Improving the efficacy of PDL1 blockade by combination with oncolytic vaccines

Aim/Background: T-lymphocytes are at the center of anti-cancer strategies, however, their activation is not sufficient as immunosuppressive pathways limit their efficacy. Immune checkpoint inhibitors (ICIs) represented a revolutionary approach to preserve the functional state of T-cells. Nevertheless, the efficacy of ICIs relies on the presence of an undergoing immunological response. We hypothesized that the number of responders to immunotherapy would be increase by the combination of ICIs with our cancer vaccine platform PeptiCRAd. Methods: We used B16OVA melanoma bearing mice, which were treated with a SIINFEKL-targeting PeptiCRAd combined with anti-PDL1 monoclonal antibody. Results: First, we optimized the combination of the two monotherapies. In fact, by overlapping PeptiCRAd and anti-PDL1 treatment we achieved a significant increase in median survival (+40% for Combo compared to monotherapies). Concerning the functional state of TILs we found that the immune therapies would enhance the percentage of activated T-lymphocytes and reduce the amount of exhausted cells compared to placebo. As expected, while PeptiCRAd monotherapy could increase the number of antigen specific CD8 T-cells only its combination with PDL1 blockade could significantly increase the ratio between activated and exhausted Pentamer positive cells (p = 0,0058). We observed that the anatomical location deeply influenced the state of CD4 and CD8 T-lymphocytes. In fact, TIM-3 expression was increased by 2 folds on Tumor infiltrating lymphocytes (TILs) compared to splenic and lymphoid T-cells. In addition, we investigated the effect of anti-adenoviral pre-existing immunity upon the combination of oncolytic vaccines (i.e. PeptiCRAd) with PDL1 blockade. Interestingly we found that pre-immunization with oncolytic adenovirus did not reduce the efficacy of the therapy. This is an important finding since the vast majority of the population shows immunity against serotype 5 adenoviruses. Conclusions: In conclusion, our data shows that PeptiCRAd can increase the number of antigen-specific cells that can be protected by the disruption of the PDL1-PD1 axis. This ultimately results in a prolonged survival of mice and improved control of non-injected primary and secondary tumors. Legal entity responsible for the study: University of Helsinki Funding: Cancer Society of Finland, Novo-Seeds, Tekes Disclosure: S. Pesonen, T. Ranki: Employed in PeptiCRAd Oy, a biotech company owning the patent based on the PeptiCRAd oncolytic vaccine platform which is used in this research. V. Cerullo: Member of the advisory board of PeptiCRAd Oy, a biotech company owning the patent based on the PeptiCRAd oncolytic vaccine platform which is used in this research. All other authors have declared no conflicts of interest.