Abstract B07: Oncolytic adenovirus 3 coding for CD40L as an enhancer of dendritic cell therapy

Abstract

Abstract Dendritic cell (DC) therapy is considered a promising immunotherapeutic approach for treatment of advanced cancer. However, the immunosuppressive tumor microenvironment leads to DC dysfunction. Therefore, in clinical trials DC therapy has generally failed to fulfill its expectations. Oncolytic adenoviruses are well tolerated and have shown to activate antitumor immune responses. Importantly, they can convert immunosuppression locally into a proinflammatory state. To improve the proper activation of transferred DCs, we armed oncolytic adenovirus with CD40 ligand (CD40L). CD40L is known to play an important role in the regulation of immune cells through its capacity to stimulate dendritic cells that leads to the activation of cytotoxic T cells. Therefore, we generated a novel virus Ad3-hTERT-CMV-hCD40L, which is fully serotype 3 adenovirus (Ad3) for intravenous delivery. It features a human telomerase reverse transcriptase (hTERT) promoter for tumor specific replication and expresses human CD40L (hCD40L) under a cytomegalovirus (CMV) promoter for induction of antitumor efficacy. Of note, human and animal data have shown the ability of Ad3 to successfully reach tumors through the intravenous route. In syngeneic studies in an immunocompetent model, DC therapy with our murine CD40L-armed adenovirus showed significant antitumor immune response. This enhanced therapeutic effect is associated with increased tumor specific T cells and induction of T-helper type 1 immune response. This synergistic effect was further evaluated in mice humanized with human peripheral blood mononuclear cells. Treatment with hCD40L-armed adenovirus and human DCs showed 100% survival in conjunction with tumor control. To conclude, CD40L armed oncolytic adenovirus 3 improves DC therapy by favorable alteration of tumor microenvironment. These findings support clinical trials where DC therapy is enhanced with oncolytic adenovirus. Citation Format: João Manuel Santos, Akseli Hemminki, Mikko Siurala, Otto Hemminki, Riikka Havunen, Victor Cervera-Carrascon, Suvi Sorsa, Hongjie Wang, Andre Lieber, Tanja de Gruijl, Anna Kanerva, Sadia Zafar. Oncolytic adenovirus 3 coding for CD40L as an enhancer of dendritic cell therapy [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr B07.