Developing T cell receptor therapies to target cancer

Immunotherapies that activate patient’s T cells to attack cancer cells have a potential to eradicate tumours. Although therapies using monoclonal antibodies have been proven effective, they are limited to targeting cell surface proteins. This limitation is overcome by T cell receptor (TCR) based approaches, as TCRs recognize a broad range of peptides presented in the context of human leukocyte antigens (HLAs).

At Immunocore, we have developed Immune mobilizing monoclonal TCRs Against Cancer (ImmTAC™), a new class of soluble bi-specific biologics comprising affinity-enhanced TCR fused to an anti-CD3 effector domain. ImmTAC molecules recognize a specific target peptide presented by HLA on tumour cells and redirect the patient’s T cells to carry out potent tumour cell killing.

Development of ImmTAC molecules is a multi-step process where safety and specificity are the key considerations. Key is affinity maturation of the TCR through mutagenesis of CDR loops. The highest-affinity mutants are further screened for specificity and cross-reactivity using a range of cellular assays.

This process has been successfully applied to produce ImmTAC molecules for a number of targets, demonstrating the robustness of the platform. As an example, IMCgp100, an ImmTAC recognizing melanoma associated protein gp100, is currently undergoing clinical trials in patients suffering from advanced malignant melanoma.