NKG2D的CAR-T细胞在小鼠体内的急性毒反应.pptxVIP

October 10, 2016;Mouse and human;NKG2D ligands are expressed on various types of tumor cells and immunosuppressive cells (e.g. Tregs and myeloid-derived suppressor cells (MDSCs) within tumor microenvironments, these ligands provide attractive targets for cancer therapy.;Results;non–tumor-bearing;Assessment of toxicity following multidoses at the maximum tolerated dose;Mouse T lymphoma cell line;An analysis of cytokines 20 h after injection of CAR T cells showed an increase in G-CSF, IL-6, IFN-g, MCP-1, IL-10, and MIG, with the highest cell dose having significant increases compared with controls;Only in mice injected with 2 ×107 NKG2D CAR T cells were clinical signs of illness observed (mean health score of 3.1）;Table 3 Histological analysis of tissues harvested after a dose of 2 x 107 CAR T cells. ;Despite their health status, mice treated with 2 ×107 NKG2D CAR T cells exhibited little pathology.;The role of CAR T cell effector mechanisms in acute toxicity;GM-CSF-/-CAR-T;The role of host immune cells;The NSG and NOD/SCID mice remained healthy throughout the experiment, whereas the NOD, Rag- 1–deficient, and IL-2Rg–deficient mice became acutely ill and lost body weight after receiving the high dose of NKG2D CAR T cells, similar to B6 mice;PK136 (anti-NK1.1 mAbs), 1A8 (anti-NK1.1 or anti-Ly6G mAb ) prior to injection of a high dose of NKG2D CAR T cells did not affect the development of CRS;The role of host cytokines;These signaling pathway was not essential in the acute illness observed;The role of genetic background;DNAM1-based CARs show similar acute CRS toxicity;These murine models may provide a system to test potential therapies to prevent or limit CRS-like responses. These findings implicate both CAR T cells and host immune cells as required contributors to the development of acute immune-related toxicity.