Armed oncolytic adenovirus expressing PD-L1 mini-antibody enhances the anti-tumor effect of chimeric antigen receptor T-cells against solid tumors
Rosewell Shaw, Amanda1,2, Tanoue, Kiyonori1,2, Watanabe, Norihiro1,2, Porter, Caroline1,2, Gottschalk, Stephen2,3, Brenner, Malcolm2,3 and Suzuki, Masataka1,2
1Department of Medicine, 2Center for Cell and Gene Therapy, 3Department of Pediatrics, Baylor College of Medicine
Increased expression of T cell checkpoint ligands such as PD-L1 on cancer cells in response to pro-inflammatory cytokines produced by chimeric antigen receptor (CAR)-modified T cells (CAR T-cells) may inhibit their functionality against solid tumors. In order to convert the immune inhibitory microenvironment into a pro-inflammatory one and enhance CAR T-cell killing, we combined the pro-inflammatory properties of an oncolytic adenovirus (Onc.Ad) with a helper-dependent Ad that expresses a PD-L1 blocking mini-antibody (HDPDL1). Cancer cells infected with HDPDL1 secrete the mini-body, which functions similarly and has similar avidity to commercial anti-PD-L1 antibody in vitro. Co-administration of Onc.Ad and HDPDL1 (CAd-VECPDL1) demonstrated oncolytic effects and produced PD-L1 mini-body locally at the tumor site in a xenograft model, while HDPDL1 alone had no anti-tumor effect. , While CAd-VECPDL1 controlled tumor growth to the same extent as treatment with Onc.Ad alone, in a HER2+ cancer xenograft model combination of CAd-VECPDL1 with HER2.CAR T-cells showed enhanced anti-tumor activity. Median survival doubled to 110 days in dual-treated mice compared to either HER2.CAR T-cells alone or HER2.CAR T-cells with Onc.Ad. Moreover, the benefits of local production of PD-L1 mini-body by the CAd-VECPDL1 could not be replicated by combining infusion of anti-PD-L1 IgG with HER2.CAR T-cells even with co-administration of Onc.Ad. Hence, local production of PD-L1 mini-body by CAd-VECPDL1 has superior potency to systemic administration of the checkpoint inhibitor when it is combined with administration of tumor directed CAR T-cells to control the growth of a solid tumor. Additionally, this dual treatment system is adaptable to multiple PD-L1+ solid tumors.