Mutation-Derived Neoantigens for Cancer Immunotherapy.

Front Immunol

Agenus Inc., Lexington, MA, United States.

Published: October 2020

AI Article Synopsis

  • Neoantigens, which are mutations present in tumors, enable T cells to identify and attack cancer cells as non-self due to their unique HLA presentation.* -
  • Immunotherapy strategies like antibody therapies and neoantigen vaccines enhance the immune response, activating T cells to target and destroy tumor cells more effectively.* -
  • Genomic profiling across various tumor types reveals differences in mutation load, such as higher mutations in basal and HER2 positive tumors compared to luminal A/B, and highlights the implications of these findings for personalized immunotherapy approaches.*

Article Abstract

Mutation-derived neoantigens distinguish tumor from normal cells. T cells can sense the HLA-presented mutations, recognize tumor cells as non-self and destroy them. Therapeutically, immunotherapy antibodies can increase the virulence of the immune system by increasing T-cell cytotoxicity targeted toward neoantigens. Neoantigen vaccines act through antigen-presenting cells, such as dendritic cells, to activate patient-endogenous T cells that recognize vaccine-encoded mutations. Infusion of mutation-targeting T cells by adoptive cell therapy (ACT) directly increases the number and frequency of cytotoxic T cells recognizing and killing tumor cells. At the same time, publicly-funded consortia have profiled tumor genomes across many indications, identifying mutations in each tumor. For example, we find basal and HER2 positive tumors contain more mutated proteins and more TP53 mutations than luminal A/B breast tumors. HPV negative tumors have more mutated proteins than HPV positive head and neck tumors and in agreement with the hypothesis that HPV activity interferes with p53 activity, only 14% of the HPV positive mutations have TP53 mutations vs. 86% of the HPV negative tumors. Lung adenocarcinomas in smokers have over four times more mutated proteins relative to those in never smokers (median 248 vs. 61, respectively). With an eye toward immunotherapy applications, we review the spectrum of mutations in multiple indications, show variations in indication sub-types, and examine intra- and inter-indication prevalence of re-occurring mutation neoantigens that could be used for warehouse vaccines and ACT.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6693295PMC
http://dx.doi.org/10.3389/fimmu.2019.01856DOI Listing

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