A PSMA-Targeted Tri-Specific Killer Engager Enhances NK Cell Cytotoxicity against Prostate Cancer

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• Natural killer (NK) cell infiltration correlates with better prognosis in metastatic castration-resistant prostate cancer (mCRPC).
• NK cell-mediated cytotoxicity is crucial for tumor surveillance but can be impaired in the mCRPC tumor microenvironment.
• Enhancing NK cell function through targeted engagement and survival signals is a potential therapeutic strategy.

Purpose of the Study:

• To develop and evaluate a novel trispecific killer engager (TriKE) construct targeting prostate-specific membrane antigen (PSMA) for enhanced NK cell activity in mCRPC.
• To assess the efficacy of PSMA TriKE in promoting NK cell expansion, degranulation, and cytokine production.
• To investigate the ability of PSMA TriKE to overcome suppressive elements within the mCRPC tumor microenvironment and improve anti-tumor responses.

Main Methods:

• Design and synthesis of a PSMA-targeted TriKE construct incorporating IL15 for NK cell support.
• In vitro assessment of TriKE binding to PSMA-expressing cells and its effects on NK cell effector functions (cytotoxicity, cytokine release, proliferation).
• Evaluation of TriKE efficacy in a simulated mCRPC tumor microenvironment (hypoxia, myeloid-derived suppressor cells) and in vivo mouse models.

Main Results:

• PSMA TriKE demonstrated specific binding to PSMA-positive mCRPC cells and significantly enhanced NK cell expansion, degranulation, and cytokine production.
• TriKE treatment facilitated bystander killing of PSMA-negative tumor cells, suggesting a mechanism to counter tumor antigen escape.
• NK cells treated with PSMA TriKE maintained potent anti-tumor function even under conditions of hypoxia and in the presence of myeloid-derived suppressor cells, unlike IL15-treated NK cells.
• In vivo studies showed that PSMA TriKE improved tumor control and survival in mice compared to controls.

Conclusions:

• PSMA TriKE represents a promising therapeutic agent for advanced prostate cancer, effectively engaging NK cells against PSMA-expressing tumors.
• The TriKE construct enhances NK cell effector functions and resilience within the hostile mCRPC tumor microenvironment.
• PSMA TriKE offers a potential strategy to maximize NK cell anti-tumor potential and improve patient outcomes in mCRPC.