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Cancer Res. 2017 Apr 15;77(8):2040-2051. doi: 10.1158/0008-5472.CAN-16-1577. Epub 2017 Feb 24.

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

Author information

1
Department of Medicine, Baylor College of Medicine, Houston, Texas.
2
Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, Houston Methodist Hospital, Houston, Texas.
3
Department of Pediatrics, Baylor College of Medicine, Houston, Texas.
4
Department of Medicine, Baylor College of Medicine, Houston, Texas. suzuki@bcm.edu.

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.

PMID:
28235763
PMCID:
PMC5392365
DOI:
10.1158/0008-5472.CAN-16-1577
[Indexed for MEDLINE]
Free PMC Article

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