More Chimeric Antigen Receptor Based Cancer Targeting

Immune cells can be engineered to selectively target cancer cells for destruction via use of chimeric antigen receptors that match up with proteins that are more common on the exterior of a cancer cell. This strategy has been in the news of late with impressive successes against leukemia. Here researchers show that better results can be obtained by chaining together two marginal targets, each of which is only slightly discriminating for cancer cells if used on its own.

T cells made to express a protein called CAR, for chimeric antigen receptor, are engineered by grafting a portion of a tumor-specific antibody onto an immune cell, allowing them to recognize antigens on the cell surface. Early first-generation CARs had one signaling domain for T-cell activation. Second-generation CARs are more commonly used and have two signaling domains within the immune cell, one for T-cell activation and another for T- cell costimulation to boost the T cell's function.

Importantly, CARs allow patients' T cells to recognize tumor antigens and kill certain tumor cells. A large number of tumor-specific, cancer-fighting CAR T cells can be generated in a specialized lab using patients' own T cells, which are then infused back into them for therapy. Despite promising clinical results, it is now recognized that some CAR-based therapies may involve toxicity against normal tissues that express low amounts of the targeted tumor-associated antigen.

To address this issue [researchers] developed an innovative dual CAR approach in which the activation signal for T cells is physically dissociated from a second costimulatory signal for immune cells. The two CARs carry different antigen specificity - mesothelin and a-folate receptor. Mesothelin is primarily associated with mesothelioma and ovarian cancer, and a-folate receptor with ovarian cancer. [Dual] CAR T cells are more selective for tumor cells since their full activity requires interaction with both antigens, which are only co-expressed on tumor cells, not normal tissue.


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