Abstract
BackgroundThe current challenge in developing effective cancer vaccines is the accurate prediction of epitopes that induce CD8+ cytotoxic T-cell responses. Recent technological advances have enabled development of patient-specific therapeutic vaccines. However, in these vaccines only about 10-20% of the predicted neoepitopes induced CD8+ T-cell responses in patients. To overcome this limitation, we developed PASCal for improved selection of peptides (epitopes) that induce T-cell responses. MethodsPASCal operates by 3 moduls: (1) a validated epitope database containing 108 true HLA-epitope pairs derived from 1300 tumor antigens and HLA class I and II molecules covering the HLA genotype of 26000 subjects. (2) Expression frequency-based shared tumor antigen database established for 19 indications based on>96000 tumor biopsies. (3) Algorithm for the dentification of immunogenic peptides by the selection of personal epitopes (PEPIs) binding to≥3 autologous HLA alleles. Using PASCal, personal 20mer peptide vaccines were designed for 3 HLA-genotyped cancer patients (with ovarian-, breast- and colorectal cancer). Immunogenicity of the vaccines was tested by ELISPOT and Intracellular Citokine Staining (ICS). ResultsPersonalized cancer vaccines contained PEPIs from 12 disease specific tumor-antigens most frequently expressed in the patients disease. T-cell responses were induced by 100% of peptides. An average of 11/12 PEPIs induced CD8+ T-cell responses and 12/12 induced CD4+ T-cell responses in each patient. Pre-existing antigen specific T-cell reactivities were detectable against 25% of vaccine antigens (demonstrating the expression of the target vaccine antigens by the patient’s tumor), the others were induced de novo. Both CD8+ and CD4+ T-cells were polyfunctional, as evident by secretion of multiple cytokines determined by ex vivo ICS. ConclusionsWe used the largest validated database of tumor epitopes reported to-date along with an algorithm successfully selecting immunogenic peptides to develop personalized cancer vaccines. PEPIs outperform reported immunogenicity of personalized neoantigen vaccines and induced unprecedented immune responses in cancer patients. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureE. Somogyi: Shareholder / Stockholder / Stock options: Treos Bio Ltd. Z. Csiszovszki: Shareholder / Stockholder / Stock options: Treos Bio Ltd. O. Lorincz: Shareholder / Stockholder / Stock options: Treos Bio Ltd. J. Toth: Shareholder / Stockholder / Stock options: Treos Bio Ltd. L. Molnar: Shareholder / Stockholder / Stock options: Treos Bio Ltd. W. Schönharting: Shareholder / Stockholder / Stock options: PMCR GmbH. S. Urban: Shareholder / Stockholder / Stock options: PMCR GmbH. K. Pántya: Shareholder / Stockholder / Stock options: Treos Bio Ltd. M. Megyesi: Shareholder / Stockholder / Stock options: Treos Bio Ltd. E.R. Tőke: Shareholder / Stockholder / Stock options: Treos Bio Ltd.; Leadership role: Treos Bio Zrt. All other authors have declared no conflicts of interest.
Published Version
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