A novel chimeric antigen receptor against prostate stem cell antigen mediates tumor destruction in a humanized mouse model of pancreatic cancer

Daniel Abate-Daga, Kiran H. Lagisetty, Eric Tran, Zhili Zheng, Luca Gattinoni, Zhiya Yu, William R. Burns, Anne M. Miermont, Yaroslav Teper, Udo Rudloff, Nicholas P. Restifo, Steven A. Feldman, Steven A. Rosenberg, Richard A. Morgan

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)1003-1012
Number of pages10
JournalHuman gene therapy
Volume25
Issue number12
DOIs
StatePublished - Dec 1 2014

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

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