Chimeric antigen receptor engineered NK cellular immunotherapy overcomes the selection of T-cell escape variant cancer cells.

Autor:	Lee MY; NIDCD, National Institutes of Health, Bethesda, Maryland, USA.; Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, Ohio, USA., Robbins Y; NIDCD, National Institutes of Health, Bethesda, Maryland, USA., Sievers C; NIDCD, National Institutes of Health, Bethesda, Maryland, USA., Friedman J; NIDCD, National Institutes of Health, Bethesda, Maryland, USA., Abdul Sater H; Genitourinary Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA., Clavijo PE; NIDCD, National Institutes of Health, Bethesda, Maryland, USA., Judd N; Mid-Atlantic Permanente Medical Group, Rockville, Maryland, USA., Tsong E; Mid-Atlantic Permanente Medical Group, Rockville, Maryland, USA., Silvin C; NIDCD, National Institutes of Health, Bethesda, Maryland, USA., Soon-Shiong P; NantKwest, Culver City, California, USA., Padget MR; Laboratory of Tumor Immunology and Biology, National Cancer Institute, Bethesda, Maryland, USA., Schlom J; Laboratory of Tumor Immunology and Biology, National Cancer Institute, Bethesda, Maryland, USA., Hodge J; Laboratory of Tumor Immunology and Biology, National Cancer Institute, Bethesda, Maryland, USA., Hinrichs C; Genitourinary Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA., Allen C; NIDCD, National Institutes of Health, Bethesda, Maryland, USA clint.allen@nih.gov.
Jazyk:	angličtina
Zdroj:	Journal for immunotherapy of cancer [J Immunother Cancer] 2021 Mar; Vol. 9 (3).
DOI:	10.1136/jitc-2020-002128
Abstrakt:	Background: As heterogeneous tumors develop in the face of intact immunity, tumor cells harboring genomic or expression defects that favor evasion from T-cell detection or elimination are selected. For patients with such tumors, T cell-based immunotherapy alone infrequently results in durable tumor control. Methods: Here, we developed experimental models to study mechanisms of T-cell escape and demonstrated that resistance to T-cell killing can be overcome by the addition of natural killer (NK) cells engineered to express a chimeric antigen receptor (CAR) targeting programmed death ligand-1 (PD-L1). Results: In engineered models of tumor heterogeneity, PD-L1 CAR-engineered NK cells (PD-L1 t-haNKs) prevented the clonal selection of T cell-resistant tumor cells observed with T-cell treatment alone in multiple models. Treatment of heterogenous cancer cell populations with T cells resulted in interferon gamma (IFN-γ) release and subsequent upregulation of PD-L1 on tumor cells that escaped T-cell killing through defects in antigen processing and presentation, priming escape cell populations for PD-L1 dependent killing by PD-L1 t-haNKs in vitro and in vivo. Conclusions: These results describe the underlying mechanisms governing synergistic antitumor activity between T cell-based immunotherapy that results in IFN-γ production, upregulation of PD-L1 on T-cell escape cells, and the use of PD-L1 CAR-engineered NK cells to target and eliminate resistant tumor cell populations. Competing Interests: Competing interests: PS-S is an employee of NantKwest. (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
Databáze:	MEDLINE
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