Weaponized, Armored and Targeted Tregs to promote robust immune tolerance – ARMSTRONG

Regulatory cell therapy raises tremendous hope to get rid of long-term immunosuppression, and ensuing infectious and neoplastic complications, especially in solid organ transplant recipients. However, the first clinical studies have yielded mixed results. The challenge of isolating and expanding donor-specific regulatory T cells is a significant bottleneck. Moreover, the fast decay of regulatory T cells after transfer, mostly due to insufficient supply in IL-2, instrumental for their survival and stability, accounts for their failure at reversing the alloimmune response, spontaneously skewed toward rejection. We propose to combine three technologies of gene therapy, invented by the two academic and industrial partners, to produce a weaponized, armored and targeted (WAT) final regulatory cell (Treg) product. Self-sufficiency in IL-2 signal through gene addition support expansion, lineage stability and ability to promote infectious tolerance (weaponized). The disruption of a gene encoding the target of a tolerogenic (FDA-approved) immunotherapy in the regulatory cells shield them from the depleting effect of this monoclonal antibody, leading to their enrichment in vivo (armored). Finally, CAR (chimeric antigen receptor) engineering allows to redirect regulatory T cells toward a donor antigen (targeted). We aim to demonstrate the capacity of this combination strategy to promote transplant tolerance using highly relevant preclinical models of graft-vs-host disease and skin transplantation in fully humanized mice. This strategy will allow to deplete effector alloreactive T cells, while sparing the WAT-Tregs, in order to tip the alloimmune response toward regulation, using a limited number of regulatory cells, manufactured over a short culture. Such achievement would lay the groundwork for a rapid clinical development at reduced cost.