Persistent signaling can drive TCR-T cells to mediate inflammatory responses against vital tissues, especially in crucial organs like the brain. Moreover, over-activation or sustained TCR signaling can dampen the therapeutic efficacy leading to T cell exhaustion or cell death. One way to overcome persistent signaling is an inducible system to switch the TCR on and off selectively. Different approaches exist to control engineered T cells. Medigene merges its TCR with the 4OH-Tamoxifen inducible system, one of the best-characterized “reversible switch” models with numerous beneficial features.
The T cell receptor assembly is a complex process. In humans, 95% of TCRs consist of an alpha (α) chain and a beta (β) chain, which can dimerize and form a heterodimer. 4OH-Tamoxifen-induced dimerization is time- and concentration-dependent, providing flexibility to control levels and duration of TCR expression (Figure 1 & 2).
Down-regulation of iM-TCRs can help TCR-T cells avoid exhaustion from TCR over-activation (rest periods). Durable responses can be maintained through the re-induction of iM-TCRs. iM-TCRs expand the safety threshold of TCR-T therapies for use against tumors in high-risk tissues such as the brain, liver and heart.
Figure 1:
Mode of Action of iM-TCRs
iM-TCR responds to antigen-specific stimulation in a manner comparable to the natural wildtype (wt)-TCR. In a co-colture experiment of antigen presenting cells (APC) loaded with either the relevant or irrelevant peptide, the Medigene iM-TCR-T cells only show activity (IFNγ-release) when incubated with dimerizer (Tamoxifen) Depending on the concentration of the dimerizer, the cytokine release of iM-TCR T cells is greater then the cytokine release of the wildtype TCR-T cells (Figure 2).
Figure 2:
Interferon γ release upon dimerizer addition
At Medigene, we are working towards a system whereby we discover highly sensitive, specific and safe TCRs to many different surface or intracellular targets and then equipped the T cell with our iM-TCR which would allow a physician to control the expression of the TCR in the patient by dosing the patient with Tamoxifen application.