Immune Mobilising Monoclonal TCRs Against Cancer (ImmTAC) molecules are a new class of bi-specific biologic specifically designed to recognize and eradicate cancer cells. ImmTAC molecules are composed of an affinity-enhanced T-cell receptor (TCR) fused to an anti-CD3 effector function engineered to recognize peptides presented by human leukocyte antigen (HLA) and induce T-cell activation and T-cell mediated killing of tumor cells. TCR-based immunotherapeutic strategies offer distinct advantages over traditional antibody-based therapies, most notably providing access to up to nine-fold more cancer targets by targeting intracellularly processed peptides presented by HLA as opposed to cell surface proteins. Preclinical testing of ImmTAC molecules can prove particularly challenging as these molecules are exquisitely human-specific, requiring a human peptidome and intact human immune system; thus the use of conventional animal models is inappropriate. Given that these molecules harness the full force of the immune system, robust preclinical testing is essential to predict safety and efficacy and inform on clinical dosing for first-in-human studies. Here we present, to our knowledge, the first entirely in vitro preclinical package that comprises a range of cellular and molecular assays to assess the efficacy, safety and specificity of ImmTAC molecules. To exemplify our approach, we draw upon the preclinical testing of multiple ImmTAC molecules, including IMCgp100, the first ImmTAC molecule to reach the clinic. We propose that this preclinical package can be applied to the testing of other TCR-based therapies to deliver a more physiologically relevant model.
Citation Format: Ana Ribeiro, Tomasz Dobrzycki, Jane Harper, Giovanna Bossi, Debbie Wright, Andrea Stacey, Nicole Bedke, Ruth Martinez-Hague, Dan Blat, Laure Humbert, Zoe Donellan, Samantha Paston, Luise Weigand, Martina Canestraro, Sophie Botta Gordon-Smith, Bent K. Jakobsen, Joseph Dukes. An in vitro preclinical package to assess the safety and efficacy of ImmTAC™ molecules [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A214.