Portillo et al. engineered expanded NK cells containing a normal complement of inhibitory and activating receptors derived from healthy donors and breast cancer patients with a HER2-targeting CAR (HER2 CAR-NK) and evaluated its cytotoxicity against malignant and non-malignant cells. Compared to non-transduced and HER2 CAR T cells, HER2 CAR NK cells demonstrated enhanced cytotoxicity against HER2-expressing breast and ovarian cancer cells in vitro and were less reactive against HER2-expressing healthy human lung epithelial cells. TGFβ and PGE2 suppressed the cytotoxicity of expanded NK cells, but not of CAR-NK cells.
Contributed by Shishir Pant
ABSTRACT: Despite the remarkable success of chimeric antigen receptor (CAR)-T cells against hematologic malignancies, severe off-tumor effects have constrained their use against solid tumors. Recently, CAR-engineered natural killer (NK) cells have emerged as an effective and safe alternative. Here, we demonstrate that HER2 CAR-expression in NK cells from healthy donors and patients with breast cancer potently enhances their anti-tumor functions against various HER2-expressing cancer cells, regardless of MHC class I expression. Moreover, HER2 CAR-NK cells exert higher cytotoxicity than donor-matched HER2 CAR-T cells against tumor targets. Importantly, unlike CAR-T cells, HER2 CAR-NK cells do not elicit enhanced cytotoxicity or inflammatory cytokine production against non-malignant human lung epithelial cells with basal HER2 expression. Further, HER2 CAR-NK cells maintain high cytotoxic function in the presence of immunosuppressive factors enriched in solid tumors. These results show that CAR-NK cells may be a highly potent and safe source of immunotherapy in the context of solid tumors.
Author Info: (1) Department of Medicine, McMaster University, Hamilton, ON L8N 3Z5, Canada. McMaster Immunology Research Centre, McMaster University, Hamilton, ON L8S 4K1, Canada. (2) McMaster
Author Info: (1) Department of Medicine, McMaster University, Hamilton, ON L8N 3Z5, Canada. McMaster Immunology Research Centre, McMaster University, Hamilton, ON L8S 4K1, Canada. (2) McMaster Immunology Research Centre, McMaster University, Hamilton, ON L8S 4K1, Canada. (3) Department of Medicine, McMaster University, Hamilton, ON L8N 3Z5, Canada. McMaster Immunology Research Centre, McMaster University, Hamilton, ON L8S 4K1, Canada. (4) Department of Medicine, McMaster University, Hamilton, ON L8N 3Z5, Canada. McMaster Immunology Research Centre, McMaster University, Hamilton, ON L8S 4K1, Canada. (5) McMaster Immunology Research Centre, McMaster University, Hamilton, ON L8S 4K1, Canada. (6) Department of Medicine, McMaster University, Hamilton, ON L8N 3Z5, Canada. McMaster Immunology Research Centre, McMaster University, Hamilton, ON L8S 4K1, Canada. (7) McMaster Immunology Research Centre, McMaster University, Hamilton, ON L8S 4K1, Canada. (8) McMaster Immunology Research Centre, McMaster University, Hamilton, ON L8S 4K1, Canada. (9) Department of Medicine, McMaster University, Hamilton, ON L8N 3Z5, Canada. McMaster Immunology Research Centre, McMaster University, Hamilton, ON L8S 4K1, Canada. (10) Department of Medicine, McMaster University, Hamilton, ON L8N 3Z5, Canada. McMaster Immunology Research Centre, McMaster University, Hamilton, ON L8S 4K1, Canada. Firestone Institute for Respiratory Health - Division of Respirology, McMaster University, Hamilton, ON L8N 3Z5, Canada. (11) Department of Medicine, McMaster University, Hamilton, ON L8N 3Z5, Canada. McMaster Immunology Research Centre, McMaster University, Hamilton, ON L8S 4K1, Canada. Firestone Institute for Respiratory Health - Division of Respirology, McMaster University, Hamilton, ON L8N 3Z5, Canada. (12) Department of Oncology, McMaster University, Hamilton, ON L8V 5C2, Canada. (13) Department of Medicine, McMaster University, Hamilton, ON L8N 3Z5, Canada. McMaster Immunology Research Centre, McMaster University, Hamilton, ON L8S 4K1, Canada. (14) Department of Medicine, McMaster University, Hamilton, ON L8N 3Z5, Canada. McMaster Immunology Research Centre, McMaster University, Hamilton, ON L8S 4K1, Canada.
