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After 17 years of painstaking work, this year Thomas Blankenstein, founder of the Berlin-based start-up T-knife, will finally see how his T cell receptor (TCR) cancer immunotherapy works in real life. The idea was conceptually simple and not entirely original: replace the TCR genes of a mouse with those from a human, as had previously been done with antibody genes. Transgenic mice with the entire complement of human immunoglobulin genes have been the starting point for several commercialized fully human monoclonal antibody therapies. But conceptually simple does not mean it was simple to do. It required inserting genes to encompass both the human TCR repertoire and human major histocompatibility complex (MHC) molecules and knocking out the cognate mouse genes, generating mouse lines bearing human genes, and then subjecting them to a succession of crosses to get all the genes together in a single mouse—the HuTCR mouse. “It was very difficult and laborious to create a transgenic mouse that allows the discovery of humanized TCRs so efficiently, and I believe others have tried and failed,” says Alex Mayweg, a partner at Versant Ventures and board member of T-knife.