Abstract
Metastatic castration-resistant prostate cancer (mCRPC) has been largely resistant to immunotherapy. Natural killer (NK) cells are cytotoxic lymphocytes that detect and kill transformed cells without prior sensitization, and their infiltration into prostate tumors corresponds with an increased overall survival among patients with mCRPC. We sought to harness this knowledge to develop an approach to NK-cell based immunotherapy for mCRPC. We engineered an NK cell line (NK-92MI) to express CD64, the sole human high-affinity IgG Fcγ receptor (FcγR1), and bound these cells with antibodies to provide interchangeable tumor-targeting elements. NK-92MICD64 cells were evaluated for cell-activation mechanisms and antibody-dependent cell-mediated cytotoxicity (ADCC). A combination of mAbs was used to target the prostate tumor antigen tumor-associated calcium signal transducer 2 (TROP2) and the cancer-associated fibroblast marker fibroblast activation protein alpha (FAP). We found that CD64, which is normally expressed by myeloid cells and associates with the adaptor molecule FcRγ, can be expressed by NK-92MI cells and mediate ADCC through an association with CD3ζ. Cytotoxicity from the combination approach was two-fold higher compared to treatment with NK-92MICD64 cells and either mAb alone, and seven-fold higher than NK-92MICD64 cells alone at an effector–target cell ratio of 20:1. The cytotoxic effect was lost when using isotype control antibodies, indicating a selective targeting mechanism. The combination approach demonstrated efficacy in vivo as well and significantly reduced tumor growth compared with the saline control. This combination therapy presents a potential approach for treating mCRPC and could improve immunotherapy response.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1270-1282 |
| Number of pages | 13 |
| Journal | Cancer Immunology Research |
| Volume | 9 |
| Issue number | 11 |
| DOIs | |
| State | Published - Nov 2021 |
Bibliographical note
Funding Information:This work was supported by NIH/NCI T32CA009138 (to H.M. Hintz); a DOD Idea Award W81XWH-19-1-0243 (to A.M. LeBeau); a 2018 Prostate Cancer Foundation Challenge Award (to A.M. LeBeau); a 2013 Prostate Cancer Foundation Young Investigator Award (to A.M. LeBeau); NIH R01s CA237272, CA233562, and CA245922 (to A.M. LeBeau); NIH R01CA203348 (to B. Walcheck); NIH R21AI149395 (to J. Wu); a Howard Hughes Medical Institute and Burroughs Wellcome Fund Medical Research Fellowship (to K.M. Snyder); and a University of Minnesota Medical School intramural grant for studying CRISPR in NK cells (to G.T. Hart). The authors also thank Colleen Forster and the Biorepository and Laboratory Services Division at the University of Minnesota for their histology and pathology support.
Funding Information:
H.M. Hintz reports grants from NIH/NCI during the conduct of the study, as well as a patent for 16/778,977 (compounds binding to fibroblast activation protein alpha and methods of making and using) pending. K.M. Snyder reports grants from Howard Hughes Medical Institute and Burroughs Wellcome Fund during the conduct of the study. J. Wu reports grants from NIH during the conduct of the study. B. Walcheck reports grants from NIH and Fate Therapeutics, and other support from Howard Hughes Medical Institute and Burroughs Wellcome Fund during the conduct of the study, as well as a patent for WO2019084388A1 pending and licensed to Fate Therapeutics. A.M. LeBeau reports a patent for 16/778,977 pending. No disclosures were reported by the other authors.
Publisher Copyright:
© 2021 American Association for Cancer Research.
