Description

Armed oncolytic adenovirus expressing PD-L1 mini-antibody enhances the anti-tumor effect of chimeric antigen receptor T-cells against solid tumors

Rosewell Shaw, Amanda^1,2, Tanoue, Kiyonori^1,2, Watanabe, Norihiro^1,2, Porter, Caroline^1,2, Gottschalk, Stephen^2,3, Brenner, Malcolm^2,3 and Suzuki, Masataka^1,2

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.