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JCI Insight. 2018 Apr 5;3(7). pii: 99573. doi: 10.1172/jci.insight.99573. eCollection 2018 Apr 5.

Pancreatic cancer therapy with combined mesothelin-redirected chimeric antigen receptor T cells and cytokine-armed oncolytic adenoviruses.

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Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Parker Institute for Cancer Immunotherapy, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
The Wistar Institute, Philadelphia, Pennsylvania, USA.
Department of Immuno-Oncology, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.
Cancer Gene Therapy Group, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
TILT Biotherapeutics Ltd, Helsinki, Finland.
Helsinki University Comprehensive Cancer Center, Helsinki, Finland.
Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.


Pancreatic ductal adenocarcinoma (PDA) is characterized by its highly immunosuppressive tumor microenvironment (TME) that limits T cell infiltration and induces T cell hypofunction. Mesothelin-redirected chimeric antigen receptor T cell (meso-CAR T cell) therapy has shown some efficacy in clinical trials but antitumor efficacy remains modest. We hypothesized that combined meso-CAR T cells with an oncolytic adenovirus expressing TNF-α and IL-2 (Ad5/3-E2F-D24-TNFa-IRES-IL2, or OAd-TNFa-IL2) would improve efficacy. OAd-TNFa-IL2 enhanced the antitumor efficacy of meso-CAR T cells in human-PDA-xenograft immunodeficient mice and efficacy was associated with robustly increased tumor-infiltrating lymphocytes (TILs), enhanced and prolonged T cell function. Mice treated with parental OAd combined with meso-CAR T developed tumor metastasis to the lungs even if primary tumors were controlled. However, no mice treated with combined OAd-TNFa-IL2 and meso-CAR T died of tumor metastasis. We also evaluated this approach in a syngeneic mouse tumor model by combining adenovirus expressing murine TNF-α and IL-2 (Ad-mTNFa-mIL2) and mouse CAR T cells. This approach induced significant tumor regression in mice engrafted with highly aggressive and immunosuppressive PDA tumors. Ad-mTNFa-mIL2 increased both CAR T cell and host T cell infiltration to the tumor and altered host tumor immune status with M1 polarization of macrophages and increased dendritic cell maturation. These findings indicate that combining cytokine-armed oncolytic adenovirus to enhance the efficacy of CAR T cell therapy is a promising approach to overcome the immunosuppressive TME for the treatment of PDA.


Cancer; Cancer gene therapy; T cells; Therapeutics

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