Poly-specific neoantigen-targeted cancer vaccines delay patient derived tumor growth

Abstract

Background Personalized cancer vaccines based on neoantigens have reached the clinical trial stage in melanoma. Different vaccination protocols showed efficacy in preclinical models without a clear indication of the quality and the number of neoantigens required for an effective cancer vaccine. Methods In an effort to develop potent and efficacious neoantigen-based vaccines, we have developed different neoantigen minigene (NAM) vaccine vectors to determine the rules for a successful neoantigen cancer vaccine (NCV) delivered by plasmid DNA and electroporation. Immune responses were analyzed at the level of single neoantigen by flow cytometry and correlated with tumor growth. Adoptive T cell transfer, from HLA-2.1.1 mice, was used to demonstrate the efficacy of the NCV pipeline against human-derived tumors. Results In agreement with previous bodies of evidence, immunogenicity was driven by predicted affinity. A strong poly-functional and poly-specific immune response was observed with high affinity neoantigens. However, only a high poly-specific vaccine vector was able to completely protect mice from subsequent tumor challenge. More importantly, this pipeline - from the selection of neoantigens to vaccine design - applied to a new model of patient derived tumor xenograft resulted in therapeutic treatment. Conclusions These results suggest a feasible strategy for a neoantigen cancer vaccine that is simple and applicable for clinical developments. Electronic supplementary material The online version of this article (10.1186/s13046-019-1084-4) contains supplementary material, which is available to authorized users.

Cancer DNA vaccines: current preclinical and clinical developments and future perspectives

“…It is still not clear whether one antigen is superior to another in terms of frequency of immune response or clinical effect [133]. In one study, it has been shown that neoantigens with a predicted high affinity are more immunogenic and that a poly-specific and poly-functional DNA vaccine encoding neoantigens was the most efficient solution to prevent tumor growth in mice [134]. Further studies are needed to generalize these findings.…”

The Immunogenicity and Anti-tumor Efficacy of a Rationally Designed Neoantigen Vaccine for B16F10 Mouse Melanoma

“…Various strategies have been attempted to improve CTL responses such as nanomaterial-based as well as DNA-based vaccination. Nanomaterial vaccines promote antigen uptake and prolong the presentation time on APC (9, 10, 39), while DNA vaccines promote antigen processing and presentation (11, 40). Nevertheless, these strategies have not been successfully used for the weak neoantigens.…”

“…Tumor neoantigens are attractive targets for cancer vaccine design (6). Both preclinical (7–11) and early phase clinical studies (12–14) found that neoantigen-based poly-epitope vaccines can substantially expand the tumor-specific T cell pools, and steer the immune system to the selective destruction of cancers with limited off-target toxicities, which leads to cancer regression and long-term tumor-free survival.…”

Delivery strategies of cancer immunotherapy: recent advances and future perspectives

“…Currently, neoantigen-based vaccines are being studied as novel cancer immunotherapies because they can enhance the immune responses to tumor cells [77, 78]. Preclinical studies have shown that the neoantigen-based cancer vaccines are effective and feasible in mouse tumor models, including melanoma, colon cancer, and glioma [68, 79–82]. For example, neopeptides containing IDH1 (R132H) p123-142 mutation region were synthesized and bound to transgenic human MHC-II molecules.…”