Quantifying requirements for mitochondrial apoptosis in CAR T killing of cancer cells.

Chimeric antigen receptor (CAR) T cell therapy is an FDA-approved treatment for several hematologic malignancies, yet not all patients respond to this treatment. While some resistance mechanisms have been identified, cell death pathways in target cancer cells remain underexplored. Impairing mitochondrial apoptosis via knockout of Bak and Bax, forced Bcl-2 and Bcl-XL expression, or caspase inhibition protected several tumor models from CAR T killing. However, impairing mitochondrial apoptosis in two liquid tumor cell lines did not protect target cells from CAR T killing. We found that whether a cell was Type I or Type II in response to death ligands explained the divergence of these results, so that mitochondrial apoptosis was dispensable for CART killing of cells that were Type I but not Type II. This suggests that the apoptotic signaling induced by CAR T cells bears important similarities to that induced by drugs. Combinations of drug and CAR T therapies will therefore require tailoring to the specific cell death pathways activated by CAR T cells in different types of cancer cells.