For years cancer therapies were mainly concentrated around surgery, chemotherapy and radiotherapy. Recently, a new domain has emerged. Immunotherapies aim to exploit, enhance and optimise the patient's immune system to be more potent at eradicating tumours. T-cell immunotherapies, however, often encounter challenges with low cell surface expression of tumour-associated-antigens (TAAs), down-regulation of class I MHC molecules and low T-cell avidity for TAAs, all contributing to tumour escape.
To address these challenges, Immunocore Ltd. has developed ImmTAC (Immune Mobilising mTCR Against Cancer) technology that aims to recruit and redirect circulating T-cells to target and kill cancer cells with high specificity. ImmTACs are composed of an affinity enhanced monoclonal T-cell receptor (mTCR) combined with an anti-CD3 specific antibody fragment (CD3-scFv). The mTCR targets cancer cells that express TAAs displayed on class I MHC molecules, with high affinity. The CD3-scFv effector domain then drives the recruitment and activation of T-cells. ImmTACs enable an immune synapse to form, leading to the destruction of cancer cells by T-cells.
TAA candidates are selected according to their level of gene expression by measuring their mRNA levels by RT-PCR in healthy and cancer cells, in order to reduce off-target toxicity, as well as by measuring their cell surface expression on class I MHCs by mass spectrometry, to verify target presentation.
We present here our current clinical ImmTAC candidate, IMCgp100, which targets the melanoma-associated gp100 antigen presented on HLA-A2. IMCgp100 has been extensively studied in vitro and is undergoing a phase IIa clinical trial in advanced melanoma patients in the UK and US. The maximum tolerated dose has been established and a dose expansion phase is currently underway. T-cell mobilisation, relevant cytokine release as well as tumour shrinkage have been monitored. The very encouraging results observed so far in our clinical trials show ImmTAC technology to be a promising efficient immunotherapy for cancer.
Citation Format: Johanne Pentier, Mary Connolly, Martina Canestraro, Ruth Ryan, Luise Weigand, Namir Hassan, Annelise Vuidepot, Bent Jakobsen. IMCgp100 ImmTAC: A new immunotherapeutic reagent for the treatment of malignant melanoma. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A037.
- ©2016 American Association for Cancer Research.