7PD - Oncolytic immunotherapy for enabling dendritic cell therapy

Abstract

Aim/Background: Vaccination with dendritic cells (DCs), the most potent professional antigen presenting cells in the body, is a promising approach in cancer immunotherapy. However, tumor induced immunosuppression suppresses and impairs DCs biological function and so far clinical outcomes with DC therapy have often been disappointing. Oncolytic viruses armed with immunostimulatory molecules constitute a potent form of immunotherapy. Virus replication, and the presence of virus per se, induces danger signals in the tumor, reducing immunosuppression and cellular anergy. CD40 ligand (CD40L) is best known for its capacity to activate and maturate dendritic cells. To achieve optimal activation of the transferred dendritic cells, we constructed a novel virus Ad3-hTERT-CMV-hCD40L which features human telomerase reverse transcriptase (hTERT) promoter for enhancing tumor selectivity and CD40L to increase antitumor efficacy. Moreover, the major obstacle with oncolytic adenoviruses is suboptimal systemic delivery, which is circumvented by using a fully Ad3 platform. Methods: To deeply dissect if CD40L-encoding adenovirus can modulate the tumor microenvironment, we generated a murine version of the virus (Ad5/3-CMV-mCD40L). Results: Data from human cancer patients treated in Advance Therapy Access Program indicated that this capsid allows effective transduction of distant tumors through the intravenous route. Moreover, we confirmed that virally produced CD40 was can activate human DCs ex vivo. In syngeneic studies in immunocompetent model, Ad5/3-CMV-mCD40L showed potent antitumor activity and triggered significant antitumor immune response in combination with DC therapy. The improved therapeutic effect by the adenovirus expressing CD40L and DCs combination treatment correlated with increased numbers of tumor infiltrating lymphocytes, induction of the T-helper type 1 cytokines IFN-γ, RANTES, and TNF-α and the reduction of immunosuppression in the tumor stroma. Conclusions: Our findings provide a suitable platform for clinical studies using the combination of DC vaccination and oncolytic adenovirus serotype 3 coding for CD40L. Legal entity responsible for the study: University of Helsinki Funding: TILT Biotherapeutics Ltd Disclosure: S. Parviainen, M. Siurala: Employee of TILT Biotherapeutics Ltd A. Hemminki: Shareholder in Targovax AS, Ltd, employee and shareholder in TILT Biotherapeutics Ltd. All other authors have declared no conflicts of interest.