In mice, CAR-T cells activated a macrophage enzyme that weakened the attack on lymphoma
In mice, CAR-T cells activated a macrophage enzyme that weakened the attack on lymphoma
On August 31, researchers described how CAR-T cells activate iNOS, a nitric oxide producing enzyme, in macrophages in a peer-reviewed version of a study on large B-cell lymphoma, an aggressive cancer of the lymphatic system. They studied axi-cel, a type of CAR-T therapy in which a patient’s T cells are engineered to express a receptor that recognizes the CD19 protein on lymphoma cells.
In a 2021 study, the same research group linked a short-lived response to axi-cel with interferon signaling in the tumor and suppressive myeloid cells. RNA analysis of biopsies collected before treatment found a higher relative proportion of M2-like macrophages, immune cells in a state that can suppress immune responses, in patients whose response to therapy was not sustained. This association identified a possible mechanism for further investigation.
In a laboratory model, the authors combined mouse CAR-T cells, B-cell tumor cells, and M2-like macrophages. After recognizing the tumor cells, the CAR-T cells released IFN-γ, an immune signaling protein. IFN-γ activated iNOS in the macrophages, and the enzyme produced nitric oxide. Nitric oxide slowed CAR-T cell proliferation and reduced their ability to kill tumor cells.
The authors tested this pathway in two ways. L-NIL, an iNOS inhibitor, and genetic inactivation of the NOS2 gene in macrophages restored the ability of CAR-T cells to proliferate and kill tumor cells. A nitric oxide releasing compound suppressed their activity again.
In a mouse model of a B-cell tumor, combining CAR-T cells with L-NIL prolonged survival compared with CAR-T cells alone. During leukapheresis, the procedure used to isolate cells from blood for manufacturing the therapy, the proportion of CD14-positive monocytes expressing iNOS was higher in patients whose response to treatment was not sustained. The authors consider iNOS a potential target for future clinical studies of CAR-T therapy.