Abstract
Simple SummaryDeveloping new therapeutic cancer vaccines is of paramount importance to counteract tumor escape observed after conventional therapies in certain types of cancer. We have previously shown that the combination of two different vaccine platforms, targeting tumor-specific antigens, resulted in potent immune responses in preclinical models. Here, we show that the heterologous prime-boost combination with a protein vaccine and a viral vector vesicular stomatitis virus immunologically reshapes the immune-excluded TC-1 tumor model as well as the inflamed MC-38 tumor model, leading to beneficial therapeutic efficacy. Furthermore, the treatment with a multi-epitope vaccine allowed us to appreciate the various repartition among three antigen-specific cytotoxic T-cell responses combined with the viral boost. The combination leads to improved efficacy in all animals and highlights the importance of combining tumor epitopes. Our vaccine strategy could be further extended to prophylactic cancer vaccines and beyond, for infectious diseases.Heterologous prime-boost settings with a protein vaccine and the viral vector vesicular stomatitis virus, both expressing tumor-associated antigens (KISIMA-TAA and VSV-GP-TAA), have been previously shown to generate potent antitumor immunity. In the cold TC-1 model (HPV antigen) and the immune-infiltrate MC-38 model (Adpgk, Reps1 and Rpl18 neo-antigens), we further investigated pivotal immune cells that educate CD8+ T cells. Heterologous prime-boost vaccination induced a superior antitumor response characterized by the increase in number and functionality of antigen-specific CD8+ T cells, recruitment of cross-presenting dendritic cells, and polarization of CD4+ T cells towards an antitumor Th1 phenotype within the tumor and tumor-draining lymph nodes, turning the cold TC-1 tumor into a hot, inflamed tumor. In the inflamed MC-38 tumor model, treatment combination markedly prolonged the overall survival of mice. Treatment with multi-epitope vaccines also induced high frequencies of multiple antigen specificities in the periphery and in the tumor. Prime-boost treatment reduced tumor-infiltrating regulatory CD4+ T cells whilst increasing cross-presenting dendritic cells in tumor-draining lymph nodes. In conclusion, heterologous prime-boost vaccination possesses the ability to induce a potent anti-tumor response in both immune-excluded and immune-infiltrated mouse tumor models. Additionally, this study highlights the design of a multi-epitope vaccine for cancer immunotherapy.
Highlights
The established therapeutic cancer vaccine platform, KISIMA®, was previously shown to generate protein vaccines able to induce a robust and prolonged immune response
Vaccine together with viral vector vesicular stomatitis virus (VSV)-GP (V), both expressing tumor-associated antigens, induced long-term memory formation, increased T-cell polyfunctionality and improved treatment efficacy compared to their homologous counterparts [12]
To further assess the immunological changes induced by the heterologous treatment combination, TC-1 tumor-bearing mice were primed s.c. with KISIMA-Mad25 (HPVE7 epitope) followed by an i.v. immunization boost with VSV-GP-HPV (HPV-E2-E6-E7 epitopes) (Figure 1A)
Summary
The established therapeutic cancer vaccine platform, KISIMA® , was previously shown to generate protein vaccines able to induce a robust and prolonged immune response. (ii) a multi-antigenic domain (Mad), rationally designed containing CD8 and CD4 epitopes from different tumor-specific antigens across a range of HLA restrictions and (iii) a TLR2/4 agonist peptide, which confers self-adjuvant activity to the vaccine [2]. KISIMA® -derived vaccines have been shown to address different therapeutic vaccination challenges, the combined effect of the CPP and the peptidic TLR2/4 agonist results in simultaneous antigen presentation and activation of antigen-presenting cells (APCs), leading to an efficient multi-antigenic cellular immune response for different HLA restrictions. VSV-based vaccines have shown their safety and potent immunogenicity against the Ebola virus, recently leading to their approval [9]. VSV-GP preferentially replicates in type-I Interferon (IFN)-deficient cells [10], found in various tumors [11], leading to cell lysis while virus propagation in normal tissues is suppressed by an intact antiviral IFN response
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