunology 

Notes

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366(26):2455–65.PubMedCentralCrossRefPubMedGoogle Scholar
  2. 2.
    Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R, et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med. 2013;369(2):134–44.PubMedCentralCrossRefPubMedGoogle Scholar
  3. 3.
    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(26):2443–54.PubMedCentralCrossRefPubMedGoogle Scholar
  4. 4.
    Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013;369(2):122–33.CrossRefPubMedGoogle Scholar
  5. 5.
    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(8):711–23.PubMedCentralCrossRefPubMedGoogle Scholar
  6. 6.
    Ribas A. Tumor immunotherapy directed at PD-1. N Engl J Med. 2012;366(26):2517–9.CrossRefPubMedGoogle Scholar
  7. 7.
    Wolchok JD, Hoos A, O’Day S, Weber JS, Hamid O, Lebbe C, et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res. 2009;15(23):7412–20.CrossRefPubMedGoogle Scholar
  8. 8.
    Cheever MA, Allison JP, Ferris AS, Finn OJ, Hastings BM, Hecht TT, et al. The prioritization of cancer antigens: a national cancer institute pilot project for the acceleration of translational research. Clin Cancer Res. 2009;15(17):5323–37.CrossRefPubMedGoogle Scholar
  9. 9.
    Parmiani G, Castelli C, Dalerba P, Mortarini R, Rivoltini L, Marincola FM, et al. Cancer immunotherapy with peptide-based vaccines: what have we achieved? Where are we going? J Natl Cancer Inst. 2002;94(11):805–18.CrossRefPubMedGoogle Scholar
  10. 10.
    Rosenberg SA, Yang JC, Restifo NP. Cancer immunotherapy: moving beyond current vaccines. Nat Med. 2004;10(9):909–15.PubMedCentralCrossRefPubMedGoogle Scholar
  11. 11.
    Simpson AJ, Caballero OL, Jungbluth A, Chen YT, Old LJ. Cancer/testis antigens, gametogenesis and cancer. Nat Rev Cancer. 2005;5(8):615–25.CrossRefPubMedGoogle Scholar
  12. 12.
    Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363(5):411–22.CrossRefPubMedGoogle Scholar
  13. 13.
    Heemskerk B, Kvistborg P, Schumacher TN. The cancer antigenome. EMBO J. 2013;32(2):194–203.PubMedCentralCrossRefPubMedGoogle Scholar
  14. 14.
    Sensi M, Anichini A. Unique tumor antigens: evidence for immune control of genome integrity and immunogenic targets for T cell-mediated patient-specific immunotherapy. Clin Cancer Res. 2006;12(17):5023–32.CrossRefPubMedGoogle Scholar
  15. 15.
    Rammensee HG, Singh-Jasuja H. HLA ligandome tumor antigen discovery for personalized vaccine approach. Expert Rev Vaccines. 2013;12(10):1211–7.PubMedCentralCrossRefPubMedGoogle Scholar
  16. 16.
    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(44):16013–8.PubMedCentralCrossRefPubMedGoogle Scholar
  17. 17.
    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(4):409–18.PubMedCentralCrossRefPubMedGoogle Scholar
  18. 18.
    Gross L. Intradermal immunization of C3H mice against a sarcoma that originated in an animal of the same line. Cancer Res. 1943;3(5):326–33.Google Scholar
  19. 19.
    Foley EJ. Antigenic properties of methylcholanthrene-induced tumors in mice of the strain of origin. Cancer Res. 1953;13(12):835–7.PubMedGoogle Scholar
  20. 20.
    Lynch RG, Graff RJ, Sirisinha S, Simms ES, Eisen HN. Myeloma proteins as tumor-specific transplantation antigens. Proc Natl Acad Sci USA. 1972;69(6):1540–4.PubMedCentralCrossRefPubMedGoogle Scholar
  21. 21.
    Kwak LW, Campbell MJ, Czerwinski DK, Hart S, Miller RA, Levy R. Induction of immune responses in patients with B-cell lymphoma against the surface-immunoglobulin idiotype expressed by their tumors. N Engl J Med. 1992;327(17):1209–15.CrossRefPubMedGoogle Scholar
  22. 22.
    Freedman A, Neelapu SS, Nichols C, Robertson MJ, Djulbegovic B, Winter JN, et al. Placebo-controlled phase III trial of patient-specific immunotherapy with mitumprotimut-T and granulocyte-macrophage colony-stimulating factor after rituximab in patients with follicular lymphoma. J Clin Oncol. 2009;27(18):3036–43.PubMedCentralCrossRefPubMedGoogle Scholar
  23. 23.
    Schuster SJ, Neelapu SS, Gause BL, Janik JE, Muggia FM, Gockerman JP, et al. Vaccination with patient-specific tumor-derived antigen in first remission improves disease-free survival in follicular lymphoma. J Clin Oncol. 2011;29(20):2787–94.PubMedCentralCrossRefPubMedGoogle Scholar
  24. 24.
    Levy R, Robertson M, Ganjoo K, JP L, J V, D D, editors. Results of a Phase 3 trial evaluating safety and efficacy of specific immunotherapy, recombinant idiotype (Id) conjugated to KLH (Id-KLH) with GM-CSF, compared to non-specific immunotherapy, KLH with GM-CSF, in patients with follicular non-Hodgkin’s lymphoma (fNHL). Proceedings of the 99th Annual Meeting of the American Association for Cancer Research; 2008; San Diego, CA: AACR.Google Scholar
  25. 25.
    Lurquin C, Van Pel A, Mariamé B, De Plaen E, Szikora JP, Janssens 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. 1989;58(2):293–303.CrossRefPubMedGoogle Scholar
  26. 26.
    Wölfel T, Hauer M, Schneider J, Serrano M, Wölfel C, Klehmann-Hieb E, et al. A p16INK4a-insensitive CDK4 mutant targeted by cytolytic T lymphocytes in a human melanoma. Science. 1995;269(5228):1281–4.CrossRefPubMedGoogle Scholar
  27. 27.
    Coulie PG, Lehmann F, Lethé B, Herman J, Lurquin C, Andrawiss M, 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. 1995;92(17):7976–80.PubMedCentralCrossRefPubMedGoogle Scholar
  28. 28.
    Robbins PF, El-Gamil M, Li YF, Kawakami Y, Loftus D, Appella E, et al. A mutated beta-catenin gene encodes a melanoma-specific antigen recognized by tumor infiltrating lymphocytes. J Exp Med. 1996;183(3):1185–92.CrossRefPubMedGoogle Scholar
  29. 29.
    Lin HH, Ray S, Tongchusak S, Reinherz EL, Brusic V. Evaluation of MHC class I peptide binding prediction servers: applications for vaccine research. BMC Immunol. 2008;9:8.PubMedCentralCrossRefPubMedGoogle Scholar
  30. 30.
    Kim Y, Ponomarenko J, Zhu Z, Tamang D, Wang P, Greenbaum J, et al. Immune epitope database analysis resource. Nucleic Acids Res. 2012;40(Web Server issue):W525–30.PubMedCentralCrossRefPubMedGoogle Scholar
  31. 31.
    Lundegaard C, Lund O, Nielsen M. Accurate approximation method for prediction of class I MHC affinities for peptides of length 8, 10 and 11 using prediction tools trained on 9mers. Bioinformatics. 2008;24(11):1397–8.CrossRefPubMedGoogle Scholar
  32. 32.
    Trost B, Bickis M, Kusalik A. Strength in numbers: achieving greater accuracy in MHC-I binding prediction by combining the results from multiple prediction tools. Immunome Res. 2007;3:5.PubMedCentralCrossRefPubMedGoogle Scholar
  33. 33.
    Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA, Kinzler KW. Cancer genome landscapes. Science. 2013;339(6127):1546–58.PubMedCentralCrossRefPubMedGoogle Scholar
  34. 34.
    Kandoth C, McLellan MD, Vandin F, Ye K, Niu B, Lu C, et al. Mutational landscape and significance across 12 major cancer types. Nature. 2013;502(7471):333–9.PubMedCentralCrossRefPubMedGoogle Scholar
  35. 35.
    Lawrence MS, Stojanov P, Polak P, Kryukov GV, Cibulskis K, Sivachenko A, et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature. 2013;499(7457):214–8.PubMedCentralCrossRefPubMedGoogle Scholar
  36. 36.
    Govindan R, Ding L, Griffith M, Subramanian J, Dees ND, Kanchi KL, et al. Genomic landscape of non-small cell lung cancer in smokers and never-smokers. Cell. 2012;150(6):1121–34.PubMedCentralCrossRefPubMedGoogle Scholar
  37. 37.
    Network CGAR. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med. 2013;368(22):2059–74.CrossRefGoogle Scholar
  38. 38.
    Wei X, Walia V, Lin JC, Teer JK, Prickett TD, Gartner J, et al. Exome sequencing identifies GRIN2A as frequently mutated in melanoma. Nat Genet. 2011;43(5):442–6.PubMedCentralCrossRefPubMedGoogle Scholar
  39. 39.
    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(3):889–92.CrossRefPubMedGoogle Scholar
  40. 40.
    Khalili JS, Hanson RW, Szallasi Z. In silico prediction of tumor antigens derived from functional missense mutations of the cancer gene census. Oncoimmunology. 2012;1(8):1281–9.PubMedCentralCrossRefPubMedGoogle Scholar
  41. 41.
    Forbes SA, Bindal N, Bamford S, Cole C, Kok CY, Beare D, et al. COSMIC: mining complete cancer genomes in the Catalogue of Somatic Mutations in Cancer. Nucleic Acids Res. 2011;39(Database issue):D945–50.PubMedCentralCrossRefPubMedGoogle Scholar
  42. 42.
    Parkhurst MR, Salgaller ML, Southwood S, Robbins PF, Sette A, Rosenberg SA, et al. Improved induction of melanoma-reactive CTL with peptides from the melanoma antigen gp100 modified at HLA-A*0201-binding residues. J Immunol. 1996;157(6):2539–48.PubMedGoogle Scholar
  43. 43.
    Keogh E, Fikes J, Southwood S, Celis E, Chesnut R, Sette A. Identification of new epitopes from four different tumor-associated antigens: recognition of naturally processed epitopes correlates with HLA-A*0201-binding affinity. J Immunol. 2001;167(2):787–96.CrossRefPubMedGoogle Scholar
  44. 44.
    Engels B, Engelhard VH, Sidney J, Sette A, Binder DC, Liu RB, et al. Relapse or eradication of cancer is predicted by peptide-major histocompatibility complex affinity. Cancer Cell. 2013;23(4):516–26.PubMedCentralCrossRefPubMedGoogle Scholar
  45. 45.
    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(6):747–52.PubMedCentralCrossRefPubMedGoogle Scholar
  46. 46.
    Wang C, Krishnakumar S, Wilhelmy J, Babrzadeh F, Stepanyan L, Su LF, et al. High-throughput, high-fidelity HLA genotyping with deep sequencing. Proc Natl Acad Sci USA. 2012;109(22):8676–81.PubMedCentralCrossRefPubMedGoogle Scholar
  47. 47.
    Liu C, Yang X, Duffy B, Mohanakumar T, Mitra RD, Zody MC, et al. ATHLATES: accurate typing of human leukocyte antigen through exome sequencing. Nucleic Acids Res. 2013;41(14):e142.PubMedCentralCrossRefPubMedGoogle Scholar
  48. 48.
    Rajasagi M, Shukla S, Fritsch E, Deluca D, Getz G, Hacohen N, et al., editors. Tumor Neoantigens Are Abundant Across Cancers. New Orleans: American Society of Hematology; 2013.Google Scholar
  49. 49.
    Lu YC, Yao X, Li YF, El-Gamil M, Dudley ME, Yang JC, et al. Mutated PPP1R3B is recognized by T cells used to treat a melanoma patient who experienced a durable complete tumor regression. J Immunol. 2013;190(12):6034–42.PubMedCentralCrossRefPubMedGoogle Scholar
  50. 50.
    Altman JD, Moss PA, Goulder PJ, Barouch DH, McHeyzer-Williams MG, Bell JI, et al. Phenotypic analysis of antigen-specific T lymphocytes. Science. 1996;274(5284):94–6.CrossRefPubMedGoogle Scholar
  51. 51.
    Rodenko B, Toebes M, Hadrup SR, van Esch WJ, Molenaar AM, Schumacher TN, et al. Generation of peptide-MHC class I complexes through UV-mediated ligand exchange. Nat Protoc. 2006;1(3):1120–32.CrossRefPubMedGoogle Scholar
  52. 52.
    Hadrup SR, Bakker AH, Shu CJ, Andersen RS, van Veluw J, Hombrink P, et al. Parallel detection of antigen-specific T-cell responses by multidimensional encoding of MHC multimers. Nat Methods. 2009;6(7):520–6.CrossRefPubMedGoogle Scholar
  53. 53.
    Newell EW, Klein LO, Yu W, Davis MM. Simultaneous detection of many T-cell specificities using combinatorial tetramer staining. Nat Methods. 2009;6(7):497–9.PubMedCentralCrossRefPubMedGoogle Scholar
  54. 54.
    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(32):e439–42.CrossRefPubMedGoogle Scholar
  55. 55.
    Nielsen M, Lundegaard C, Lund O, Keşmir C. The role of the proteasome in generating cytotoxic T-cell epitopes: insights obtained from improved predictions of proteasomal cleavage. Immunogenetics. 2005;57(1–2):33–41.CrossRefPubMedGoogle Scholar
  56. 56.
    Sette A, Sidney J. HLA supertypes and supermotifs: a functional perspective on HLA polymorphism. Curr Opin Immunol. 1998;10(4):478–82.CrossRefPubMedGoogle Scholar
  57. 57.
    Rao X, Hoof I, Costa AI, van Baarle D, Kesmir C. HLA class I allele promiscuity revisited. Immunogenetics. 2011;63(11):691–701.PubMedCentralCrossRefPubMedGoogle Scholar
  58. 58.
    Fleischhauer K, Tanzarella S, Wallny HJ, Bordignon C, Traversari C. Multiple HLA-A alleles can present an immunodominant peptide of the human melanoma antigen Melan-A/MART-1 to a peptide-specific HLA-A*0201+ cytotoxic T cell line. J Immunol. 1996;157(2):787–97.PubMedGoogle Scholar
  59. 59.
    Nielsen M, Lund O, Buus S, Lundegaard C. MHC class II epitope predictive algorithms. Immunology. 2010;130(3):319–28.PubMedCentralCrossRefPubMedGoogle Scholar
  60. 60.
    Nepom GT. MHC class II tetramers. J Immunol. 2012;188(6):2477–82.PubMedCentralCrossRefPubMedGoogle Scholar
  61. 61.
    Vollers SS, Stern LJ. Class II major histocompatibility complex tetramer staining: progress, problems, and prospects. Immunology. 2008;123(3):305–13.PubMedCentralCrossRefPubMedGoogle Scholar
  62. 62.
    Kennedy R, Celis E. Multiple roles for CD4+ T cells in anti-tumor immune responses. Immunol Rev. 2008;222:129–44.CrossRefPubMedGoogle Scholar
  63. 63.
    Dunn GP, Bruce AT, Ikeda H, Old LJ, Schreiber RD. Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol. 2002;3(11):991–8.CrossRefPubMedGoogle Scholar
  64. 64.
    Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science. 2011;331(6024):1565–70.CrossRefPubMedGoogle Scholar
  65. 65.
    DuPage M, Mazumdar C, Schmidt LM, Cheung AF, Jacks T. Expression of tumour-specific antigens underlies cancer immunoediting. Nature. 2012;482(7385):405–9.PubMedCentralCrossRefPubMedGoogle Scholar
  66. 66.
    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(7385):400–4.CrossRefPubMedGoogle Scholar
  67. 67.
    Shah SP, Morin RD, Khattra J, Prentice L, Pugh T, Burleigh A, et al. Mutational evolution in a lobular breast tumour profiled at single nucleotide resolution. Nature. 2009;461(7265):809–13.CrossRefPubMedGoogle Scholar
  68. 68.
    Navin N, Kendall J, Troge J, Andrews P, Rodgers L, McIndoo J, et al. Tumour evolution inferred by single-cell sequencing. Nature. 2011;472(7341):90–4.PubMedCentralCrossRefPubMedGoogle Scholar
  69. 69.
    Gerlinger M, Rowan AJ, Horswell S, Larkin J, Endesfelder D, Gronroos E, et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med. 2012;366(10):883–92.CrossRefPubMedGoogle Scholar
  70. 70.
    Xu X, Hou Y, Yin X, Bao L, Tang A, Song L, et al. Single-cell exome sequencing reveals single-nucleotide mutation characteristics of a kidney tumor. Cell. 2012;148(5):886–95.CrossRefPubMedGoogle Scholar
  71. 71.
    Yachida S, Jones S, Bozic I, Antal T, Leary R, Fu B, et al. Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature. 2010;467(7319):1114–7.PubMedCentralCrossRefPubMedGoogle Scholar
  72. 72.
    Campbell PJ, Yachida S, Mudie LJ, Stephens PJ, Pleasance ED, Stebbings LA, et al. The patterns and dynamics of genomic instability in metastatic pancreatic cancer. Nature. 2010;467(7319):1109–13.PubMedCentralCrossRefPubMedGoogle Scholar
  73. 73.
    Wood LD, Parsons DW, Jones S, Lin J, Sjöblom T, Leary RJ, et al. The genomic landscapes of human breast and colorectal cancers. Science. 2007;318(5853):1108–13.CrossRefPubMedGoogle Scholar
  74. 74.
    Kubuschok B, Neumann F, Breit R, Sester M, Schormann C, Wagner C, et al. Naturally occurring T-cell response against mutated p21 ras oncoprotein in pancreatic cancer. Clin Cancer Res. 2006;12(4):1365–72.CrossRefPubMedGoogle Scholar
  75. 75.
    Cai A, Keskin DB, DeLuca DS, Alonso A, Zhang W, Zhang GL, et al. Mutated BCR-ABL generates immunogenic T-cell epitopes in CML patients. Clin Cancer Res. 2012;18(20):5761–72.PubMedCentralCrossRefPubMedGoogle Scholar
  76. 76.
    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(8987):1399–400.CrossRefPubMedGoogle Scholar
  77. 77.
    Pinilla-Ibarz J, Cathcart K, Korontsvit T, Soignet S, Bocchia M, Caggiano J, et al. Vaccination of patients with chronic myelogenous leukemia with bcr-abl oncogene breakpoint fusion peptides generates specific immune responses. Blood. 2000;95(5):1781–7.PubMedGoogle Scholar
  78. 78.
    Carbone DP, Ciernik IF, Kelley MJ, Smith MC, Nadaf S, Kavanaugh D, et al. Immunization with mutant p53- and K-ras-derived peptides in cancer patients: immune response and clinical outcome. J Clin Oncol. 2005;23(22):5099–107.CrossRefPubMedGoogle Scholar
  79. 79.
    Rojas JM, Knight K, Wang L, Clark RE. Clinical evaluation of BCR-ABL peptide immunisation in chronic myeloid leukaemia: results of the EPIC study. Leukemia. 2007;21(11):2287–95.CrossRefPubMedGoogle Scholar
  80. 80.
    Castle JC, Kreiter S, Diekmann J, Löwer M, van de Roemer N, de Graaf J, et al. Exploiting the mutanome for tumor vaccination. Cancer Res. 2012;72(5):1081–91.CrossRefPubMedGoogle Scholar
  81. 81.
    Warren RL, Holt RA. A census of predicted mutational epitopes suitable for immunologic cancer control. Hum Immunol. 2010;71(3):245–54.CrossRefPubMedGoogle Scholar
  82. 82.
    Zitvogel L, Tesniere A, Kroemer G. Cancer despite immunosurveillance: immunoselection and immunosubversion. Nat Rev Immunol. 2006;6(10):715–27.CrossRefPubMedGoogle Scholar
  83. 83.
    Hinrichs CS, Borman ZA, Cassard L, Gattinoni L, Spolski R, Yu Z, et al. Adoptively transferred effector cells derived from naive rather than central memory CD8+ T cells mediate superior antitumor immunity. Proc Natl Acad Sci USA. 2009;106(41):17469–74.PubMedCentralCrossRefPubMedGoogle Scholar
  84. 84.
    Ott P. A phase I study with a personalized NeoAntigen cancer vaccine in Melanoma 2013.Google Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Division of Oncology, Department of MedicineStanford UniversityStanfordUSA

Personalised recommendations