title: T cells bearing a chimeric antigen receptor against prostate-specific membrane antigen mediate vascular disruption and result in tumor regression.
abstract: Aberrant blood vessels enable tumor growth, provide a barrier to immune infiltration, and serve as a source of protumorigenic signals. Targeting tumor blood vessels for destruction, or tumor vascular disruption therapy, can therefore provide significant therapeutic benefit. Here, we describe the ability of chimeric antigen receptor (CAR)-bearing T cells to recognize human prostate-specific membrane antigen (hPSMA) on endothelial targets in vitro as well as in vivo. CAR T cells were generated using the anti-PSMA scFv, J591, and the intracellular signaling domains: CD3ζ, CD28, and/or CD137/4-1BB. We found that all anti-hPSMA CAR T cells recognized and eliminated PSMA(+) endothelial targets in vitro, regardless of the signaling domain. T cells bearing the third-generation anti-hPSMA CAR, P28BBζ, were able to recognize and kill primary human endothelial cells isolated from gynecologic cancers. In addition, the P28BBζ CAR T cells mediated regression of hPSMA-expressing vascular neoplasms in mice. Finally, in murine models of ovarian cancers populated by murine vessels expressing hPSMA, the P28BBζ CAR T cells were able to ablate PSMA(+) vessels, cause secondary depletion of tumor cells, and reduce tumor burden. Taken together, these results provide a strong rationale for the use of CAR T cells as agents of tumor vascular disruption, specifically those targeting PSMA. Cancer Immunol Res; 3(1); 68-84. ©2014 AACR.
authors.affiliation: Ovarian Cancer Research Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Santoro
authors.affiliation: Ovarian Cancer Research Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Soorin
authors.initials: S
authors.lastname: Kim
authors.affiliation: Ovarian Cancer Research Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Gregory T
authors.initials: GT
authors.lastname: Motz
authors.affiliation: Ovarian Cancer Research Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Alatzoglou
authors.affiliation: Ovarian Cancer Research Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Chunsheng
authors.initials: C
authors.lastname: Li
authors.affiliation: Ludwig Center for Cancer Research at the University of Lausanne, Epalinges, Switzerland.
authors.forename: Melita
authors.initials: M
authors.lastname: Irving
authors.affiliation: Ovarian Cancer Research Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Powell
authors.affiliation: Ovarian Cancer Research Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. Ludwig Center for Cancer Research at the University of Lausanne, Epalinges, Switzerland. Department of Oncology, University Hospital of Lausanne (CHUV), Lausanne, Switzerland. george.coukos@chuv.ch.
authors.forename: George
authors.initials: G
authors.lastname: Coukos
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000276:immunology*; D002460:Cell Line; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000276:immunology*; D005260:Female; D043425:Glutamate Carboxypeptidase II / Q000276:immunology*; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D010051:Ovarian Neoplasms / Q000473:pathology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D015398:Signal Transduction; D057127:Single-Chain Antibodies / Q000276:immunology*; D014161:Transduction, Genetic; D047368:Tumor Burden; D019043:Vascular Neoplasms / Q000628:therapy*
chemical_list: D000954:Antigens, Surface; D011948:Receptors, Antigen, T-Cell; D057127:Single-Chain Antibodies; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II