Oncolytic adenovirus with MUC16-BiTE shows enhanced antitumor immune response by reversing the tumor microenvironment in PDX model of ovarian cancer

Abstract

ABSTRACT The improved survival rate of ovarian cancer (OC) is related to the action of infiltrating cytotoxic T lymphocytes (CTLs). Recently, oncolytic adenoviruses (OAds) have emerged as a key player in treating solid tumors; however, the immunosuppressive tumor microenvironment (TME) and the body-mediated antiviral immune response limit their therapeutic effect. In this study, we tested the hypothesis that bispecific T-cell engagers (BiTEs) could activate and redirect CTLs to increase the anti-tumor effect of OAds. We modified the parental OAd to express a MUC16-targeting BiTE antibody (OAd-MUC16-BiTE), which retained its oncolytic properties and replication ability in vitro. This BiTE secreted from infected tumor cells into the microenvironment binds to MUC16 on target cells and cross‐links them to CD3 on T cells, leading to activation, proliferation, and toxicity of T cells against MUC16+ tumor cells. In cell coculture assays, OAd-MUC16-BiTE–mediated oncolysis enhanced T-cell–mediated tumor cell killing and bystander effect. In ex vivo tumor cultures freshly derived from OC patients, OAd-MUC16-BiTE overcame the suppressed immune TME, achieving stronger toxicity than the parental virus. Moreover, in the cell-derived xenograft and patient-derived xenograft model, OAd-MUC16-BiTE showed stronger antitumor activity and increased the number of CTLs, compared with the parental virus. Further, we demonstrated that the OAd-MUC16-BiTE-mediated anti-tumor activity is related to the reversal of the TME and improved MHC I antigen presentation. Overall, our results show how arming OAds with BiTE can overcome limitations in oncolytic virotherapy, yielding a potent therapy that is ready for clinical assessment.