Research Article
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Published Online: 2 April 2014

A Novel Chimeric Antigen Receptor Against Prostate Stem Cell Antigen Mediates Tumor Destruction in a Humanized Mouse Model of Pancreatic Cancer

Publication: Human Gene Therapy
Volume 25, Issue Number 12

Abstract

Despite advances in the understanding of its molecular pathophysiology, pancreatic cancer remains largely incurable, highlighting the need for novel therapies. We developed a chimeric antigen receptor (CAR) specific for prostate stem cell antigen (PSCA), a glycoprotein that is overexpressed in pancreatic cancer starting at early stages of malignant transformation. To optimize the CAR design, we used antigen-recognition domains derived from mouse or human antibodies, and intracellular signaling domains containing one or two T cell costimulatory elements, in addition to CD3zeta. Comparing multiple constructs established that the CAR based on human monoclonal antibody Ha1-4.117 had the greatest reactivity in vitro. To further analyze this CAR, we developed a human pancreatic cancer xenograft model and adoptively transferred CAR-engineered T cells into animals with established tumors. CAR-engineered human lymphocytes induced significant antitumor activity, and unlike what has been described for other CARs, a second-generation CAR (containing CD28 cosignaling domain) induced a more potent antitumor effect than a third-generation CAR (containing CD28 and 41BB cosignaling domains). While our results provide evidence to support PSCA as a target antigen for CAR-based immunotherapy of pancreatic cancer, the expression of PSCA on selected normal tissues could be a source of limiting toxicity.

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Information & Authors

Information

Published In

cover image Human Gene Therapy
Human Gene Therapy
Volume 25Issue Number 12December 2014
Pages: 1003 - 1012
PubMed: 24694017

History

Published in print: December 2014
Published ahead of print: 5 May 2014
Published online: 2 April 2014
Accepted: 1 April 2014
Received: 2 December 2013

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    Authors

    Affiliations

    Daniel Abate-Daga*
    Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
    Kiran H. Lagisetty*
    Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
    Eric Tran
    Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
    Zhili Zheng
    Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
    Luca Gattinoni
    Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
    Zhiya Yu
    Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
    William R. Burns
    Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
    Anne M. Miermont
    Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
    Yaroslav Teper
    Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
    Udo Rudloff
    Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
    Nicholas P. Restifo
    Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
    Steven A. Feldman
    Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
    Steven A. Rosenberg
    Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
    Richard A. Morgan
    Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
    Current address: BlueBird Bio, Cambridge, MA 02141.

    Notes

    *
    These two authors contributed equally to this work.
    Address correspondence to:Dr. Daniel Abate-DagaNational Institutes of HealthBuilding 10, CRC, Room 3W-386410 Center DriveBethesda, MD 20892E-mail: [email protected]

    Author Disclosure Statement

    No competing financial interests exist.

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