Produção de linfócitos T reguladores específicos do dador para antigénios do doente para o tratamento da doença do enxerto contra o hospedeiro crónica, após transplante alogénico de progenitores hematopoiéticos.

This project aims to develop a new cell therapy to treat cGVHD, the single most important cause of non-relapse mortality after allo-HSCT [7]. The high incidence of cGVHD and the lack of curative treatments for the majority of patients, stresses the unmet need for new strategies to treat this condition. Our team has performed pioneering research in the field of cGVHD over the past 10 years[4][5]. After showing that patients with cGVHD have low Treg numbers, we hypothesized that these patients would likely benefit from the infusion of fresh Treg[6]. This was the rationale behind a clinical trial infusing fresh donor Treg in patients with moderate/severe cGVHD. Despite the promising results, the infused Treg were not specific and broadly immunosuppressive, leading us to develop a Treg product specific for disparate mHA from an HLA-matched sibling donor, recapitulating the immunologic milieu of allo-HSCT. By including in our team the know-how and infrastructure from Stemmatters, we expect to be in a position to bring this therapy to clinical trials at the end of the project. The aims of the project are the following: 1- Develop optimal methods to expand clinically relevant numbers of mAgSpTreg generated by the co-culture of purified Treg and antigen presenting cells from HLA-matched siblings. 2- Evaluate the suppressive function, phenotype and TCR diversity of expanded mAgSpTreg. 3- Perform proof-of-concept studies following GMP principles, for the generation and expansion of mAgSpTreg. NOVELTY The novelty in our approach is based on 2 main aspects: A) It moves away from the use of polyclonal Treg, thus circumventing the problem of unspecific broad immunosuppression. In previous studies, polyclonal Treg were either infused directly, expanded in vitro before infusion, or induced to expand in vivo with low dose IL-2 [8][9][10][11][12]. B) It develops a Treg product that is specific to an array of mHAs involved in cGVHD, thus reducing off target activity and increasing the suppression of donor-derived T-cell aggression of patients ́ healthy tissues. STRATEGY We aim to develop a novel approach, for which we have strong preliminary data (see preliminary data), to select and expand mAgSpTreg. These cells are obtained in an HLA-matched setting, similar to that of allo-HSCT. This will result in the generation of a highly personalized ATMP that can be obtained from a small volume of peripheral blood, bypassing the need for donor leukapheresis to achieve the desired Treg numbers for infusion. Finally, we will collaborate with Stemmatters, a company that has know-how in the cellular immunotherapy area, who took interest in joining our team, to move the preparation and expansion of mAgSpTreg a step closer to the GMP-compliant setting. IMPACT While aiming to develop a novel therapeutic approach for cGVHD, bringing it as close as possible to clinical testing in partnership with Stemmatters, we expect a positive impact on both teams, as they can exchange know-how, technology and ideas, thus fostering new partnerships. Importantly, by bringing a novel approach to tackle cGVHD closer to the clinical setting, we expect to reduce disease burden in these patients and ultimately to improve transplantation outcomes.