Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Anti-PSMA CAR-Engineered NK-92 Cells: An Off-the-Shelf Cell Therapy for Prostate Cancer

Version 1 : Received: 14 May 2020 / Approved: 15 May 2020 / Online: 15 May 2020 (17:39:20 CEST)

A peer-reviewed article of this Preprint also exists.

Montagner, I.M.; Penna, A.; Fracasso, G.; Carpanese, D.; Pietà, A.D.; Barbieri, V.; Zuccolotto, G.; Rosato, A. Anti-PSMA CAR-engineered NK-92 Cells: An Off-the-shelf Cell Therapy for Prostate Cancer. Cells 2020, 9, 1382. Montagner, I.M.; Penna, A.; Fracasso, G.; Carpanese, D.; Pietà, A.D.; Barbieri, V.; Zuccolotto, G.; Rosato, A. Anti-PSMA CAR-engineered NK-92 Cells: An Off-the-shelf Cell Therapy for Prostate Cancer. Cells 2020, 9, 1382.

Journal reference: Cells 2020, 9, 1382
DOI: 10.3390/cells9061382

Abstract

Prostate cancer (PCa) has become the most common tumor among males in Europe and the USA. Adoptive immunotherapy appears as a promising strategy to control the advanced stages of the disease by specific targeting the tumor, in particular through chimeric antigen receptor T (CAR-T) cell therapy. Despite the advancements of CAR-T technology in the treatment of hematological malignancies, solid tumors still represent a challenge. To overcome current limits, other cellular effectors than T lymphocytes are under study as possible candidates for CAR-engineered cancer immunotherapy. A novel approach involves the NK-92 cell line, which mediates strong cytotoxic responses against a variety of tumor cells but has no effect on non-malignant healthy counterparts. Here, we report a therapeutic approach against PCa based on engineering of NK-92 cells with a CAR recognizing the human prostate-specific membrane antigen (PSMA), which is overexpressed in prostatic neoplastic cells. Upon CAR transduction, NK-92/CAR cells acquired high and specific lytic activity against PSMA-expressing prostate cancer cells in vitro, and also underwent degranulation and produced high levels of IFN-γ in response to antigen recognition. Lethal irradiation of the effectors, a safety measure requested for the clinical application of retargeted NK-92 cells, fully abrogated replication but did not impact on phenotype and short-term functionality. PSMA-specific recognition and antitumor activity were retained in vivo, as adoptive transfer of irradiated NK-92/CAR cells in prostate cancer-bearing mice restrained tumor growth and improved survival. Anti-PSMA CAR-modified NK-92 cells represent a universal, off-the-shelf, renewable and cost-effective product endowed with relevant potentialities as a therapeutic approach for PCa immunotherapy.

Subject Areas

cancer immunotherapy; prostate cancer; CAR; PSMA; NK-92 cell line

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