Autologous T-cell therapies against cancer face disadvantages in terms of production cost, logistics, and compromised T-cell fitness. The use of allogeneic T cells can partially bypass these limitations but it brings new challenges involving host-versus-graft (HvG) and graft-versus-host (GvH) reactions.
Our aim is to develop a strategy to bypass these two obstacles by leveraging on the substantial flexibility of mRNA electroporation technology in engineering allogeneic mRNA TCR-T cells for multiple infusions into patients.
Instead of reducing allogeneic T cell immunogenicity through irreversible genetic approaches, we propose to prevent HvG reactions by transiently suppressing the host's immune system with a finite treatment of immunosuppression (Tacrolimus). At the same time, the functionality of these allogeneic T cells will be preserved through the conferment of transient Tacrolimus resistance by introducing a modified version of calcineurin B into T cells through mRNA electroporation. Our in vitro data show that Tacrolimus can effectively suppress the HvG reactions with minimal impact on the functionality of the Tacrolimus-resistant engineered allogeneic T cells.
To minimize the risk of GvH disease, we utilized different cytokine cocktails to expand our T cells into populations with reduced GvH reactions. We showed that expanding T cells with the addition of IL-4 and IL-7 resulted in allogeneic T cells with significantly lower GvH disease potential than conventional IL-2 expanded T cells, while maintaining both tumoricidal efficacy and electroporation efficiency.
Taken together, our preliminary results showed that mRNA electroporation and T cell expansion procedures can be utilized in combination to develop a safe and effective ‘off-the-shelf’ allogeneic TCR-T cell therapy product.