A novel chimeric antigen receptor against prostate stem cell antigen mediates tumor destruction in a humanized mouse model of pancreatic cancer.
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.
Surgery Branch, National Cancer Institute , National Institutes of Health, Bethesda, MD 20892.
Daniel
D
Abate-Daga
Kiran H
KH
Lagisetty
Eric
E
Tran
Zhili
Z
Zheng
Luca
L
Gattinoni
Zhiya
Z
Yu
William R
WR
Burns
Anne M
AM
Miermont
Yaroslav
Y
Teper
Udo
U
Rudloff
Nicholas P
NP
Restifo
Steven A
SA
Feldman
Steven A
SA
Rosenberg
Richard A
RA
Morgan
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use; D000951:Antigens, Neoplasm / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D058851:GPI-Linked Proteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D006801:Humans; D016219:Immunotherapy, Adoptive; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use*; D015398:Signal Transduction / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D058851:GPI-Linked Proteins; D009363:Neoplasm Proteins; C110843:PSCA protein, human; D011948:Receptors, Antigen, T-Cell