Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All ...
  • Videos
  • Collections
    • Resource and Technical Advances
    • Clinical Medicine
    • Reviews
    • Editorials
    • Perspectives
    • Top read articles
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • In-Press Preview
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
Pancreatic cancer therapy with combined mesothelin-redirected chimeric antigen receptor T cells and cytokine-armed oncolytic adenoviruses
Keisuke Watanabe, … , Akseli Hemminki, Carl H. June
Keisuke Watanabe, … , Akseli Hemminki, Carl H. June
Published April 5, 2018
Citation Information: JCI Insight. 2018;3(7):e99573. https://doi.org/10.1172/jci.insight.99573.
View: Text | PDF
Research Article Therapeutics

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

  • Text
  • PDF
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.

Authors

Keisuke Watanabe, Yanping Luo, Tong Da, Sonia Guedan, Marco Ruella, John Scholler, Brian Keith, Regina M. Young, Boris Engels, Suvi Sorsa, Mikko Siurala, Riikka Havunen, Siri Tähtinen, Akseli Hemminki, Carl H. June

×

Figure 1

Oncolytic adenovirus (OAd) expressing TNF-α and IL-2, Ad5/3-E2F-D24-TNFa-IRES-IL2 (Ad5/3-OAd-TNFa-IL2), enhances activation, proliferation, and lytic activity of mesothelin-redirected chimeric antigen receptor T cells (meso-CAR T cells).

Options: View larger image (or click on image) Download as PowerPoint
Oncolytic adenovirus (OAd) expressing TNF-α and IL-2, Ad5/3-E2F-D24-TNFa...
(A) Kinetics of pancreatic ductal adenocarcinoma (PDA) tumor cell lysis incubated with the combination of OAd-TNFa-IL2 with meso-CAR T cells measured by the real-time xCELLigence cell analyzer. Means of cell index from triplicate wells are shown. Data are representative of 3 experiments from 3 different donors. (B) Upregulation of CD69 on T cells upon stimulation with PDA cell lines preinfected with OAds. Histograms show CD69 expression of T cells at day 3 after coculture with control media alone (unstimulated) or coculture with the indicated tumor cell lines preinfected with either control media (media), parental OAd (OAd), or OAd-TNFa-IL2 (OAd-TNFa-IL2). Data are representative of 3 experiments from 3 different donors. (C) Fold increase of percentage CD69-positive T cells from pooled data. Fold increase of percentage CD69-positive T cells by coculturing with tumor cell lines pretreated either with OAd or OAd-TNFa-IL2 relative to those by coculturing with cell lines pretreated with control media (set to 1) are shown. Means and SEM of pooled data from 3 experiments are shown. *P < 0.05, ****P < 0.0001 by 1-way ANOVA with Turkey’s post hoc test. (D) T cell proliferation upon the stimulation with tumor cell lines preinfected with OAds. Using the same coculture method as in B and C, T cell expansion was determined at day 5 by flow cytometry using counting beads. Means and SD from triplicate wells are shown. Data are representative of 4 experiments from 3 different donors. (E) Relative fold expansion of T cells upon stimulation with tumor cell lines preinfected with OAds. Fold expansion of T cells cocultured with cell lines pretreated with control media was set to 1. Means and SEM of pooled data from 4 experiments are shown. *P < 0.05 by 1-way ANOVA with Tukey’s post hoc test.

Copyright © 2022 American Society for Clinical Investigation
ISSN 2379-3708

Sign up for email alerts