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A PSMA-targeted Tri-specific Killer Engager enhances NK cell cytotoxicity against prostate cancer

细胞毒性 前列腺癌 癌症研究 免疫疗法 自然杀伤细胞 癌症免疫疗法 癌症 免疫学 化学 医学 内科学 体外 生物化学
作者
Shee Kwan Phung,Nicholas A. Zorko,Yvette Soignier,Rhett L. Waller,Madison Shackelford,Joshua T. Walker,Trygve D. Nelson,Carly Selleck,Laura E. Bendzick,Laura E. Kotz,Quinlan M. Kile,Asha J. Bozicevich,S.H. Miller,Melissa Khaw,Mihir Shetty,Peter Hinderlie,Michael Ehrhardt,Yingming Li,Xianghua Luo,Scott M. Dehm
出处
期刊:Cancer immunology research [American Association for Cancer Research]
卷期号:13 (2): 258-272 被引量:1
标识
DOI:10.1158/2326-6066.cir-24-0273
摘要

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.
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