1932

Abstract

Cancer vaccines can generate and amplify tumor-specific T cell responses with the promise to provide long-term control of cancer. All cancer cells harbor genetic alterations encoding neoantigens that are specific to the tumor and not present in normal tissue. Similar to foreign antigens targeted by T cells in infectious disease settings, neoantigens represent the long elusive immunogens for cancer vaccination. Since the vast majority of mutations are unique to individual tumors, neoantigen vaccines require custom design for each patient. The availability of rapid and cost-effective genome sequencing, along with advanced bioinformatics tools, now allows neoantigen-target discovery and vaccine manufacturing in sufficient time for the treatment of cancer patients. Clinical trials in melanoma and glioblastoma have demonstrated the feasibility, immunogenicity, and signals of efficacy of this personalized immunotherapy approach. Key unresolved areas include identification of the most effective vaccine delivery platforms, validation and consensus of neoantigen target selection, and optimal strategies for partnering immunotherapies. Given the universal presence of mutations in cancer and the patient-tailored paradigm, personalized neoantigen vaccines have potential applicability for all cancer patients.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-cancerbio-060820-111701
2021-03-04
2024-05-06
Loading full text...

Full text loading...

/deliver/fulltext/cancerbio/5/1/annurev-cancerbio-060820-111701.html?itemId=/content/journals/10.1146/annurev-cancerbio-060820-111701&mimeType=html&fmt=ahah

Literature Cited

  1. Abelin JG, Harjanto D, Malloy M, Suri P, Colson T et al. 2019. Defining HLA-II ligand processing and binding rules with mass spectrometry enhances cancer epitope prediction. Immunity 51:766–79.e17
    [Google Scholar]
  2. Abelin JG, Keskin DB, Sarkizova S, Hartigan CR, Zhang W et al. 2017. Mass spectrometry profiling of HLA-associated peptidomes in mono-allelic cells enables more accurate epitope prediction. Immunity 46:315–26
    [Google Scholar]
  3. Adalsteinsson VA, Ha G, Freeman SS, Choudhury AD, Stover DG et al. 2017. Scalable whole-exome sequencing of cell-free DNA reveals high concordance with metastatic tumors. Nat. Commun. 8:1324
    [Google Scholar]
  4. Balachandran VP, Luksza M, Zhao JN, Makarov V, Moral JA et al. 2017. Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer. Nature 551:512–16
    [Google Scholar]
  5. Barnell EK, Ronning P, Campbell KM, Krysiak K, Ainscough BJ et al. 2019. Standard operating procedure for somatic variant refinement of sequencing data with paired tumor and normal samples. Genet. Med. 21:972–81
    [Google Scholar]
  6. Bassani-Sternberg M, Pletscher-Frankild S, Jensen LJ, Mann M 2015. Mass spectrometry of human leukocyte antigen class I peptidomes reveals strong effects of protein abundance and turnover on antigen presentation. Mol. Cell Proteom. 14:658–73
    [Google Scholar]
  7. Brown SD, Warren RL, Gibb EA, Martin SD, Spinelli JJ et al. 2014. Neo-antigens predicted by tumor genome meta-analysis correlate with increased patient survival. Genome Res 24:743–50
    [Google Scholar]
  8. Bulik-Sullivan B, Busby J, Palmer CD, Davis MJ, Murphy T et al. 2018. Deep learning using tumor HLA peptide mass spectrometry datasets improves neoantigen identification. Nat. Biotechnol. 37:55–63
    [Google Scholar]
  9. Buonaguro L, Petrizzo A, Tornesello ML, Buonaguro FM 2011. Translating tumor antigens into cancer vaccines. Clin. Vaccine Immunol. 18:23–34
    [Google Scholar]
  10. Calviello L, Ohler U. 2017. Beyond read-counts: Ribo-seq data analysis to understand the functions of the transcriptome. Trends Genet 33:728–44
    [Google Scholar]
  11. Carreno BM, Magrini V, Becker-Hapak M, Kaabinejadian S, Hundal J et al. 2015. A dendritic cell vaccine increases the breadth and diversity of melanoma neoantigen-specific T cells. Science 348:803–8
    [Google Scholar]
  12. Carter SL, Cibulskis K, Helman E, McKenna A, Shen H et al. 2012. Absolute quantification of somatic DNA alterations in human cancer. Nat. Biotechnol. 30:413–21
    [Google Scholar]
  13. Castle JC, Kreiter S, Diekmann J, Lower M, van de Roemer N et al. 2012. Exploiting the mutanome for tumor vaccination. Cancer Res 72:1081–91
    [Google Scholar]
  14. Chen YT, Scanlan MJ, Sahin U, Tureci O, Gure AO et al. 1997. A testicular antigen aberrantly expressed in human cancers detected by autologous antibody screening. PNAS 94:1914–18
    [Google Scholar]
  15. Chong C, Muller M, Pak H, Harnett D, Huber F et al. 2020. Integrated proteogenomic deep sequencing and analytics accurately identify non-canonical peptides in tumor immunopeptidomes. Nat. Commun. 11:1293
    [Google Scholar]
  16. Dadali T, Tjon E, Agnihotri P, Croshier M, Cabral C et al. 2019. ATLAS™ identifies relevant neoantigens for therapeutic anti-tumor vaccination and may serve as a biomarker for efficacy of immunotherapy of solid tumors Poster presented at 34th Annual Meeting of the Society for Immunotherapy of Cancer (SITC 2019) Washington, DC:
  17. Dagogo-Jack I, Shaw AT. 2018. Tumour heterogeneity and resistance to cancer therapies. Nat. Rev. Clin. Oncol. 15:81–94
    [Google Scholar]
  18. Dalet A, Robbins PF, Stroobant V, Vigneron N, Li YF et al. 2011. An antigenic peptide produced by reverse splicing and double asparagine deamidation. PNAS 108:E323–31
    [Google Scholar]
  19. Datta S, Malhotra L, Dickerson R, Chaffee S, Sen CK, Roy S 2015. Laser capture microdissection: big data from small samples. Histol. Histopathol. 30:1255–69
    [Google Scholar]
  20. Disis ML, Wallace DR, Gooley TA, Dang Y, Slota M et al. 2009. Concurrent trastuzumab and HER2/neu-specific vaccination in patients with metastatic breast cancer. J. Clin. Oncol. 27:4685–92
    [Google Scholar]
  21. Fennemann FL, de Vries IJM, Figdor CG, Verdoes M 2019. Attacking tumors from all sides: personalized multiplex vaccines to tackle intratumor heterogeneity. Front. Immunol. 10:824
    [Google Scholar]
  22. Frankiw L, Baltimore D, Li G 2019. Alternative mRNA splicing in cancer immunotherapy. Nat. Rev. Immunol. 19:675–87
    [Google Scholar]
  23. George S, Miao D, Demetri GD, Adeegbe D, Rodig SJ et al. 2017. Loss of PTEN is associated with resistance to anti-PD-1 checkpoint blockade therapy in metastatic uterine leiomyosarcoma. Immunity 46:197–204
    [Google Scholar]
  24. Gerlinger M, Rowan AJ, Horswell S, Math M, Larkin J et al. 2012. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N. Engl. J. Med. 366:883–92
    [Google Scholar]
  25. Godet Y, Moreau-Aubry A, Guilloux Y, Vignard V, Khammari A et al. 2008. MELOE-1 is a new antigen overexpressed in melanomas and involved in adoptive T cell transfer efficiency. J. Exp. Med. 205:2673–82
    [Google Scholar]
  26. Greaves M, Maley CC. 2012. Clonal evolution in cancer. Nature 481:306–13
    [Google Scholar]
  27. Gubin MM, Zhang X, Schuster H, Caron E, Ward JP et al. 2014. Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens. Nature 515:577–81
    [Google Scholar]
  28. Guo Y, Lei K, Tang L 2018. Neoantigen vaccine delivery for personalized anticancer immunotherapy. Front. Immunol. 9:1499
    [Google Scholar]
  29. Hanada K, Yewdell JW, Yang JC 2004. Immune recognition of a human renal cancer antigen through post-translational protein splicing. Nature 427:252–56
    [Google Scholar]
  30. Hanahan D, Weinberg RA. 2011. Hallmarks of cancer: the next generation. Cell 144:646–74
    [Google Scholar]
  31. Hilf N, Kuttruff-Coqui S, Frenzel K, Bukur V, Stevanovic S et al. 2019. Actively personalized vaccination trial for newly diagnosed glioblastoma. Nature 565:240–45
    [Google Scholar]
  32. Hu Z, Leet D, Sarkizova S, Holden R, Sun J et al. 2019. Personalized neoantigen-targeting vaccines for high-risk melanoma generate long-term memory T cell response and epitope spreading Paper presented at Fifth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference Paris, Sept 25–28
  33. Hu Z, Ott PA, Wu CJ 2018. Towards personalized, tumour-specific, therapeutic vaccines for cancer. Nat. Rev. Immunol. 18:168–82
    [Google Scholar]
  34. Ingolia NT. 2016. Ribosome footprint profiling of translation throughout the genome. Cell 165:22–33
    [Google Scholar]
  35. Jaganathan K, Kyriazopoulou Panagiotopoulou S, McRae JF, Darbandi SF, Knowles D et al. 2019. Predicting splicing from primary sequence with deep learning. Cell 176:535–48.e24
    [Google Scholar]
  36. Jiang Y, Wang Y, Brudno M 2012. PRISM: pair-read informed split-read mapping for base-pair level detection of insertion, deletion and structural variants. Bioinformatics 28:2576–83
    [Google Scholar]
  37. Joura EA, Giuliano AR, Iversen OE, Bouchard C, Mao C et al. 2015. A 9-valent HPV vaccine against infection and intraepithelial neoplasia in women. N. Engl. J. Med. 372:711–23
    [Google Scholar]
  38. Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ et al. 2010. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N. Engl. J. Med. 363:411–22
    [Google Scholar]
  39. Kenter GG, Welters MJ, Valentijn AR, Lowik MJ, Berends-van der Meer DM et al. 2008. Phase I immunotherapeutic trial with long peptides spanning the E6 and E7 sequences of high-risk human papillomavirus 16 in end-stage cervical cancer patients shows low toxicity and robust immunogenicity. Clin. Cancer Res. 14:169–77
    [Google Scholar]
  40. Kenter GG, Welters MJ, Valentijn AR, Lowik MJ, Berends-van der Meer DM et al. 2009. Vaccination against HPV-16 oncoproteins for vulvar intraepithelial neoplasia. N. Engl. J. Med. 361:1838–47
    [Google Scholar]
  41. Keskin DB, Anandappa AJ, Sun J, Tirosh I, Mathewson ND et al. 2019. Neoantigen vaccine generates intratumoral T cell responses in phase Ib glioblastoma trial. Nature 565:234–39
    [Google Scholar]
  42. Kranz LM, Diken M, Haas H, Kreiter S, Loquai C et al. 2016. Systemic RNA delivery to dendritic cells exploits antiviral defence for cancer immunotherapy. Nature 534:396–401
    [Google Scholar]
  43. Kreiter S, Vormehr M, van de Roemer N, Diken M, Lower M et al. 2015. Mutant MHC class II epitopes drive therapeutic immune responses to cancer. Nature 520:692–96
    [Google Scholar]
  44. Landau DA, Carter SL, Stojanov P, McKenna A, Stevenson K et al. 2013. Evolution and impact of subclonal mutations in chronic lymphocytic leukemia. Cell 152:714–26
    [Google Scholar]
  45. Larocca C, Schlom J. 2011. Viral vector-based therapeutic cancer vaccines. Cancer J 17:359–71
    [Google Scholar]
  46. Larsen MV, Lundegaard C, Lamberth K, Buus S, Brunak S et al. 2005. An integrative approach to CTL epitope prediction: a combined algorithm integrating MHC class I binding, TAP transport efficiency, and proteasomal cleavage predictions. Eur. J. Immunol. 35:2295–303
    [Google Scholar]
  47. Laumont CM, Vincent K, Hesnard L, Audemard E, Bonneil E et al. 2018. Noncoding regions are the main source of targetable tumor-specific antigens. Sci. Transl. Med. 10:eaau5516
    [Google Scholar]
  48. Lennerz V, Fatho M, Gentilini C, Frye RA, Lifke A et al. 2005. The response of autologous T cells to a human melanoma is dominated by mutated neoantigens. PNAS 102:16013–18
    [Google Scholar]
  49. Lu YC, Yao X, Crystal JS, Li YF, El-Gamil M et al. 2014. Efficient identification of mutated cancer antigens recognized by T cells associated with durable tumor regressions. Clin. Cancer Res. 20:3401–10
    [Google Scholar]
  50. Luksza M, Riaz N, Makarov V, Balachandran VP, Hellmann MD et al. 2017. A neoantigen fitness model predicts tumour response to checkpoint blockade immunotherapy. Nature 551:517–20
    [Google Scholar]
  51. Lundegaard C, Lamberth K, Harndahl M, Buus S, Lund O, Nielsen M 2008. 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 36:W509–12
    [Google Scholar]
  52. Luxembourg A, Hannaman D, Ellefsen B, Nakamura G, Bernard R 2006. Enhancement of immune responses to an HBV DNA vaccine by electroporation. Vaccine 24:4490–93
    [Google Scholar]
  53. Maby P, Tougeron D, Hamieh M, Mlecnik B, Kora H et al. 2015. Correlation between density of CD8+ T-cell infiltrate in microsatellite unstable colorectal cancers and frameshift mutations: a rationale for personalized immunotherapy. Cancer Res 75:3446–55
    [Google Scholar]
  54. Mandelboim O, Berke G, Fridkin M, Feldman M, Eisenstein M, Eisenbach L 1994. CTL induction by a tumour-associated antigen octapeptide derived from a murine lung carcinoma. Nature 369:67–71
    [Google Scholar]
  55. Mandelboim O, Vadai E, Fridkin M, Katz-Hillel A, Feldman M et al. 1995. Regression of established murine carcinoma metastases following vaccination with tumour-associated antigen peptides. Nat. Med. 1:1179–83
    [Google Scholar]
  56. Melief CJ, van Hall T, Arens R, Ossendorp F, van der Burg SH 2015. Therapeutic cancer vaccines. J. Clin. Investig. 125:3401–12
    [Google Scholar]
  57. Nielsen M, Andreatta M. 2016. 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
    [Google Scholar]
  58. Nielsen M, Lundegaard C, Lund O, Kesmir C 2005. The role of the proteasome in generating cytotoxic T-cell epitopes: insights obtained from improved predictions of proteasomal cleavage. Immunogenetics 57:33–41
    [Google Scholar]
  59. Obeid J, Hu Y, Slingluff CL Jr 2015. Vaccines, adjuvants, and dendritic cell activators—current status and future challenges. Semin. Oncol. 42:549–61
    [Google Scholar]
  60. Oh E, Choi YL, Kwon MJ, Kim RN, Kim YJ et al. 2015. Comparison of accuracy of whole-exome sequencing with formalin-fixed paraffin-embedded and fresh frozen tissue samples. PLOS ONE 10:e0144162
    [Google Scholar]
  61. Ott PA, Hodi FS. 2013. The B7-H1/PD-1 pathway in cancers associated with infections and inflammation: opportunities for therapeutic intervention. Chin. Clin. Oncol. 2:7
    [Google Scholar]
  62. Ott PA, Hu Z, Keskin DB, Shukla SA, Sun J et al. 2017. An immunogenic personal neoantigen vaccine for patients with melanoma. Nature 547:217–21
    [Google Scholar]
  63. Pardi N, Hogan MJ, Porter FW, Weissman D 2018. mRNA vaccines—a new era in vaccinology. Nat. Rev. Drug Discov. 17:261–79
    [Google Scholar]
  64. Porgador A, Irvine KR, Iwasaki A, Barber BH, Restifo NP, Germain RN 1998. Predominant role for directly transfected dendritic cells in antigen presentation to CD8+ T cells after gene gun immunization. J. Exp. Med. 188:1075–82
    [Google Scholar]
  65. Prickett TD, Crystal JS, Cohen CJ, Pasetto A, Parkhurst MR et al. 2016. Durable complete response from metastatic melanoma after transfer of autologous T cells recognizing 10 mutated tumor antigens. Cancer Immunol. Res. 4:669–78
    [Google Scholar]
  66. Quandt D, Dieter Zucht H, Amann A, Wulf-Goldenberg A, Borrebaeck C et al. 2017. Implementing liquid biopsies into clinical decision making for cancer immunotherapy. Oncotarget 8:48507–20
    [Google Scholar]
  67. Ratan A, Olson TL, Loughran TP Jr, Miller W 2015. Identification of indels in next-generation sequencing data. BMC Bioinform 16:42
    [Google Scholar]
  68. Rice J, Ottensmeier CH, Stevenson FK 2008. DNA vaccines: precision tools for activating effective immunity against cancer. Nat. Rev. Cancer 8:108–20
    [Google Scholar]
  69. Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V et al. 2015. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 348:124–28
    [Google Scholar]
  70. Robinson JT, Thorvaldsdottir H, Winckler W, Guttman M, Lander ES et al. 2011. Integrative genomics viewer. Nat. Biotechnol. 29:24–26
    [Google Scholar]
  71. Sahin U, Derhovanessian E, Miller M, Kloke BP, Simon P et al. 2017. Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer. Nature 547:222–26
    [Google Scholar]
  72. Sahin U, Tureci O. 2018. Personalized vaccines for cancer immunotherapy. Science 359:1355–60
    [Google Scholar]
  73. Sarkizova S, Klaeger S, Le PM, Li LW, Oliveira G et al. 2020. A large peptidome dataset improves HLA class I epitope prediction across most of the human population. Nat. Biotechnol. 38:199–209
    [Google Scholar]
  74. Saunders CT, Wong WS, Swamy S, Becq J, Murray LJ, Cheetham RK 2012. Strelka: accurate somatic small-variant calling from sequenced tumor-normal sample pairs. Bioinformatics 28:1811–17
    [Google Scholar]
  75. Schumacher T, Bunse L, Pusch S, Sahm F, Wiestler B et al. 2014. A vaccine targeting mutant IDH1 induces antitumour immunity. Nature 512:324–27
    [Google Scholar]
  76. Sensi M, Anichini A. 2006. Unique tumor antigens: evidence for immune control of genome integrity and immunogenic targets for T cell-mediated patient-specific immunotherapy. Clin. Cancer Res. 12:5023–32
    [Google Scholar]
  77. Slingluff CL Jr 2011. The present and future of peptide vaccines for cancer: single or multiple, long or short, alone or in combination. ? Cancer J 17:343–50
    [Google Scholar]
  78. Snyder A, Makarov V, Merghoub T, Yuan J, Zaretsky JM et al. 2014. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N. Engl. J. Med. 371:2189–99
    [Google Scholar]
  79. Tondini E, Arakelian T, Oosterhuis K, Camps M, van Duikeren S et al. 2019. A poly-neoantigen DNA vaccine synergizes with PD-1 blockade to induce T cell-mediated tumor control. OncoImmunology 8:1652539
    [Google Scholar]
  80. Tran E, Ahmadzadeh M, Lu YC, Gros A, Turcotte S et al. 2015. Immunogenicity of somatic mutations in human gastrointestinal cancers. Science 350:1387–90
    [Google Scholar]
  81. Tran E, Turcotte S, Gros A, Robbins PF, Lu YC et al. 2014. Cancer immunotherapy based on mutation-specific CD4+ T cells in a patient with epithelial cancer. Science 344:641–45
    [Google Scholar]
  82. Truex NL, Holden RL, Wang BY, Chen PG, Hanna S et al. 2020. Automated flow synthesis of tumor neoantigen peptides for personalized immunotherapy. Sci. Rep. 10:723
    [Google Scholar]
  83. Turajlic S, Litchfield K, Xu H, Rosenthal R, McGranahan N et al. 2017. Insertion-and-deletion-derived tumour-specific neoantigens and the immunogenic phenotype: a pan-cancer analysis. Lancet Oncol 18:1009–21
    [Google Scholar]
  84. Van Allen EM, Miao D, Schilling B, Shukla SA, Blank C et al. 2015. Genomic correlates of response to CTLA-4 blockade in metastatic melanoma. Science 350:207–11
    [Google Scholar]
  85. van Rooij N, van Buuren MM, Philips D, Velds A, Toebes M et al. 2013. Tumor exome analysis reveals neoantigen-specific T-cell reactivity in an ipilimumab-responsive melanoma. J. Clin. Oncol. 31:e439–42
    [Google Scholar]
  86. Verdegaal EM, de Miranda NF, Visser M, Harryvan T, van Buuren MM et al. 2016. Neoantigen landscape dynamics during human melanoma–T cell interactions. Nature 536:91–95
    [Google Scholar]
  87. Yadav M, Jhunjhunwala S, Phung QT, Lupardus P, Tanguay J et al. 2014. Predicting immunogenic tumour mutations by combining mass spectrometry and exome sequencing. Nature 515:572–76
    [Google Scholar]
  88. Zacharakis N, Chinnasamy H, Black M, Xu H, Lu YC et al. 2018. Immune recognition of somatic mutations leading to complete durable regression in metastatic breast cancer. Nat. Med. 24:724–30
    [Google Scholar]
/content/journals/10.1146/annurev-cancerbio-060820-111701
Loading
/content/journals/10.1146/annurev-cancerbio-060820-111701
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error