Methods to improve CAR T cell efficacy and safety by modulating mediators of phagocytosis

There are several barriers to widespread use of CAR T-cell therapy. One of them is toxicity, primarily cytokine release syndrome (CRS) and neurologic toxicity, but also on-target off-tumor toxicity. Another barrier is the lack of CAR T cell persistence, and more efficacious CAR-T cell therapies are needed especially those targeting solid tumors.

The Mackall Lab at Stanford invented a novel way to harness the macrophage – CAR T cell interaction with the goal to address those two limitations: 1) Create a safety switch to quickly deplete CAR T cells in cases of toxicity, and 2) manipulate CAR T cells to enhance their persistence, improving their anti-tumor activity. The safety switch works by blocking "don't eat me" signals on the surface of CAR-T cells, resulting in efficient and fast elimination of CAR T cells by macrophages. Having an off-the-shelf antibody which can effectively deplete CAR T cells when they cause toxicity can be a valuable tool for immunotherapy. To obtain the opposite outcome and increase expansion and persistence exploiting the same CAR-T cell/macrophage regulatory axis, we over-express "don't eat me" signals on CAR T cells. This manipulation has no deleterious effect on their cytotoxic activity, but yields CAR-T cells more resistant to elimination by macrophages, leading to superior activity in models of solid and liquid tumors.