title: PSMA-specific CAR-engineered T cells eradicate disseminated prostate cancer in preclinical models.
abstract: Immunology-based interventions have been proposed as a promising curative chance to effectively attack postoperative minimal residual disease and distant metastatic localizations of prostate tumors. We developed a chimeric antigen receptor (CAR) construct targeting the human prostate-specific membrane antigen (hPSMA), based on a novel and high affinity specific mAb. As a transfer method, we employed last-generation lentiviral vectors (LV) carrying a synthetic bidirectional promoter capable of robust and coordinated expression of the CAR molecule, and a bioluminescent reporter gene to allow the tracking of transgenic T cells after in vivo adoptive transfer. Overall, we demonstrated that CAR-expressing LV efficiently transduced short-term activated PBMC, which in turn were readily stimulated to produce cytokines and to exert a relevant cytotoxic activity by engagement with PSMA+ prostate tumor cells. Upon in vivo transfer in tumor-bearing mice, CAR-transduced T cells were capable to completely eradicate a disseminated neoplasia in the majority of treated animals, thus supporting the translation of such approach in the clinical setting.
authors.affiliation: Department of Medicine, University of Padua, Padua, Italy.
authors.forename: Gaia
authors.initials: G
authors.lastname: Zuccolotto
authors.affiliation: Department of Pathology and Diagnostics, Section of Immunology, University of Verona, Verona, Italy.
authors.forename: Giulio
authors.initials: G
authors.lastname: Fracasso
authors.affiliation: Veneto Institute of Oncology IOV - IRCCS, Padua, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Merlo
authors.affiliation: Veneto Institute of Oncology IOV - IRCCS, Padua, Italy.
authors.forename: Isabella Monia
authors.initials: IM
authors.lastname: Montagner
authors.affiliation: Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Rondina
authors.affiliation: Ludwig Center for Cancer Research, University of Lausanne, Lausanne, Switzerland.
authors.forename: Sara
authors.initials: S
authors.lastname: Bobisse
authors.affiliation: Molecular Therapies Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Mariangela
authors.initials: M
authors.lastname: Figini
authors.affiliation: Medical Oncology, Azienda Ospedaliera Universitaria Integrata (AOUI), Verona, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Cingarlini
authors.affiliation: Department of Pathology and Diagnostics, Section of Immunology, University of Verona, Verona, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Colombatti
authors.affiliation: Veneto Institute of Oncology IOV - IRCCS, Padua, Italy; Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Zanovello
authors.affiliation: Veneto Institute of Oncology IOV - IRCCS, Padua, Italy; Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Rosato
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000276:immunology*; D017209:Apoptosis; D015153:Blotting, Western; D049109:Cell Proliferation; D005434:Flow Cytometry; D005822:Genetic Vectors; D043425:Glutamate Carboxypeptidase II / Q000276:immunology*; D006801:Humans; D016219:Immunotherapy, Adoptive; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D011471:Prostatic Neoplasms / Q000276:immunology / Q000517:prevention & control* / Q000556:secondary; D015202:Protein Engineering; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000637:transplantation; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000954:Antigens, Surface; D011948:Receptors, Antigen, T-Cell; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II