For all the iterations and advances in TCR therapies for cancer, any experimental treatments involving T cell receptors share one trait: By definition, they only recognize antigens presented as peptides on the major histocompatibility complex (MHC) on cells.
Versant reckons its time to expand the arsenal. With $30 million in initial funding, its Ridgeline Discovery Engine in Switzerland has been working on a non-peptidic approach that it says has tumor-agnostic potential, especially in solid tumors. Theyve named it Matterhorn, after a Swiss mountain as they did with the three other companies that have emerged from the Basel-based incubator.
The key discoveries by founding scientists Gennaro De Libero and Lucia Mori at the University of Basel have to do with MR1, or MHC class I-related molecule 1.
When they began probing the protein more than 10 years ago, MR1 was mostly known for binding to molecules of bacterial origin and thus its role in infections. But De Libero and Mori predicted that endogenous molecules could be presented as well. And they were right. Not only did they find metabolites tied to tumor cell proliferation that are not found on healthy cells, they also stumbled upon a class of T cells that could specifically target MR1.
We published that the frequency of these cells in the blood is similar to the frequency of peptide-specific T cells, De Libero told Endpoints News. And they were overlooked.
Because MR1 is identical across humans acting as a surveillance system for aberrant metabolism, it lends itself to an off-the-shelf therapy, with no HLA matching necessary.
The idea then is to generate a library of compounds that are metabolites, that accumulate in the tumor, together with a library of predefined T cell receptors, he said. So that if your tumor expresses a compound A, you will utilize receptor A that you know is specific to that combination.
Although Matterhorns targets and receptors are new, the method of getting them into T cells isnt. Much like CAR-T and other TCR therapies, scientists will knock out endogenous TCR genes and transduce T cells with their own receptors.
Based on the preclinical data he and Mori, the CSO of Matterhorn, alongside 10 staffers have generated to date, De Libero believes that their library would ultimately consist of a relatively small number of metabolites and corresponding T cell receptors much less than 100 in total.
The research so far also indicates that while certain tumors carry rare metabolites, there are other metabolites that are present in a whole basket of different tumors and tissues. We dont want to say that we have the silver bullet against everything here, but it has a breadth that no other T cell therapy right now really has, Alex Mayweg, managing director at Versant and a board member at Matterhorn, said.
The plan now is to go through the collection of MR1 T cells and receptors theyve assembled and nominate a lead clinical candidate later this year, aiming to be ready for the clinic in early 2022. Meanwhile, the Ridgeline team will fade out as Matterhorn grows its internal payroll to 15 to 20 by the end of this year.