ImmTAC molecules are T Cell Receptor (TCR)-anti-CD3 bispecific fusion proteins that can redirect and activate polyclonal T cells to kill tumor cells in an MHC-restricted manner. Tebentafusp, a gp100-directed ImmTAC, is the first TCR therapeutic to demonstrate survival benefit in a solid tumor and has been approved in 2022 by the FDA and the EMA for the treatment of HLA-A*02:01+ adults with unresectable or metastatic uveal melanoma (mUM).
The use of TCRs as therapeutics allows access to a multitude of intracellular targets not available for conventional antibody therapeutics. To overcome moderate binding affinities of natural cancer specific TCRs (mM to nM range) we developed a platform to affinity enhance TCRs to pM values, before fusing them to an anti-CD3 scFv effector arm, with nM affinity. The long half life of target-bound molecules favours engagement of T cell in the tumor microenvironment, creating an inflammatory milieu and promoting recruitment of rejuvenated T cells from the circulation.
To make ImmTAC treatment available to more patients, we are expanding the platform to αβ and γδ TCRs targeting monomorphic unconventional antigen presenting molecules, including CD1 and MR1. Tumor associated unconventional T cells, including MAIT, iNKT cells and γδ T cells, are positively associated with clinical outcome in several cancers. Unconventional T cells recognize cancer dysregulated metabolites, lipids and stress molecules which may offer a unique window of specificity over normal tissues. We have successfully engineered three unconventional TCRs: a metabolite specific MR1-restricted TCR; a CD1c-restricted lipid-agnostic TCR and a butyrophilin-specific Vδ2 Vγ9 TCR. We demonstrate selective recognition of antigen positive targets, with minimal off target effect.
This important proof of principle paves the way for harnessing unconventional T cell receptors in cancer immunotherapy, despite the challenges in ligand identification, which will be discussed.