1. NKG2D-CAR memory T cells target pediatric T-cell acute lymphoblastic leukemia in vitro and in vivo but fail to eliminate leukemia initiating cells.
- Author
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Ibáñez-Navarro M, Fernández A, Escudero A, Esteso G, Campos-Silva C, Navarro-Aguadero MÁ, Leivas A, Caracuel BR, Rodríguez-Antolín C, Ortiz A, Navarro-Zapata A, Mestre-Durán C, Izquierdo M, Balaguer-Pérez M, Ferreras C, Martínez-López J, Valés-Gómez M, Pérez-Martínez A, and Fernández L
- Subjects
- Humans, Child, Mice, Animals, NK Cell Lectin-Like Receptor Subfamily K metabolism, Cell Line, Tumor, Memory T Cells, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma therapy, Receptors, Chimeric Antigen
- Abstract
Introduction: Refractory/relapsed pediatric acute leukemia are still clinically challenging and new therapeutic strategies are needed. Interactions between Natural Killer Group 2D (NKG2D) receptor, expressed in cytotoxic immune cells, and its ligands (NKG2DL), which are upregulated in leukemic blasts, are important for anti-leukemia immunosurveillance. Nevertheless, leukemia cells may develop immunoescape strategies as NKG2DL shedding and/or downregulation., Methods: In this report, we analyzed the anti-leukemia activity of NKG2D chimeric antigen receptor (CAR) redirected memory (CD45RA
- ) T cells in vitro and in a murine model of T-cell acute lymphoblastic leukemia (T-ALL). We also explored in vitro how soluble NKG2DL (sNKG2DL) affected NKG2D-CAR T cells' cytotoxicity and the impact of NKG2D-CAR T cells on Jurkat cells gene expression and in vivo functionality., Results: In vitro , we found NKG2D-CAR T cells targeted leukemia cells and showed resistance to the immunosuppressive effects exerted by sNKG2DL. In vivo , NKG2D-CAR T cells controlled T cell leukemia burden and increased survival of the treated mice but failed to cure the animals. After CAR T cell treatment, Jurkat cells upregulated genes related to proliferation, survival and stemness, and in vivo , they exhibited functional properties of leukemia initiating cells., Discussion: The data here presented suggest, that, in combination with other therapeutic approaches, NKG2D-CAR T cells could be a novel treatment for pediatric T-ALL., Competing Interests: MB-P was previously employed by the company Medpace Germany, GmbH, though not at the time of the study, and is currently employed by the company Medpace Spain. 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. The handling editor FM declared a shared committee the National Network of Advanced therapies TerAv with the author AP-M at the time of review., (Copyright © 2023 Ibáñez-Navarro, Fernández, Escudero, Esteso, Campos-Silva, Navarro-Aguadero, Leivas, Caracuel, Rodríguez-Antolín, Ortiz, Navarro-Zapata, Mestre-Durán, Izquierdo, Balaguer-Pérez, Ferreras, Martínez-López, Valés-Gómez, Pérez-Martínez and Fernández.)- Published
- 2023
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