PITAGORAS Project

The PITAGORAS project seeks to develop a platform for the identification of tumor antigen-specific TCRs for immunotherapy of solid tumors.

The TCR is the natural receptor on T cells that allows them to recognize foreign cells, such as tumor cells. Therapy with T cells genetically modified to express these receptors (TCR-T cells) is a new cell therapy modality for cancer treatment. The great advantage of this therapy over related therapies, such as CAR-T therapy, is the abundance of tumor antigens that are intracellular and therefore can only be recognized by the TCR. This is of vital importance in the context of solid tumors, where the lack of good antigens for CAR-T cells is limiting their efficacy. 

There are currently two approaches to TCR-T therapies: with "shared TCRs", which recognize tumor antigens shared by different patients; and with "personalized TCRs", which recognize the patient's own tumor antigens, the most frequent. The challenges differ for both approaches: while shared TCRs require solutions that facilitate their implementation in clinical practice, personalized TCRs need simple methods to identify tumor-specific TCRs and thus make their way into personalized medicine. At PITAGORAS we address both challenges.

Taking as a starting point "shared TCRs" specific to human tumor antigens identified by FIMA, we propose to establish protocols for clinical-scale production of TCR-T cells to facilitate their translation to the clinic. On the other hand, in order to propose improved versions of TCRs and combination treatments that enhance TCR-T therapy, we will study the molecular structure of these TCRs, their interaction with tumor cells, by image analysis and using in vitro and in vivo models in zebrafish, as well as the mechanisms of tumor resistance to attack by TCR-T cells. For the development of "personalized TCR" therapies, we propose to develop a rapid and novel method to identify tumor-specific TCRs using next-generation sequencing (NGS) data and the genetic profile of T lymphocytes. 

It is funded by the Government of Navarra within its call for Strategic R&D Projects 2023.