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Cheryl McAlpine

Immunocore Ltd, Abingdon, Oxfordshire, UK

Title: ImmTACs: Bi-specific TCR-based reagents for targeted cancer immunotherapy

Biography

Biography: Cheryl McAlpine

Abstract

Immune system based therapies constitute a promising class of treatment for many types of cancers. Whilst T cells can mediate tumor destruction, their effectiveness is limited due to negative thymic selection, down-regulation of HLA expression by cancer cells and an immunosuppressive microenvironment. To overcome the poor immunogenicity of tumors, Immunocore has developed ImmTACs (immune mobilizing monoclonal T cell receptors (mTCR) against cancer). A soluble mTCR, engineered to recognise a given tumor associated peptide-HLA complex with exceptionally high sensitivity and specificity, redirects host polyclonal T cells via an anti-CD3 antibody fragment, facilitating targeted T cell recognition of tumors. Antigens that exist on tumor cells but not on normal cells are rare, thus the selection and validation of appropriate target antigens and the testing of ImmTACs for specificity is critical. Antigen candidates are selected based on their levels of expression in cancer vs healthy tissues by RT-PCR and the presence of the targeted peptide on the cell surface is confirmed by mass spectrometry. As ImmTACs are specific for humans, efficacy, specificity and off target effects are determined through a detailed molecular and cellular testing programme, using antigen positive tumor cells and HLA appropriate primary human cell lines representing a range of tissues. IMCgp100, the lead ImmTAC, is currently in a Phase I/II clinical trial for the treatment of advanced melanoma. The maximum tolerated dose has been established and emerging data demonstrate several durable responses. IMCgp100 is well tolerated and there is evidence of T cell mobilisation in the tumor microenvironment, release of cytokines and tumor shrinkage.