Heterologous prime-boost vaccination targeting MAGE-Type antigens promotes tumor T-cell infiltration and improves checkpoint blockade therapy

Abstract

Background The clinical benefit of immune checkpoint blockade (ICB) therapy is often limited by the lack of pre-existing CD8 + T cells infiltrating the tumor. In principle, CD8 + T-cell infiltration could be promoted by therapeutic vaccination. However, this remains challenging given the paucity of vaccine platforms able to induce the strong cytotoxic CD8 + T-cell response required to reject tumors. A therapeutic cancer vaccine that induces a robust cytotoxic CD8 + T-cell response against shared tumor antigens and can be combined with ICB could improve the outcome of cancer immunotherapy. Methods Here, we developed a heterologous prime-boost vaccine based on a chimpanzee adenovirus (ChAdOx1) and a modified vaccinia Ankara (MVA) encoding MAGE-Type antigens, which are tumor-specific shared antigens expressed in different tumor types. The mouse MAGE-Type antigen P1A was used as a surrogate to study the efficacy of the vaccine in combination with ICB in murine tumor models expressing the P1A antigen. To characterize the vaccine-induced immune response, we performed flow cytometry and transcriptomic analyses. Results The ChAdOx1/MVA vaccine displayed strong immunogenicity with potent induction of CD8 + T cells. When combined with anti-Programmed Cell Death Protein 1 (PD-1), the vaccine induced superior tumor clearance and survival in murine tumor models expressing P1A compared with anti-PD-1 alone. Remarkably, ChAdOx1/MVA P1A vaccination promoted CD8 + T-cell infiltration in the tumors, and drove inflammation in the tumor microenvironment, turning â € cold' tumors into â € hot' tumors. Single-cell transcriptomic analysis of the P1A-specific CD8 + T cells revealed an expanded population of stem-like T cells in the spleen after the combination treatment as compared with vaccine alone, and a reduced PD-1 expression in the tumor CD8 + T cells. Conclusions These findings highlight the synergistic potency of ChAdOx1/MVA MAGE vaccines combined with anti-PD-1 for cancer therapy, and establish the foundation for clinical translation of this approach. A clinical trial of ChadOx1/MVA MAGE-A3/NY-ESO-1 combined with anti-PD-1 will commence shortly.