A5*
TReAT - A Novel Tacrolimus-Resistant Antiviral T-Cell-Therapy
Dr Leila Amini, Charité - Universitätsmedizin Berlin; Dr Michael Schmück-Henneresse, Charité - Universitätsmedizin Berlin; Prof. Petra Reinke, Charité - Universitätsmedizin Berlin; Prof. Hans-Dieter Volk, Charité - Universitätsmedizin Berlin; Dr Dimitrios Laurin Wagner, Charité - Universitätsmedizin Berlin
Ascenion GmbH
Challenge
Immunosuppressive therapy is needed in essentially all patients following allogeneic hematopoietic stem cell transplantation (HSCT) and solid organ transplantation (SOT) in order to prevent graft versus host disease (GVHD) or acute graft rejection and chronic graft loss, respectively. However, immunocompromised individuals are at major risk for severe infectious complications. Viral infections or reactivation of latent viruses including CMV, EBV, human herpes virus 6 (HHV-6), adenoviruses, BKV, and JC virus (JCV) are a serious threat to patient health and are responsible for significant morbidity and mortality. For instance, 30% of patients experience CMV viremia or disease following SOT and are treated with antiviral therapies which can be associated with significant toxicities and are often ineffective due to development of resistance. Adoptive virus-specific T cell therapy (VST) is a very promising treatment approach to reconstitute effective immunity and is already proven to be effective in HSCT patients. Despite an initially effective reduction of symptoms and viral load, limited persistence and longevity of VST are major challenges that have to be addressed.
Technology
Immunosuppression therapy to control allo-antigen-reactive effector T cells comprises the use of calcineurin inhibitors (CNI) such as tacrolimus and cyclosporine which are currently the most effective treatment for sustained suppression. However, CNI are also expected to interfere with VST since they directly block the same activation pathways that antiviral T cells need to function and expand after infusion. A promising strategy to solve this problem is induction of CNI resistance by gene editing VST. The TReAT-project has developed a personalized therapeutic platform providing tacrolimus-resistant antiviral T-cell products. Key step is CRISPR/Cas9 mediated gene editing in order to knock-out the FKBP12 gene which is the adaptor protein needed for the immunosuppressive function of tacrolimus in T cells. VST (e.g. against CMV) are isolated from peripheral blood mononuclear cells (PBMCs), expanded for 1 week and followed by FKBP12 KO achieved by electroporation with RNP complexes of Cas9 and a specific sgRNA. This protocol yields VST that remain highly functional after tacrolimus treatment while showing comparable killing capacity as unmodified VST. The robust protocol is GMP-compatible and resulting VST are extensively characterized to ensure safety of the product. Next steps in the project are GMP process validation and initiation of a phase I/II clinical trial with VST against CMV after HSCT or SOT. The interdisciplinary TReAT project is located at Charité - Universitätsmedizin Berlin, within the Berlin Center for Advanced Therapies (BeCAT) which is dedicated to the development and application of novel ATMP within a state-of-the-art research facility. The BeCAT has a manufacturing license for various T-cell products, among others a tacrolimus resistant Treg product, and a GMP facility.
Commercial Opportunity
Available for licensing and cooperation
Development Status
Preclinical, protocol for manufacturing process GMP-compatible
Patent Situation
National patent applications with priority date 21.8.2020:
European patent application EP4196572
US patent application US20230174936
Chinese patent application CN2023072800395560
Canadian patent application CA3182371
Australian patent application AU2021323392
Further Reading
Amini L, et al. CRISPR-Cas9-Edited Tacrolimus-Resistant Antiviral T Cells for Advanced Adoptive Immunotherapy in Transplant Recipients. Mol Ther. 2021 Jan 6;29(1);32-46.
