Researchers led by Ludwig Johns Hopkins Co-director Kenneth Kinzler and investigator Shibin Zhou reported in a March issue of the Proceedings of the National Academy of Sciences the prototype of a new cancer immunotherapy. The approach, relying on a biochemical approximation of Boolean logic, uses chimeric antigen receptor (CAR) T cells to target a common and largely exclusive genetic aberration of cancers: the loss of expression of one of the usual two copies (or alleles) of a gene due to chromosome losses commonly known as “loss of heterozygosity” (LOH). The NASCAR T cell expresses the CAR that targets an allele expressed on the cancer cell as well as an inhibitory CAR (iCAR) against the allele product that is missing due to LOH. If both proteins—equivalent to the expression, A and B—are expressed on a cell encountered by the NASCAR T cell, the iCAR is simultaneously activated, and the presumably normal cell is left untouched. If, however, one allele product is present and the other missing—A and NOT B—the NASCAR T cell is activated to kill the deficient, cancerous cell. The researchers designed NASCAR T cells that target LOH cell surface molecules known as HLA and tested it successfully on three independent cell lines and in mouse models.
This article appeared in the August 2021 issue of Ludwig Link. Click here to download a PDF (2MB).