Neoepitope

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Neoepitopes are a class of major histocompatibility complex (MHC) bounded peptides that arise from tumor-specific mutations.1 They represent the antigenic determinants of neoantigens. Neoepitopes are recognized by the immune system as targets for T cells and can elicit immune response to cancer.23

Description

Epitopes, also referred to as antigenic determinants, are parts of an antigen that are recognized by the immune system. A neoepitope is an epitope the immune system has not encountered before. Therefore it is not subject to tolerance mechanisms of the immune system.4 As the mutant gene product is only expressed in tumors and is not found in non-cancerous cells, neoepitopes may evoke a vigorous T cell response.5 Tumor Mutational Burden (TMB, the number of mutations within a targeted genetic region in the cancerous cell’s DNA) correlates with the number of neoepitopes, and have been suggested to correlate with patient survival post immunotherapy, although the findings about the neoantigen/immunogenicity association are disputed.6789

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Neoepitopes arise from post-translational modifications. The mRNA translates information from the DNA into polypeptide composed of 20 standard amino acids and then proteins. Several of the standard amino acids can be posttranslationally modified by enzymatic processes, or can be altered through spontaneous (nonenzymatic) biochemical reactions.10

There is increasing evidence that immune recognition of neoepitopes produced by cancer-specific mutations is a key mechanism for the induction of immune-mediated tumor rejection. Opportunities for therapeutic targeting of cancer specific neoepitopes are under investigation.11

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As target for immunotherapy

Cancer is a patient-specific disease, and no two tumors are alike. Thus, the immunogenicity of each tumor is unique.12 A novel strategy against cancer is epitope selection for mutanome-directed individualized cancer immunotherapy.4

Individualized cancer immunotherapy leverages the adaptive immune system by targeting T cells to tumor cells that have a tumor specific mutant antigen (neoantigen) with neoepitopes recognized by a receptor on T cells.13 One challenge is to identify the neoepitopes that trigger a suitable immune response, that is, to find out which neoepitopes in the individual tumor are highly immunogenic.14

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Cancer vaccines

Individualized cancer immunotherapy includes vaccination with tumor mutation-derived neoepitopes. The concept is based on a mapping of the tumor-specific individual mutanome with identification of a range of suitable neoepitopes for a patient-specific vaccine.15 It is expected that the neoepitopes in the vaccine will trigger T cell responses to the specific cancer. For the concept of individualized cancer vaccination first data are available.16171819

References

  1. ^

    Leclerc M, Mezquita L, Guillebot De Nerville G, Tihy I, Malenica I, Chouaib S, Mami-Chouaib F (2019). “Recent Advances in Lung Cancer Immunotherapy: Input of T-Cell Epitopes Associated With Impaired Peptide Processing”. Frontiers in Immunology. 10: 1505. doi:10.3389/fimmu.2019.01505. PMC 6616108. PMID 31333652.

  2. ^ Vormehr M, Diken M, Boegel S, Kreiter S, Türeci Ö, Sahin U (April 2016). “Mutanome directed cancer immunotherapy”. Current Opinion in Immunology. 39: 14–22. doi:10.1016/j.coi.2015.12.001. PMID 26716729.
  3. ^ Katsnelson A (February 2016). “Mutations as munitions: Neoantigen vaccines get a closer look as cancer treatment”. Nature Medicine. 22 (2): 122–4. doi:10.1038/nm0216-122. PMID 26845402.
  4. ^ ab Vormehr M, Türeci Ö, Sahin U (January 2019). “Harnessing Tumor Mutations for Truly Individualized Cancer Vaccines”. Annual Review of Medicine. 70: 395–407. doi:10.1146/annurev-med-042617-101816. PMID 30691374.
  5. ^ Heemskerk B, Kvistborg P, Schumacher TN (January 2013). “The cancer antigenome”. The EMBO Journal. 32 (2): 194–203. doi:10.1038/emboj.2012.333. PMC 3553384. PMID 23258224.
  6. ^ Gurjao C, Tsukrov D, Imakaev M, Luquette LJ, Mirny LA (2020-09-04). “Limited evidence of tumour mutational burden as a biomarker of response to immunotherapy”. bioRxiv: 2020.09.03.260265. doi:10.1101/2020.09.03.260265.
  7. ^ Liu D, Schilling B, Liu D, Sucker A, Livingstone E, Jerby-Arnon L, et al. (December 2019). “Integrative molecular and clinical modeling of clinical outcomes to PD1 blockade in patients with metastatic melanoma”. Nature Medicine. 25 (12): 1916–1927. doi:10.1038/s41591-019-0654-5. PMC 6898788. PMID 31792460.
  8. ^ Motzer RJ, Robbins PB, Powles T, Albiges L, Haanen JB, Larkin J, et al. (November 2020). “Avelumab plus axitinib versus sunitinib in advanced renal cell carcinoma: biomarker analysis of the phase 3 JAVELIN Renal 101 trial”. Nature Medicine. 26 (11): 1733–1741. doi:10.1038/s41591-020-1044-8. PMID 32895571.
  9. ^ Wood MA, Weeder BR, David JK, Nellore A, Thompson RF (March 2020). “Burden of tumor mutations, neoepitopes, and other variants are weak predictors of cancer immunotherapy response and overall survival”. Genome Medicine. 12 (1): 33. doi:10.1186/s13073-020-00729-2. PMC 7106909. PMID 32228719.
  10. ^ James EA, Pietropaolo M, Mamula MJ (June 2018). “Immune Recognition of β-Cells: Neoepitopes as Key Players in the Loss of Tolerance”. Diabetes. 67 (6): 1035–1042. doi:10.2337/dbi17-0030. PMC 5961411. PMID 29784651.
  11. ^ Wilson EA, Anderson KS (December 2018). “Lost in the crowd: identifying targetable MHC class I neoepitopes for cancer immunotherapy”. Expert Review of Proteomics. 15 (12): 1065–1077. doi:10.1080/14789450.2018.1545578. PMID 30408427.
  12. ^ Brennick CA, George MM, Corwin WL, Srivastava PK, Ebrahimi-Nik H (March 2017). “Neoepitopes as cancer immunotherapy targets: key challenges and opportunities”. Immunotherapy. 9 (4): 361–371. doi:10.2217/imt-2016-0146. PMID 28303769.
  13. ^ Feng YY, Griffith OL, Griffith M (August 2017). “Clinical implications of neoepitope landscapes for adult and pediatric cancers”. Genome Medicine. 9 (1): 77. doi:10.1186/s13073-017-0470-9. PMC 5577778. PMID 28854952.
  14. ^ Saini SK, Rekers N, Hadrup SR (December 2017). “Novel tools to assist neoepitope targeting in personalized cancer immunotherapy”. Annals of Oncology. 28 (suppl_12): xii3–xii10. doi:10.1093/annonc/mdx544. PMID 29092006.
  15. ^ Türeci Ö, Vormehr M, Diken M, Kreiter S, Huber C, Sahin U (April 2016). “Targeting the Heterogeneity of Cancer with Individualized Neoepitope Vaccines”. Clinical Cancer Research. 22 (8): 1885–96. doi:10.1158/1078-0432.CCR-15-1509. PMID 27084742.
  16. ^ Sahin U, Derhovanessian E, Miller M, Kloke BP, Simon P, Löwer M, et al. (July 2017). “Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer”. Nature. 547 (7662): 222–226. Bibcode:2017Natur.547..222S. doi:10.1038/nature23003. PMID 28678784.
  17. ^ Ott PA, Hu Z, Keskin DB, Shukla SA, Sun J, Bozym DJ, et al. (July 2017). “An immunogenic personal neoantigen vaccine for patients with melanoma”. Nature. 547 (7662): 217–221. Bibcode:2017Natur.547..217O. doi:10.1038/nature22991. PMC 5577644. PMID 28678778.
  18. ^ Hilf N, Kuttruff-Coqui S, Frenzel K, Bukur V, Stevanović S, Gouttefangeas C, et al. (January 2019). “Actively personalized vaccination trial for newly diagnosed glioblastoma”. Nature. 565 (7738): 240–245. doi:10.1038/s41586-018-0810-y. PMID 30568303.
  19. ^ Keskin DB, Anandappa AJ, Sun J, Tirosh I, Mathewson ND, Li S, et al. (January 2019). “Neoantigen vaccine generates intratumoral T cell responses in phase Ib glioblastoma trial”. Nature. 565 (7738): 234–239. doi:10.1038/s41586-018-0792-9. PMC 6546179. PMID 30568305.
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