Anti-PSMA CAR-engineered NK-92 Cells: An Off-the-shelf Cell Therapy for Prostate Cancer.

Isabella Monia Montagner,Antonio Rosato,Giulio Fracasso,Vito Barbieri,Debora Carpanese,Gaia Zuccolotto,Anna Dalla Pietà,Alessandro Penna

doi:10.3390/cells9061382

Abstract

Prostate cancer (PCa) has become the most common cancer among males in Europe and the USA. Adoptive immunotherapy appears a promising strategy to control the advanced stages of the disease by specifically 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 novel 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. More importantly, the potential utility of NK-92/CAR cells to treat PCa has not yet been explored. 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.

Highlights

Remarkable therapeutic responses have been recently achieved with T cells expressing chimeric antigen receptors (CARs) to tumor antigens, especially in patients with lymphoid malignancies [1,2,3,4]. these data highlight the potentiality of immune cells to translate into powerful therapeutic agents, successes in the hematological setting have yet to find full validation in solid tumors
The availability of continuously expanding natural killer (NK) cell lines provides a potentially unlimited source of effector cells, which can be investigated for genetic engineering [5,6,7], and hold the potential for the development as standardized off-the-shelf therapeutics for adoptive cancer immunotherapy (ACT)
The use of NK-92/CAR cells in treating Prostate cancer (PCa) has not yet been investigated. In this novel approach, using a prostate-specific membrane antigen (PSMA)-specific CAR [19] to redirect NK-92 cells, we showed that genetically modified NK-92/CAR cells acquired the ability to and effectively lyse PSMA-expressing

Summary

Introduction

Remarkable therapeutic responses have been recently achieved with T cells expressing chimeric antigen receptors (CARs) to tumor antigens, especially in patients with lymphoid malignancies [1,2,3,4]. These data highlight the potentiality of immune cells to translate into powerful therapeutic agents, successes in the hematological setting have yet to find full validation in solid tumors. An increasing number of investigators believe that natural killer (NK) cells obtained from the peripheral blood of either the patient (autologous) or a healthy donor (allogeneic), might represent safer effectors for targeted cancer therapy than T cells.

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