Efficacy of anti-LAG3 and anti-PD-1 combination checkpoint inhibitor therapy against head and neck squamous cell carcinoma in a genetically engineered mouse model.

Abstract

Head and neck squamous cell carcinoma (HNSCC) continues to be among the most common malignancies worldwide with limited treatment options for patients. Targeting the PD-1/PDL-1 axis is currently the only FDA approved immune checkpoint inhibitor treatment for HNSCC. Novel therapies targeting other pathways are needed along with testing a combinational approach to find new and more efficient ways to treat this disease. We utilized a tamoxifen inducible TgfβR1/Pten deletion mouse model to explore the efficacy of combined anti-LAG-3 and anti-PD-1 therapy against tongue HNSCC and determine underlying immunological mechanisms. Combined anti-LAG-3/anti-PD-1 therapy was effective at decreasing the tumor burden and lymphatic metastasis compared to anti-LAG-3 treatment but not when compared to the anti-PD-1 treatment alone. Anti-tumoral effects of anti-PD1 and anti-LAG-3/anti-PD-1 combined therapy were associated with increased CD4+ and CD8+ T-cell proliferative responses in secondary lymphoid organs along with increased CD8+ T-cell tumor infiltration. Anti-LAG-3 treatment potentiated the anti-tumoral properties of CD4+ T-cells treated with anti-PD-1, including enhanced systemic IFN-γ production and TNF-α production in the tumor microenvironment. Further, anti-tumoral cytotoxic CD8+ T-cell effector function and granzyme B production were enhanced by anti-PD-1 and combinatorial anti-LAG-3/anti-PD-1 immunotherapy, resulting in greater tumor cell death. Our results demonstrate that anti-LAG-3 has the potential to enhance the efficacy of anti-PD-1 therapy; however, humanized mouse models that better recapitulate the human disease with FDA approved antibodies are needed to further characterize the efficacy of this treatment as a viable treatment option for HNSCC patients.