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00925njm 22002777a 4500 dc Aparicio Fernández, Cristina author Queipo Riera, Mónica author Belver, Marina author Espeso, Francisco author Serna Pérez, Julia author Enríquez Rodríguez, Lucía author Acebal, Carlos author Martín Muñoz, Álvaro author Valeri, Antonio author Leivas, Alejandra author Río, Paula author Powell, Daniel J. author Lobo Valentín, Rosa María author Arrabal, David author Martínez López, Joaquín author Sánchez, Ana author Fuente García, Miguel Ángel de la author González-Vallinas Garrachón, Margarita author 2025 Chimeric Antigen Receptor (CAR)-T cell therapy has shown significant success in treating hematological cancers, but commercialized autologous CAR-T therapies face challenges such as high costs, manufacturing delays, complex standardization and the risk of tumor relapses due to single-antigen targeting. To address these issues, a novel allogeneic CAR-T therapy with broader target specificity was developed, optimizing its manufacturing process. Using CRISPR/Cas9, TCR and HLA class I complex expression were eliminated from donor T cells to reduce the risk of immune rejection and graft-versus-host disease. Additionally, NKG2D CAR, targeting eight ligands upregulated in both solid and hematological tumors, was lentivirally transduced. This study optimized CAR-T cell manufacture by testing various interleukin supplements (IL-2, IL-7/IL-15, IL-7/IL-15/IL-21). Results showed that IL-7/IL-15/IL-21 supplementation produced CAR-T cells with the most suitable characteristics in terms of genetic modification efficiency, cell proliferation, antitumor activity and memory profile. This new allogeneic NKG2D CAR-T therapy represents a promising universal treatment for a variety of cancers. Cancers, 2025, vol. 17, n. 19, p. 3186. 2072-6694 https://uvadoc.uva.es/handle/10324/81890 10.3390/cancers17193186 3186 19 Cancers 17 2072-6694 A novel early memory-enriched allogeneic NKG2D CAR-T cell therapy based on CRISPR/Cas9 technology for solid tumors