Armed oncolytic adenovirus-expressing PD-L1 mini-body enhances antitumor effects of Chimeric antigen receptor t cells in solid tumors

Kiyonori Tanoue, Amanda Rosewell Shaw, Norihiro Watanabe, Caroline Porter, Bhakti Rana, Stephen Gottschalk, Malcolm Brenner, Masataka Suzuki

Research output: Contribution to journalArticle

71 Scopus citations

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 tumordirected CAR T cells to control the growth of solid tumors.

Original languageEnglish (US)
Pages (from-to)2040-2051
Number of pages12
JournalCancer research
Volume77
Issue number8
DOIs
StatePublished - Apr 15 2017

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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