Anti-PD-1 antibody therapy potently enhances the eradication of established tumors by gene-modified T cells
Menée à l'aide d'un modèle murin, cette étude évalue l'activité antitumorale et la toxicité d'un traitement combinant un anticorps anti PD-1 et une immunothérapie adoptive à base de lymphocytes T modifiés pour exprimer un récepteur antigénique chimérique
Purpose: To determine the antitumor efficacy and toxicity of a novel combination approach involving adoptive T cell immunotherapy utilizing chimeric antigen receptor (CAR) T cells with an immunomodulatory reagent for blocking immunosuppression. Experimental Design: We examined whether administration of a PD-1 blocking antibody could increase the therapeutic activity of CAR T cells against two different Her-2+ tumors. The use of a self-antigen mouse model enabled investigation into the efficacy, mechanism and toxicity of this combination approach. Results: In this study we first demonstrated a significant increase in the level of PD-1 expressed on transduced anti-Her-2 CD8+ T cells following antigen-specific stimulation with PD-L1+ tumor cells and that markers of activation and proliferation were increased in anti-Her-2 T cells in the presence of anti-PD-1 antibody. In adoptive transfer studies in Her-2 transgenic recipient mice, we demonstrated a significant improvement in growth inhibition of two different Her-2+ tumors treated with anti-Her-2 T cells in combination with anti-PD-1 antibody. The therapeutic effects observed correlated with increased function of anti-Her-2 T cells following PD-1 blockade. Strikingly a significant decrease in the percentage of Gr1+ CD11b+ myeloid derived suppressor cells (MDSC) was observed in the tumor microenvironment of mice treated with the combination therapy. Importantly, increased anti-tumor effects were not associated with any autoimmune pathology in normal tissue expressing Her-2 antigen. Conclusion: This study demonstrates that specifically blocking PD-1 immunosuppression can potently enhance CAR T cell therapy that has significant implications for potentially improving therapeutic outcomes of this approach in cancer patients.