CAR memory-like NK cells targeting the membrane proximal domain of mesothelin demonstrate promising activity in ovarian cancer.

Autor: Tarannum M; Division of Transplantation and Cellular Therapies, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA., Dinh K; Division of Transplantation and Cellular Therapies, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA., Vergara J; Division of Transplantation and Cellular Therapies, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA., Birch G; Division of Transplantation and Cellular Therapies, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA., Abdulhamid YZ; Division of Transplantation and Cellular Therapies, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA., Kaplan IE; Division of Transplantation and Cellular Therapies, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA., Ay O; Division of Transplantation and Cellular Therapies, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA., Maia A; Division of Transplantation and Cellular Therapies, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA., Beaver O; Division of Transplantation and Cellular Therapies, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA., Sheffer M; Division of Transplantation and Cellular Therapies, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA., Shapiro R; Division of Transplantation and Cellular Therapies, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA., Ali AK; Division of Transplantation and Cellular Therapies, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA., Dong H; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA., Ham JD; Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA., Bobilev E; Division of Transplantation and Cellular Therapies, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA., James S; Lurie Family Imaging Center, Center for Biomedical Imaging in Oncology, Dana Farber Cancer Institute, Boston, MA, USA., Cameron AB; Lurie Family Imaging Center, Center for Biomedical Imaging in Oncology, Dana Farber Cancer Institute, Boston, MA, USA., Nguyen QD; Lurie Family Imaging Center, Center for Biomedical Imaging in Oncology, Dana Farber Cancer Institute, Boston, MA, USA., Ganapathy S; Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA., Chayawatto C; Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA., Koreth J; Division of Transplantation and Cellular Therapies, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA., Paweletz CP; Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA., Gokhale PC; Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA., Barbie DA; Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.; Division of Thoracic Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA., Matulonis UA; Division of Gynecologic Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA., Soiffer RJ; Division of Transplantation and Cellular Therapies, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA., Ritz J; Division of Transplantation and Cellular Therapies, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA., Porter RL; Division of Gynecologic Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA., Chen J; Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA., Romee R; Division of Transplantation and Cellular Therapies, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Jazyk: angličtina
Zdroj: Science advances [Sci Adv] 2024 Jul 12; Vol. 10 (28), pp. eadn0881. Date of Electronic Publication: 2024 Jul 12.
DOI: 10.1126/sciadv.adn0881
Abstrakt: Epithelial ovarian cancer (EOC) remains one of the most lethal gynecological cancers. Cytokine-induced memory-like (CIML) natural killer (NK) cells have shown promising results in preclinical and early-phase clinical trials. In the current study, CIML NK cells demonstrated superior antitumor responses against a panel of EOC cell lines, increased expression of activation receptors, and up-regulation of genes involved in cell cycle/proliferation and down-regulation of inhibitory/suppressive genes. CIML NK cells transduced with a chimeric antigen receptor (CAR) targeting the membrane-proximal domain of mesothelin (MSLN) further improved the antitumor responses against MSLN-expressing EOC cells and patient-derived xenograft tumor cells. CAR arming of the CIML NK cells subtanstially reduced their dysfunction in patient-derived ascites fluid with transcriptomic changes related to altered metabolism and tonic signaling as potential mechanisms. Lastly, the adoptive transfer of MSLN-CAR CIML NK cells demonstrated remarkable inhibition of tumor growth and prevented metastatic spread in xenograft mice, supporting their potential as an effective therapeutic strategy in EOC.
Databáze: MEDLINE