A novel chimeric antigen receptor against prostate stem cell antigen mediates tumor destruction in a humanized mouse model of pancreatic cancer
Human gene therapy, 2014•liebertpub.com
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 …
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 …
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.
Mary Ann Liebert