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Cited by 283

The DOI matches its Crossref record; 49 of the 49 references it cites were found in a registry or an index.

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

Open access
Watanabe, Keisuke, Luo, Yanping, Da, Tong, Guedan, Sonia, Ruella, Marco, Scholler, John, Keith, Brian, Young, Regina M., Engels, Boris, Sorsa, Suvi, Siurala, Mikko, Havunen, Riikka, Tähtinen, Siri, Hemminki, Akseli, June, Carl H.·2018·JCI Insight
DOI 10.1172/jci.insight.99573
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Abstract

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.

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Metadata

Authors
Watanabe, K., Luo, Y., Da, T., Guedan, S., Ruella, M., Scholler, J., Keith, B., Young, R. M., Engels, B., Sorsa, S., Siurala, M., Havunen, R., Tähtinen, S., Hemminki, A., & June, C. H.
Venue
JCI Insight
Publisher
American Society for Clinical Investigation
Published
2018-04-05
Volume
3
Issue
7
ISSN
2379-3708 (ISSN-L)
DOI
10.1172/jci.insight.99573
OpenAlex
W2795515854
Cited by
283
References
49
FWCI
15.69
Type
journal article
Language
en
Open access
gold

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CoChat. (2026). Citation check: Pancreatic cancer therapy with combined mesothelin-redirected chimeric antigen receptor T cells and cytokine-armed oncolytic adenoviruses. https://app.cochat.ai/papers/10.1172/jci.insight.99573
The paper
Watanabe, K., Luo, Y., Da, T., Guedan, S., Ruella, M., Scholler, J., Keith, B., Young, R. M., Engels, B., Sorsa, S., Siurala, M., Havunen, R., Tähtinen, S., Hemminki, A., & June, C. H. (2018). Pancreatic cancer therapy with combined mesothelin-redirected chimeric antigen receptor T cells and cytokine-armed oncolytic adenoviruses. JCI Insight. https://doi.org/10.1172/jci.insight.99573

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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).

Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.