Heterologous prime-boost vaccination targeting MAGE-type antigens promotes tumor T-cell infiltration and improves checkpoint blockade therapy.
(2021) Journal for immunotherapy of cancer — Vol. 9, n° 9 (2021)
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- 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. 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. 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 'cold' tumors into '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. 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.
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McAuliffe, J., Chan, H. F., Noblecourt, L., Ramirez-Valdez, R. A., Pereira-Almeida, V., Zhou, Y., Pollock, E., Cappuccini, F., Redchenko, I., Hill, A. V., Leung, C. S. K., & Van den Eynde, B. (2021). Heterologous prime-boost vaccination targeting MAGE-type antigens promotes tumor T-cell infiltration and improves checkpoint blockade therapy. Journal for immunotherapy of cancer, 9(9). https://doi.org/10.1136/jitc-2021-003218 (Original work published 2021)