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 (iM-) to switch the TCR on and off selectively. Different approaches exist to control engineered T cells. Medigene merges its TCR with the 4OH-Tamoxifen (iM-TCR) 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).
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

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.