NKG2D-CAR-transduced natural killer cells efficiently target multiple myeloma
Alejandra Leivas, Antonio Valeri, Laura Córdoba, Almudena García-Ortiz, Alejandra Ortiz-Ruiz, Laura Sánchez-Vega, Osvaldo Graña‐Castro, Lucía Fernández, Gonzalo Carreño‐Tarragona, Manuel Pérez‐Martínez, Diego Megı́as, María Liz Paciello, José María Sánchez‐Pina, Antonio Pérez‐Martínez, Dean A. Lee, Daniel J. Powell, Paula Rı́o, Joaquín Martínez‐López
Abstract
Abstract CAR-T-cell therapy against MM currently shows promising results, but usually with serious toxicities. CAR-NK cells may exert less toxicity when redirected against resistant myeloma cells. CARs can be designed through the use of receptors, such as NKG2D, which recognizes a wide range of ligands to provide broad target specificity. Here, we test this approach by analyzing the antitumor activity of activated and expanded NK cells (NKAE) and CD45RA − T cells from MM patients that were engineered to express an NKG2D-based CAR. NKAE cells were cultured with irradiated Clone9.mbIL21 cells. Then, cells were transduced with an NKG2D-4-1BB-CD3z-CAR. CAR-NKAE cells exhibited no evidence of genetic abnormalities. Although memory T cells were more stably transduced, CAR-NKAE cells exhibited greater in vitro cytotoxicity against MM cells, while showing minimal activity against healthy cells. In vivo, CAR-NKAE cells mediated highly efficient abrogation of MM growth, and 25% of the treated mice remained disease free. Overall, these results demonstrate that it is feasible to modify autologous NKAE cells from MM patients to safely express a NKG2D-CAR. Additionally, autologous CAR-NKAE cells display enhanced antimyeloma activity demonstrating that they could be an effective strategy against MM supporting the development of NKG2D-CAR-NK-cell therapy for MM.