CAR T cell cytolytic mechanisms and paracrine effects

Upon recognition of a tumour-associated antigen (TAA) by a chimeric antigen receptor (CAR) T cell, an immune synapse is formed, followed by CAR T cell activation. Subsequently, cytotoxic granules containing perforin and granzymes are released, with the latter entering the target cell via perforin channels, triggering intrinsic apoptosis by damaging mitochondria and activating caspases,. Additionally, CAR T cells upregulate FAS ligand, which engages the FAS receptor on target cells, triggering the extrinsic pathway of apoptosis and caspase-mediated targeted cell death. Further, CAR T cells release IFNγ and TNF that activate immune cells such as macrophages. CAR T cells might recognize TAAs on non-malignant cells, leading to undesired lysis of healthy tissues. Next-generation CAR T cells can also be equipped with additional effector functions (such as IL-12 secretion) that extend the immune response to include endogenous T cells,. OTOT, on-target, off-tumour toxicity.

Publication

Overcoming on-target, off-tumour toxicity of CAR T cell therapy for solid tumours. (2023) Christian L. Flugel, et al. Nat Rev Clin Oncol. ;20(1):49-62. Figure: F2. All organisms Homo sapiens Mus musculus Danio rerio Drosophila melanogaster

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