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NKG2D-CAR-transduced natural killer cells efficiently target multiple myeloma
oleh: Alejandra Leivas, Antonio Valeri, Laura Córdoba, Almudena García-Ortiz, Alejandra Ortiz, Laura Sánchez-Vega, Osvaldo Graña-Castro, Lucía Fernández, Gonzalo Carreño-Tarragona, Manuel Pérez, Diego Megías, María Liz Paciello, Jose Sánchez-Pina, Antonio Pérez-Martínez, Dean A. Lee, Daniel J. Powell, Paula Río, Joaquín Martínez-López
Format: | Article |
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Diterbitkan: | Nature Publishing Group 2021-08-01 |
Deskripsi
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.