Chimeric antigen-receptor (CAR)-T cell therapy involves taking a patient’s peripheral blood T cells and engineering them with a receptor that redirects them to attack their tumor. Though such therapies have been approved for blood cancers, their application to solid tumors has proved challenging, in part because the microenvironments of solid tumors suppress immune responses. Meanwhile, due to technical difficulties associated with developing mouse CAR-T cells, new CAR therapies have typically been preclinically evaluated using human CAR-T cells in mice that lack an immune system. The CAR-T cells are thus not challenged in the context of inhibitory immune infiltrates in tumors. In November, Ludwig Lausanne’s Melita Irving, George Coukos, Evripidis Lanitis and colleagues reported in the Journal of Experimental Medicine a method to overcome that difficulty involving, among other things, the sequential use of three immune factors known as interleukins (IL-2, 7 and 15) in the cultivation of mouse CAR-T cells. The team also developed “4th generation” (4G) CAR-T cells engineered to co-express the IL-15 protein, which stimulates T cell proliferation and survival, and showed that their CAR-T cells were superior in persistence, fitness and efficacy in a mouse model of melanoma. Notably, the 4G CAR-T cells reprogramed the tumor microenvironment by activating tumor-targeting natural killer cells and causing a decline in M2 macrophages that can suppress anti-cancer responses.
This article appeared in the April 2021 issue of Ludwig Link. Click here to download a PDF (1.4 MB).