A tri-specific killer engager against mesothelin targets NK cells towards lung cancer.

Autor:	Kennedy PR; Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN, United States., Vallera DA; Department of Radiation Oncology, University of Minnesota, Minneapolis, MN, United States., Ettestad B; Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN, United States., Hallstrom C; Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN, United States., Kodal B; Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN, United States., Todhunter DA; Department of Radiation Oncology, University of Minnesota, Minneapolis, MN, United States., Bendzick L; Department of Obstetrics, Gynecology and Women's Health, University of Minnesota, Minneapolis, MN, United States., Hinderlie P; Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN, United States., Walker JT; Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN, United States., Pulkrabek B; Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN, United States., Pastan I; National Cancer Institute, National Institutes of Health, Bethesda, MD, United States., Kratzke RA; Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN, United States., Fujioka N; Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN, United States., Miller JS; Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN, United States., Felices M; Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN, United States.
Jazyk:	angličtina
Zdroj:	Frontiers in immunology [Front Immunol] 2023 Feb 22; Vol. 14, pp. 1060905. Date of Electronic Publication: 2023 Feb 22 (Print Publication: 2023).
DOI:	10.3389/fimmu.2023.1060905
Abstrakt:	New treatments are required to enhance current therapies for lung cancer. Mesothelin is a surface protein overexpressed in non-small cell lung cancer (NSCLC) that shows promise as an immunotherapeutic target in phase I clinical trials. However, the immunosuppressive environment in NSCLC may limit efficacy of these therapies. We applied time-of-flight mass cytometry to examine the state of circulating mononuclear cells in fourteen patients undergoing treatment for unresectable lung cancer. Six patients had earlier stage NSCLC (I-IVA) and eight had highly advanced NSCLC (IVB). The advanced NSCLC patients relapsed with greater frequency than the earlier stage patients. Before treatment, patients with very advanced NSCLC had a greater proportion of CD14 - myeloid cells than patients with earlier NSCLC. These patients also had fewer circulating natural killer (NK) cells bearing an Fc receptor, CD16, which is crucial to antibody-dependent cellular cytotoxicity. We designed a high affinity tri-specific killer engager (TriKE ® ) to enhance NK cytotoxicity against mesothelin + targets in this environment. The TriKE consisted of CD16 and mesothelin binding elements linked together by IL-15. TriKE enhanced proliferation of lung cancer patient NK cells in vitro . Lung cancer lines are refractory to NK cell killing, but the TriKE enhanced cytotoxicity and cytokine production by patient NK cells when challenged with tumor. Importantly, TriKE triggered NK cell responses from patients at all stages of disease and treatment, suggesting TriKE can enhance current therapies. These pre-clinical studies suggest mesothelin-targeted TriKE has the potential to overcome the immunosuppressive environment of NSCLC to treat disease. Competing Interests: NF served on the advisory board for Takeda in 2020 and 2021 and the advisory board for Astra Zeneca in 2020. Neither Takeda nor Astra Zeneca provided any funding for the work herein. DV, JM and MF receive research support and, with the University of Minnesota, are shared owners of the TriKE technology licensed by the University to GT Biopharma Inc. In addition, JM and MF consult for and hold stock options in GT BioPharma Inc. These interests have been reviewed and managed by the University of Minnesota in accordance with its conflict of interest policy. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2023 Kennedy, Vallera, Ettestad, Hallstrom, Kodal, Todhunter, Bendzick, Hinderlie, Walker, Pulkrabek, Pastan, Kratzke, Fujioka, Miller and Felices.)
Databáze:	MEDLINE
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