Armed Oncolytic Adenovirus-Expressing PD-L1 Mini-Body Enhances Antitumor Effects of Chimeric Antigen Receptor T Cells in Solid Tumors.

Abstract

Chimeric antigen receptor-modified T cells (CAR T cells) produce proinflammatory cytokines that increase expression of T-cell checkpoint signals such as PD-L1, which may inhibit their functionality against solid tumors. In this study, we evaluated in human tumor xenograft models the proinflammatory properties of an oncolytic adenovirus (Onc.Ad) with a helper-dependent Ad (HDAd) that expresses a PD-L1 blocking mini-antibody (mini-body; HD<i>PDL1</i>) as a strategy to enhance CAR T-cell killing. Coadministration of these agents (CAd-VEC<i>PDL1</i>) exhibited oncolytic effects with production of PD-L1 mini-body locally at the tumor site. On their own, HD<i>PDL1</i> exhibited no antitumor effect and CAd-VEC<i>PDL1</i> alone reduced tumors only to volumes comparable to Onc.Ad treatment. However, combining CAd-VEC<i>PDL1</i> with HER2.CAR T cells enhanced antitumor activity compared with treatment with either HER2.CAR T cells alone or HER2.CAR T cells plus Onc.Ad. The benefits of locally produced PD-L1 mini-body by CAd-VEC<i>PDL1</i> could not be replicated by infusion of anti-PD-L1 IgG plus HER2.CAR T cells and coadministration of Onc.Ad in an HER2⁺ prostate cancer xenograft model. Overall, our data document the superiority of local production of PD-L1 mini-body by CAd-VEC<i>PDL1</i> combined with administration of tumor-directed CAR T cells to control the growth of solid tumors. <i>Cancer Res; 77(8); 2040-51. ©2017 AACR</i>.