MICA/MICB (alpha-3 domain)

Class

iPSC-derived, multiplexed-engineered allogeneic CAR T-cell therapy

Pathway

MICA/B alpha-3-domain binding, independent of canonical NKG2D shedding-mediated immune escape, driving cytolytic tumor cell killing

MICA and MICB are stress-induced surface proteins that appear on cells undergoing DNA damage, transformation, or infection, acting as danger signals recognized by natural killer (NK) cells and cytotoxic T cells through the NKG2D receptor. This is part of the innate immune surveillance system that normally helps eliminate abnormal cells before they establish tumors. Many cancers evade this surveillance by shedding MICA/MICB from their surface through proteolytic cleavage at the alpha-3 domain, releasing a soluble form that removes the signal from the tumor cell and also desensitizes NKG2D receptors throughout the immune system, dulling surveillance broadly. Therapeutics can address this in two complementary ways: an antibody binding the alpha-3 domain can physically block the cleavage site, preventing shedding and preserving the stress signal on tumor cells; alternatively, an engineered cell therapy can be built to recognize this same alpha-3 domain directly as an antigen, allowing manufactured immune cells to kill MICA/MICB-expressing tumor cells regardless of whether endogenous NKG2D signaling has already been blunted. Because MICA/MICB expression spans many stressed and malignant cell types, this mechanism is relevant across a range of solid and blood cancers as a way to counteract a common tumor immune-evasion strategy.