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Published on: July 12, 2018
A PSMA-Targeted Tri-Specific Killer Engager Enhances NK Cell Cytotoxicity against Prostate Cancer
Shee Kwan Phung1, Nicholas A Zorko1,2, Yvette Soignier1
1Masonic Cancer Center, Minneapolis, Minnesota.
Abstract:
NK cell tumor infiltration is associated with good prognosis in patients with metastatic castration-resistant prostate cancer (mCRPC). NK cells recognize and kill targets by a process called natural cytotoxicity. We hypothesized that promoting an antigen-specific synapse with coactivation may enhance NK cell function in mCRPC. We describe a tri-specific killer engager (TriKE) construct that engages with the activating receptor CD16 on NK cells and prostate-specific membrane antigen (PSMA) on mCRPC cells and has an IL15 moiety that is essential for NK cell survival, proliferation, and priming. We show that the PSMA TriKE specifically binds to PSMA-expressing cells and significantly enhances expansion, degranulation, and cytokine production of NK cells derived from healthy donors or patients with prostate cancer. Bystander killing of PSMA-negative tumor cells was also achieved with PSMA TriKE treatment when cocultured with PSMA-positive cells, suggesting potential PSMA TriKE benefit in controlling tumor antigen escape. When tested under physiologic conditions recapitulating the mCRPC tumor microenvironment, NK cells treated with PSMA TriKE and prolonged exposure to hypoxia or myeloid-derived suppressor cells maintained their potent function whereas IL15-treated NK cells showed greatly impaired cytotoxicity. Finally, in vivo testing of PSMA TriKE showed improved tumor control and survival of mice as compared with IL15-treated and untreated control groups. In conclusion, PSMA TriKE demonstrates potential as a new therapy for advanced prostate cancer by providing additional signals to NK cells to maximize their antitumor potential in prostate cancer, especially in the setting of a hostile tumor microenvironment.
Insights
A novel trispecific killer engager (TriKE) therapy enhances natural killer (NK) cell function against prostate cancer. This approach shows promise for improving outcomes in metastatic castration-resistant prostate cancer (mCRPC) by overcoming tumor microenvironment challenges.
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.
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