Cancer immunosuppression prevents the effective activation of antigen-specific cytotoxic T cell responses against tumor cells. The activation of tumor-specific responses has the potential to halt the progression of cancer and, in some circumstances, eradicate it. Designing the therapeutic interventions that can achieve this intended mechanism of action (T cell eradication of tumors) aims to harness the known specificity of the T cell: target cell interaction to simultaneously a) lead to death of tumor target cells expressing the antigen and b) to limit surrounding tissue damage and thus manage potential toxicity. Previous design approaches of bispecific therapeutic molecules to redirect T cell responses against cancer cells have utilized antibody binding domains to recognize tumor cell-surface proteins. These first generation bi-specifics have proven efficacy in hematologic malignancies, and novel approaches such as TCR targeting have the goal of enhancing activity in solid tumor settings. The ImmTACs (immune-mobilizing monoclonal TCRs against cancer) are a new class of bispecific therapeutic molecule, utilizing the physiologic antigen recognition system of the T cell, the monoclonal T cell receptor (TCR), as the targeting effector fused to an anti-CD3 domain. The soluble TCRs have been engineered to possess extremely high affinity for their tumor antigen peptide-HLA complex. ImmTACs thus overcome the problem of low affinity tumor-specific T cells imposed by thymic selection, and provide a means to target intracellular tumor antigens not accessible to antibody binding domains. The ImmTACs drive recruitment of polyclonal T cells to the tumor, resulting in potent redirected T cell response and tumor cell destruction in an antigen-specific manner. The first ImmTAC tested in the clinic is IMCgp100, an engineered TCR recognizing the gp100 melanoma antigen in the context of HLA-A2 with promising, preliminary single agent activity in both cutaneous and uveal melanoma.
Citation Format: Christina M. Coughlin. Immune mobilizing TCR therapies against cancer (ImmTAC): A novel class of antigen-specific tumor immunotherapy [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr IA21.
- ©2016 American Association for Cancer Research.