The ability to precisely engineer genes of cells using CRISPR/Cas9 has opened up new avenues. We are T cell immunologists working in the laboratory of Dirk Busch at the Technical University of Munich. Our group tries to understand which and how antigen-specific T cell responses can protect against disease, like infection or cancer. And in this context, the adoptive transfer of T cells that recombinantly express defined TCRs provides an interesting field for therapy development. A few years back, when we learned about CRISPR/Cas9, we thought: "How cool would it be if we could actually replace a T cell's receptor with this tool?". This would give us a chance to eliminate the endogenous receptor, introduce a new receptor of our choice, and even integrate it into the cell in a highly precise fashion.

To make a long story short, this process – which we called "orthotopic TCR replacement" – enables to engineer T cells and equip them with a receptor of our choice, but it simultaneously preserves the T cell's physiological function (Schober, Müller et al. Nat Biomed Eng 2019). We think that, mostly, natural biological processes have evolved to function pretty well. Most of the time, we are protected from infections. Most of the time, we do not get cancer. But once in a while, there's a hole in the system. And then we can fill this hole with genetically engineered T cells that closely resembly physiological T cells. Most of the time, we can probably not outsmart evolution. But once in a while, we may. So, generally, we try to engineer as much as necessary, but as little as possible.

Orthotopic TCR replacement (OTR) has proven to be a game changer. Not only in the Busch lab, where OTR has become the new standard of T cell engineering and therapy development, but also for us, the two first authors of the study. Us, that's Thomas Müller, a PhD student, and Kilian Schober, an MD and research fellow. The paper was our first major publication. By now, we have just submitted a manuscript, with Thomas Müller being the leading first author, describing how OTR makes T cell responses more predictable. We have secured new funding, with Kilian Schober starting his own research group at the beginning of next year. We have developed a research focus and an expertise.

To name something a "game changer" carries a certain risk. Has the change really been grand enough to justify such an expression? Don't we hear these phrases too often. Aren't they corny? Often enough, they are. But this case is different. Will OTR become the new gold standard for TCR engineering in our research field? Will patients be treated with this technology? We are pretty optimistic, but we cannot be certain. What's certain, though, is the change OTR has induced in our careers. For that, we consider ourselves fortunate.

From left to right: Senior author Dirk Busch and the two first authors Thomas Müller and Kilian Schober. The photo was taken for the press release of the original study on orthotopic TCR replacement in 2019.