Preclinical Evaluation of Off-The-Shelf PD-L1+ Human Natural Killer Cells Secreting IL15 to Treat Non-Small Cell Lung Cancer.

Autor:	Lu T; Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, California.; Hematologic Malignancies Research Institute, City of Hope National Medical Center, Los Angeles, California., Ma R; Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, California., Mansour AG; Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, California., Bustillos C; Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, California., Li Z; Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, California., Li Z; Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, California., Ma S; Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, California., Teng KY; Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, California., Chen H; Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, California., Zhang J; Department of Computational and Quantitative Medicine, City of Hope National Medical Center, Los Angeles, California., Villalona-Calero MA; Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Los Angeles, California.; City of Hope Comprehensive Cancer Center, Los Angeles, California., Caligiuri MA; Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, California.; Hematologic Malignancies Research Institute, City of Hope National Medical Center, Los Angeles, California.; City of Hope Comprehensive Cancer Center, Los Angeles, California., Yu J; Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, California.; Hematologic Malignancies Research Institute, City of Hope National Medical Center, Los Angeles, California.; City of Hope Comprehensive Cancer Center, Los Angeles, California.; Department of Immuno-Oncology, Beckman Research Institute of City of Hope, Los Angeles, California.
Jazyk:	angličtina
Zdroj:	Cancer immunology research [Cancer Immunol Res] 2024 Jun 04; Vol. 12 (6), pp. 731-743.
DOI:	10.1158/2326-6066.CIR-23-0324
Abstrakt:	We described previously a human natural killer (NK) cell population that upregulates PD-L1 expression upon recognizing and reacting to tumor cells or exposure to a combination of IL12, IL18, and IL15. Here, to investigate the safety and efficacy of tumor-reactive and cytokine-activated (TRACK) NK cells, human NK cells from umbilical cord blood were expanded, transduced with a retroviral vector encoding soluble (s) IL15, and further cytokine activated to induce PD-L1 expression. Our results show cryopreserved and thawed sIL15_TRACK NK cells had significantly improved cytotoxicity against non-small cell lung cancer (NSCLC) in vitro when compared with non-transduced (NT) NK cells, PD-L1+ NK cells lacking sIL15 expression (NT_TRACK NK), or NK cells expressing sIL15 without further cytokine activation (sIL15 NK cells). Intravenous injection of sIL15_TRACK NK cells into immunodeficient mice with NSCLC significantly slowed tumor growth and improved survival when compared with NT NK and sIL15 NK cells. The addition of the anti-PD-L1 atezolizumab further improved control of NSCLC growth by sIL15_TRACK NK cells in vivo. Moreover, a dose-dependent efficacy was assessed for sIL15_TRACK NK cells without observed toxicity. These experiments indicate that the administration of frozen, off-the-shelf allogeneic sIL15_TRACK NK cells is safe in preclinical models of human NSCLC and has potent antitumor activity without and with the administration of atezolizumab. A phase I clinical trial modeled after this preclinical study using sIL15_TRACK NK cells alone or with atezolizumab for relapsed or refractory NSCLC is currently underway (NCT05334329). (©2024 American Association for Cancer Research.)
Databáze:	MEDLINE
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