TITLE: “Innovative approaches for T cell immunotherapy post allogeneic hematopoietic cell transplantation”

Opportunistic infections and graft-versus-host-disease (GvHD) represent leading causes of morbidity and mortality in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT), hence limiting its broader application and success. Conventional treatment of opportunistic infections or GvHD with pharmacologic agents (anti-viral/anti-fungal or immunosuppressive drugs, respectively) is often ineffective, can lead to resistance while it is also associated with substantial toxicities. Due to the failure and the toxicities associated with conventional therapies, both the human and the financial burden is enormous.

Over the last years, adoptive immunotherapies arose as appealing alternative strategies for the treatment of post-transplant complications. The generation and administration of donor’s antigen-specific T cells simultaneously targeting multiple viruses to treat post-transplant viral infections, or T regulatory cells (Tregs) suppressing the immune response against alloantigens to treat GvHD, has provided highly promising clinical results. Τhe developmental pathway of T-cell therapies differs substantially from the conventional pharmaceutical model; each product is customized to each individual treated, rather than being prepared in bulk and a standardized form. This in itself is a challenge to the robust scalability required for late phase clinical studies.

In the current proposal we aim to develop and administer, for the first time in Greece, advanced T-cell therapies by using cost-effective and “user-friendly” protocols for the treatment of opportunistic infections and GvHD, representing the major complications post allo-HSCT. This endeavor will be accomplished through a productive and complementary partnership between 3 research organizations and 2 enterprises. Our goal is to release for use, after preclinical development, GMP validation, in-depth immunophenotypic, molecular and functional characterization and after obtaining approvals from the regulatory agencies, two innovative T-cell products: i) pentavalent-specific T cells (penta-STs) for the treatment of life-threatening infections from cytomegalovirus-CMV, Epstein Barr virus-EBV, adenovirus-ADV, polyomavirus type I-BK and the fungus Aspergillus and ii) inducible, through pharmacological hypomethylation, T regulatory cells expressing the HLA-G+ (iG-Tregs) for the treatment of severe GvHD.

The academic partners will be responsible for the preclinical development, GMP validation and quality control of the T-cell therapy products by standard approaches [Gene and Cell Therapy Center (GCTC), Hematopoietic Cell Transplantation Unit (HCTU) – G. Papanicolaou Hospital (GPH) and Bone Marrow Transplantation Unit (BMTU) – University of Patras (UoP)], as well as the NGS characterization of the T cell receptor repertoire before and after T cell administration [Institute of Applied Biosciences (INEB) – Center of Research and Technology (CERTH)]. The business enterprise 1 (ΑΝΤΙSEL ΑFΟΙ Α. SELIDISΑ.Ε.-E1) will be responsible for the in-depth immunophenotypic and functional characterization, as well as the quality control of the T-cell products through the development and standardization of new analysis platforms. The 2nd industrial partner (Pharmassist Ltd.-E2), in collaboration with the academic partners, will organize and submit to the regulatory agencies the clinical studies’ dossier and will undertake their monitoring including pharmacovigillance. E2 will also map out promotional plans for the products and file patent application.

Our ambition is to cultivate a fertile ground for cooperation between research organizations and enterprises paving the way towards the gradual transition from the academic, small scale production of T-cell products to the industrial, scale up production, for a broader application of adoptive immunotherapy in all HSCT Units in Greece and beyond.

The documents for the initiation of the clinical trial phase I-II  for the iG-Tregs evaluation (EudraCT-2021-006367-26) have been submitted to the regulation authorities, National Organization of Medicines [103690/03/03-10-2022 (ISO 129/22)] and National Ethics Commitee (A/A 119465/10-11-2022).