Expanded human NK cells armed with CAR uncouple potent anti-tumor activity from off-tumor toxicity against solid tumors

• Published in: iScience Vol. 24; no. 6; p. 102619
• Main Authors: Portillo, Ana L., Hogg, Richard, Poznanski, Sophie M., Rojas, Eduardo A., Cashell, Niamh J., Hammill, Joanne A., Chew, Marianne V., Shenouda, Mira M., Ritchie, Tyrah M., Cao, Quynh T., Hirota, Jeremy A., Dhesy-Thind, Sukhbinder, Bramson, Jonathan L., Ashkar, Ali A.
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 25.06.2021; Elsevier
• Subjects: Cancer; Immunology; Immunology; Cancer
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2021.102619

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. [Display omitted] •Primary HER2 CAR-NK cells from patients with cancer have potent anti-tumor functions•HER2 CAR-NK cells have a higher tumor killing capacity than HER2 CAR-T cells•HER2 CAR-NK cells are not overly activated against HER2+ lung epithelial cells•CAR-NK cells can overcome inhibition by the immunosuppressive factors TGF-β and PGE2 Immunology; Cancer