For 17 years, Thomas Blankenstein has been working on his Berlin-based start-up T-knife and is finally going to be able to test his T-cell receptor (TCR) cancer immunotherapy. To make this immunotherapy, they replaced the TCR genes of a mouse with those of a human and inserted genes to encompass both the human TCR repertoire and human major histocompatibility complex (MHC) molecules. They eliminated genes from related mice, generating mouse lines carrying human genes, and then subjected them to a succession of crosses to bring all the genes together in a single mouse, the HuTCR mouse. Designing transgenic mice with such efficient humanized TCRs has been very difficult and laborious. However, TCR-T cells are capable of more extensive signaling and killing than CAR-T cells. The engineered TCRs integrate seamlessly into the signal transduction pathways of T cells: there are ten subunits in a TCR versus one subunit in a CAR, they have ten immunoreceptor tyrosine activation motifs versus three in a CAR, and they are associated with more co-stimulatory receptors: CD3, CD4, CD2. In addition, unlike CARs that only bind to antigens on the cell surface, TCRs can target intracellular as well as extracellular tumor antigens.
