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

• Published in: Cancer research (Chicago, Ill.) Ill.), 2017-04, Vol.77 (8), p.2040-2051
• Main Authors: Tanoue, Kiyonori, Rosewell Shaw, Amanda, Watanabe, Norihiro, Porter, Caroline, Rana, Bhakti, Gottschalk, Stephen, Brenner, Malcolm, Suzuki, Masataka
• Format: Article
• Language: English
• Subjects: A549 Cells; Adenoviridae; Adenoviridae - genetics; Adenoviridae - immunology; Adenoviruses; Animals; Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal - biosynthesis; Antibodies, Monoclonal - genetics; Antibodies, Monoclonal - immunology; Antigens; Antitumor activity; B7-H1 Antigen - antagonists & inhibitors; B7-H1 Antigen - immunology; Cell Line, Tumor; Chimeric antigen receptors; Cytokines; ErbB-2 protein; Female; Hep G2 Cells; Humans; Immunoglobulin G; Inflammation; Lymphocytes; Lymphocytes T; Male; Mice; Mice, Nude; Neoplasms - immunology; Neoplasms - therapy; Neoplasms - virology; Oncolysis; Oncolytic Virotherapy - methods; PD-L1 protein; Prostate cancer; Receptors, Antigen, T-Cell - immunology; Recombinant Fusion Proteins - immunology; Solid tumors; Tumors; Xenograft Model Antitumor Assays; Xenografts
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-16-1577

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 ) as a strategy to enhance CAR T-cell killing. Coadministration of these agents (CAd-VEC ) exhibited oncolytic effects with production of PD-L1 mini-body locally at the tumor site. On their own, HD exhibited no antitumor effect and CAd-VEC alone reduced tumors only to volumes comparable to Onc.Ad treatment. However, combining CAd-VEC 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 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 combined with administration of tumor-directed CAR T cells to control the growth of solid tumors. .