Personalized neoantigen viro-immunotherapy platform for triple-negative breast cancer

Abstract

BackgroundTriple-negative breast cancer (TNBC) corresponds to approximately 20% of all breast tumors, with a high propensity for metastasis and a poor prognosis. Because TNBC displays a high mutational load compared with other breast cancer types, a neoantigen-based immunotherapy strategy could be effective. One major bottleneck in the development of a neoantigen-based vaccine for TNBC is the selection of the best targets, that is, tumor-specific neoantigens which are presented at the surface of tumor cells and capable of eliciting robust immune responses. In this study, we aimed to set up a platform for identification and delivery of immunogenic neoantigens in a vaccine regimen for TNBC using oncolytic vaccinia virus (VV).MethodsWe used bioinformatic tools and cell-based assays to identify immunogenic neoantigens in TNBC patients’ samples, human and murine cell lines. Immunogenicity of the neoantigens was tested in vitro (human) and ex vivo (murine) in T-cell assays. To assess the efficacy of our regimen, we used a preclinical model of TNBC where we treated tumor-bearing mice with neoantigens together with oncolytic VV and evaluated the effect on induction of neoantigen-specific CD8+T cells, tumor growth and survival.ResultsWe successfully identified immunogenic neoantigens and generated neoantigen-specific CD8+T cells capable of recognizing a human TNBC cell line expressing the mutated gene. Using a preclinical model of TNBC, we showed that our tumor-specific oncolytic VV was able to change the tumor microenvironment, attracting and maintaining mature cross-presenting CD8α+dendritic cells and effector T-cells. Moreover, when delivered in a prime/boost regimen together with oncolytic VV, long peptides encompassing neoantigens were able to induce neoantigen-specific CD8+T cells, slow tumor growth and increase survival.ConclusionsOur study provides a promising approach for the development of neoantigen-based immunotherapies for TNBC. By identifying immunogenic neoantigens and developing a delivery system through tumor-specific oncolytic VV, we have demonstrated that neoantigen-based vaccines could be effective in inducing neoantigen-specific CD8+T cells response with significant impact on tumor growth. Further studies are needed to determine the safety and efficacy of this approach in clinical trials.

New hopes for the breast cancer treatment: perspectives on the oncolytic virus therapy

“…TILs are indicative of pre-existing immunity which is essential for OV efficacy. Specifically, a robust presence of CD8+ T cells within the TME indicates a potentially favourable response ( 118 , 119 ). Important to predict a response are not only higher levels of TILs but also the spatial distribution of TILs and their functional state ( 120 ).…”

“…Such a characteristic allows its simultaneous intravenous and intratumoral injection, as well as evading neutralising antibodies ( 43 ). OVV has been recently used as a vector for personalised neoantigen immunotherapy against triple-negative breast cancer in a study assessing such a therapeutic approach ( 44 ).…”

Modulation of the tumor microenvironment and mechanism of immunotherapy-based drug resistance in breast cancer

“…However, vaccines are not equally active in all patients due to spatial mutational heterogeneity within individual tumors. Therefore, personalized neoantigen vaccines are generated and tested in clinical trials against TNBC [ 85 , 86 ].…”

Transplantable Murine Tumors in the Studies of Peptide Antitumor Vaccines

“…Then the authors immunized the mice with a pool of long peptides, an adjuvant and a PD-1 inhibitor. The experimental animals had slower tumor growth and longer survival compared to the untreated control mice or animal group receiving the adjuvant and a PD-1 inhibitor [ 35 ]. Other researchers, such as L. Li et al searched for and studied neoantigens of the E0771 cells [ 33 ].…”