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

Abstract

BackgroundThe 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.MethodsHere, 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.ResultsThe 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.ConclusionsThese 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.

Recombinant single-cycle influenza virus with exchangeable pseudotypes allows repeated immunization to augment anti-tumour immunity with immune checkpoint inhibitors

“…Suppression of T cell function is mediated through PD-1 signalling with its ligands PD-L1 and PD-L2 in murine ( Zhang et al, 2009 ), patient tumours ( Sato et al, 2005 ), and the successful reduction of the tumours has been achieved with checkpoint inhibitors ( Lin et al, 2015 ; Andrews et al, 2019 ; Errico, 2015 ; Tumeh et al, 2014 ; Philippou et al, 2020 ). Recently, an enhanced anti-tumour effect has been reported in adenovirus-based vaccine co-administered with immune checkpoint inhibitor ( McAuliffe et al, 2021 ). In our study, treatment with anti-PD-1 antibody showed a modest tumour reduction on its own, while the administration in combination with intramuscular delivery of NY-ESO-1 S-FLU virus displayed a synergistic effect with a drastic reduction in tumour size.…”

Viral vector‐based cancer treatment and current clinical applications

“…Adenoviral vectors are widely used for cancer vaccines and treatment. Both replication‐defective and replication‐competent adenoviral vectors can deliver tumor‐associated antigens to produce cancer vaccines, such as prostate‐specific antigen (PSA), 60,61 5T4 oncofetal antigen, 62 melanoma‐associated antigen 3 (MAGE‐A3), 63,64 HPV‐related tumor antigen E6/E7, 65,66 and carcinoembryonic antigen (CEA) 67,68 . OAdVs have been developed as promising tools for clinical application in current cancer treatment because of their tumor tropism and long duration of therapeutic gene expression.…”

Vaccine Therapy in Non-Small Cell Lung Cancer

“…Phase II clinical trials of TG4010 in combination with chemotherapy demonstrated encouraging efficacy results and no safety signals [ 38 ]. TG4010 therapy has been demonstrated to correlate with T cell responses against MUC1, and broader CD8 responses were also seen against non-targeted TAA, likely due to the induction of epitope spreading [ 62 ]. TG4010 is currently being investigated in combination with nivolumab in the second-line setting (NCT02823990).…”