020 The combination of intratumoral delivery of inactivated modified vaccinia virus Ankara with systemic delivery of immune checkpoint blockade enhances antitumor immunity

Abstract

Preclinical and clinical studies have shown that viral-based immunotherapy has the potential to overcome resistance to immune checkpoint blockade (ICB) and to fill the unmet needs of many cancer patients. Poxviruses, such as modified vaccinia virus Ankara (MVA), have the potential as cancer immunotherapeutic agents. We recently showed that intratumoral (IT) delivery of inactivated modified vaccinia virus Ankara (iMVA) induces antitumor systemic immunity via the STING-mediated cytosolic DNA-sensing pathway and Batf3–dependent CD103+/CD8+ dendritic cells (DCs). The combination of IT iMVA and systemic delivery of ICB is highly effective in treating large established tumors and distant metastasis (Dai et al., Science Immunology, 2017). In this study, we investigated the immunological mechanisms underlying the superiority of combination therapy over monotherapy with either IT Heat-iMVA or with systemic ICB alone. Using a bilateral tumor implantation model, in which only the larger tumors were injected with IT iMVA, we found that the combination therapy with systemic ICB induced higher numbers of activated CD8+ and CD4+ T cells and higher levels of type I IFN and proinflammatory cytokines and chemkines in both injected and non-injected tumors, and more antitumor-specific memory CD8+ T cells in the spleens of mice compared with IT iMVA alone. In addition, concomitant IT iMVA and IT ICB at one ten of the dose used for systemic delivery elicited superior antitumor effects compared with IT iMVA alone. In conclusion, our results demonstrate that IT iMVA generates systemic antitumor effector and memory T cell responses via in situ vaccination, which can be augmented in the presence of ICB therapy.