An immunotherapeutic design approach an alphavirus-based immunotherapeutic vaccine, PD-1 blockade and sunitinib

摘要: Combination treatment strategies are emerging as a rational design approach for enhancing anti-tumor efficacy of cancer immunotherapeutic approaches in cancer patients. In this study, the therapeutic potential of combining a cancer vaccination strategy with an antibody targeting programmed death-ligand 1 (PD-1) and a drug decreasing the number of suppressor cells (sunitinib) was assessed in a preclinical model of cervical cancer. The vaccine is based on Semliki Forest virus (SFV) replicon particles encoding for a fusion protein of E6 and E7 from human papillomavirus type 16 (SFVeE6, 7). Firstly, we assessed whether SFVeE6, 7 altered the expression of PD-1 and PDL1 in the tumor microenvironment with or without PD-1 blockade. Analysis of the tumor microenvironment demonstrates that SFVeE6, 7 immunization results in an increase in CD8+ tumor infiltrating lymphocytes (TIL) infiltration which includes those that express PD-1. This further corresponded with an increase in programmed death-ligand 1 (PD-L1) in tumor cells. The combination of anti-PD-1 and SFVeE6, 7 led to a reduction in tumor PDL1 expression as well as PD-1+ CD8+ TIL. Unexpectedly, PD-1 blockade did not enhance the therapeutic benefit of SFVeE6, 7 with approximately 33% of mice developing larger tumors 3 weeks post tumor inoculation. Furthermore, combination with sunitinib with PD-1 blockade and SFVE6, 7 as a triple treatment regimen neither improved the antitumor effect. This study reveals that SFVeE6, 7 immunization is able to elicit potent antitumor immune responses despite the upregulation in PD-1 and PD-L1. Caution is required when optimizing …