Armed oncolytic adenovirus–expressing PD-L1 mini-body enhances antitumor effects of chimeric antigen receptor T cells in solid tumors

K Tanoue, A Rosewell Shaw, N Watanabe… - Cancer …, 2017 - aacrjournals.org
K Tanoue, A Rosewell Shaw, N Watanabe, C Porter, B Rana, S Gottschalk, M Brenner
Cancer research, 2017aacrjournals.org
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 PDL1) as a strategy to enhance CAR T-cell killing. Coadministration of these agents …
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; HDPDL1) as a strategy to enhance CAR T-cell killing. Coadministration of these agents (CAd-VECPDL1) exhibited oncolytic effects with production of PD-L1 mini-body locally at the tumor site. On their own, HDPDL1 exhibited no antitumor effect and CAd-VECPDL1 alone reduced tumors only to volumes comparable to Onc.Ad treatment. However, combining CAd-VECPDL1 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-VECPDL1 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-VECPDL1 combined with administration of tumor-directed CAR T cells to control the growth of solid tumors. Cancer Res; 77(8); 2040–51. ©2017 AACR.
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