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

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.

The Landscape of CAR-T Cell Clinical Trials against Solid Tumors—A Comprehensive Overview

“…Furthermore, new vehicles for CARs [251,252] hold great promise for broadening the applicability. For example, the possibility of the off-the-shelf use of CAR-NK cells [253] or allogeneic CAR-T cells [254] can reduce costs for CAR-cell therapy and make it affordable for many more patients.…”

Allogeneic CAR T Cells: An Alternative to Overcome Challenges of CAR T Cell Therapy in Glioblastoma

“…In order to overcome this limitation, NK-92 CARs must be infused several times in patients, a concept that has already been proven as feasible in an anti-Her2 therapy (140)(141)(142). Furthermore, despite the fact that CAR NK-92 cells showed pre-clinical activity against several tumor targets such as CD19, EGFR, Her2, and PSMA, they still need to be validated in a clinical setting (137,143). Finally, among other population that have been explored to generate allogeneic CARs are iNKT cells (144).…”

Arming Immune Cells for Battle: A Brief Journey through the Advancements of T and NK Cell Immunotherapy

“…Furthermore, NK-92 cells must be irradiated prior to their application due to the lymphoma origin of this cell line, leading to a reduced in vivo proliferative capacity. The effect of irradiation on the cytotoxic capacity of NK-92 cells is controversially discussed [ 67 , 68 ].…”