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

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.

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Publication Details

Journal
Cancer Immunology Research
Published
2024-11-15
DOI
https://doi.org/10.1158/2326-6066.cir-24-0273
Citations
8
Primary Topic
Immune Cell Function and Interaction
Type
article
Field-Weighted Citation Impact
1.92

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article

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

Xianghua Luo, Joshua T. Walker, Quinlan M. Kile, S.H. Miller et al.
8 citations
Cancer Immunology Research
Immune Cell Function and Interaction
1.92
article

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

Xianghua Luo, Joshua T. Walker, Quinlan M. Kile, S.H. Miller, Nicholas A. Zorko, Trygve D. Nelson, Carly Selleck, Jeffrey S. Miller, Yvette Soignier, Martin Felices, Mihir Shetty, Peter Hinderlie, Asha J. Bozicevich, Scott M. Dehm, Philippa R Kennedy, Melissa Khaw, Michael Ehrhardt, Laura E. Bendzick, Shee Kwan Phung, Laura E. Kotz, Yingming Li, Rhett L. Waller, Madison Shackelford, Emmanuel S. Antonarakis
article en
8 citations

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.

Cancer Immunology ResearchVol. 13(2)
University of Minnesota (US), University of Minnesota System (US), University of Minnesota Medical Center (US), Minnesota Department of Health (US), Minnesota Oncology (US)
U.S. Department of Defense, Prostate Cancer Foundation, Bristol-Myers Squibb, Pfizer, Sanofi, Celgene, University of Minnesota, Randy Shaver Cancer Research and Community Fund, MacroGenics, National Institutes of Health, Masonic Cancer Center, University of Minnesota, National Cancer Institute, DOD Prostate Cancer Research Program
Good health and well-being
Openalex Percentile: Top 13%
Immune Cell Function and Interaction
1.92
DOIOpen Access PDFOpenAlex
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