PSMA-specific CAR-engineered T cells eradicate disseminated prostate cancer in preclinical models.

Gaia Zuccolotto, Giulio Fracasso, Anna Merlo, Isabella Monia Montagner, Maria Rondina, Sara Bobisse, Mariangela Figini, Sara Cingarlini, Marco Colombatti, Paola Zanovello, Antonio Rosato

Index: PLoS ONE 9(10) , e109427, (2014)

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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.