Cancer vaccines used in combination with TCR-like antibody blockade of the Qa-1b/Qdm complex, the ligand for the immune checkpoint NKG2A, induce anti-tumor immunity

Abstract

Abstract Antagonizing antibodies against immune checkpoint inhibitory molecules (ICI) has gained an excellent reputation in immuno-oncology. Anti CTLA-4 and anti-PD-1 are among the first cancer checkpoint immunotherapies that got FDA approval to treat certain malignancies. However, not everyone can benefit from them due to the insufficient expression of the checkpoint marker on the surface of the tumor cells. CD94/NKG2A receptor is another inhibitory marker known to be expressed by natural killer cells and sub-population of CD8+ T cells. Specific peptides loaded by Qa-1b (mouse) or HLAE (human) on the surface of tumor cells, immune infiltrating lymphocytes, and myeloid cells are NKG2A ligand and are known to have a significant role in modulating anti-tumor effector cell responses. Our group previously developed a single-domain T-cell receptor-like antibody (EXX-1) with specificity for the Qa-1b/Qdm peptide complex, the ligand for the murine NKG2A/CD94 receptor. We have shown that treating tumor-bearing mice with EXX-1 as a single agent blocking antibody can create a modest delay in mice tumor growth and overall survival time. The presented study focused on utilizing EXX-1efficacy as a checkpoint blocking antibody in combination with a cancer vaccine. Our findings indicate that cancer vaccine effectiveness can be markedly enhanced when combined with EXX-1 antibody, leading to tumor-free survival in 35% of the mice compared to control groups. Taken together, our results indicate targeting the NKG2A axis through blocking Qa-1b/Qdm peptide complex is an effective means to treat cancer. Also, using HLAE/Qa-1b blocking antibody can improve the efficacy of the cancer vaccines and lead to better clinical outcomes when combined.