Expanded human NK cells armed with CAR uncouple potent anti-tumor activity from off-tumor toxicity against solid tumors
Ana L. Portillo,
Richard Hogg,
Sophie M. Poznanski,
Eduardo A. Rojas,
Niamh J. Cashell,
Joanne A. Hammill,
Marianne V. Chew,
Mira M. Shenouda,
Tyrah M. Ritchie,
Quynh T. Cao,
Jeremy A. Hirota,
Sukhbinder Dhesy-Thind,
Jonathan L. Bramson,
Ali A. Ashkar
Affiliations
Ana L. Portillo
Department of Medicine, McMaster University, Hamilton, ON L8N 3Z5, Canada; McMaster Immunology Research Centre, McMaster University, Hamilton, ON L8S 4K1, Canada
Richard Hogg
McMaster Immunology Research Centre, McMaster University, Hamilton, ON L8S 4K1, Canada
Sophie M. Poznanski
Department of Medicine, McMaster University, Hamilton, ON L8N 3Z5, Canada; McMaster Immunology Research Centre, McMaster University, Hamilton, ON L8S 4K1, Canada
Eduardo A. Rojas
Department of Medicine, McMaster University, Hamilton, ON L8N 3Z5, Canada; McMaster Immunology Research Centre, McMaster University, Hamilton, ON L8S 4K1, Canada
Niamh J. Cashell
McMaster Immunology Research Centre, McMaster University, Hamilton, ON L8S 4K1, Canada
Joanne A. Hammill
Department of Medicine, McMaster University, Hamilton, ON L8N 3Z5, Canada; McMaster Immunology Research Centre, McMaster University, Hamilton, ON L8S 4K1, Canada
Marianne V. Chew
McMaster Immunology Research Centre, McMaster University, Hamilton, ON L8S 4K1, Canada
Mira M. Shenouda
McMaster Immunology Research Centre, McMaster University, Hamilton, ON L8S 4K1, Canada
Tyrah M. Ritchie
Department of Medicine, McMaster University, Hamilton, ON L8N 3Z5, Canada; McMaster Immunology Research Centre, McMaster University, Hamilton, ON L8S 4K1, Canada
Quynh T. Cao
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
Jeremy A. Hirota
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
Sukhbinder Dhesy-Thind
Department of Oncology, McMaster University, Hamilton, ON L8V 5C2, Canada
Jonathan L. Bramson
Department of Medicine, McMaster University, Hamilton, ON L8N 3Z5, Canada; McMaster Immunology Research Centre, McMaster University, Hamilton, ON L8S 4K1, Canada
Ali A. Ashkar
Department of Medicine, McMaster University, Hamilton, ON L8N 3Z5, Canada; McMaster Immunology Research Centre, McMaster University, Hamilton, ON L8S 4K1, Canada; Corresponding author
Summary: 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.
