Abstract 5616: Soluble, high affinity TCRs fused to anti-CD3 redirect T cells to kill cancer cells presenting MAGE-A3 and NY-ESO antigens
Authors: Hassan Namir J. , Liddy Nathaniel , Mahon Tara , Bossi Giovanna , Adams Katherine , Gavarret Jessie , Bianchi Frayne , Lissin Nikolai , Molloy Peter , Li Yi , Pumphrey Nick , Cameron Brian , Sami Malkit , Baston Emma , Harper Jane , Ashfield Rebecca , Johnson Andrew , Vuidepot Annelise , McGrath Yvonne , Todorov Penio , Paston Samantha , Dennis Rebecca , Sewell Andrew K. , Price David A. , Harwood Naomi , Lissina Anna , Gostick Emma , June Carl , Kalos Michael , Plesa Gabriela , Sutton Deborah , Williams Daniel , Jakobsen Bent K. 
Published: February 2011

In the last decade, major efforts in the fight against cancer have focussed on galvanising the adaptive immune system to kill tumours. Many of these endeavours are based on the development and clinical use of monoclonal antibodies (mAb) which are the most successful class of immune modulating agent identified to date. However, while mAbs show promise against certain cancers, their specificity is limited to integral membrane proteins; this hinders their extensive development for the purposes of targeting cancer cells.

In contrast to mAbs, T cell receptors (TCRs) recognise peptides bound to major histocompatibility complex class I (MHC I) molecules. These peptides are derived from endogenously processed proteins, and therefore represent a different repertoire of targets to those recognised by mAbs. This alternate spectrum of antigens provides the potential to target cancers using an untapped source of well-validated epitopes. Naturally occurring TCRs, however, have relatively low affinities for their antigen compared to antibody binding. Advances in engineering techniques have allowed the generation of high affinity monoclonal TCRs (mTCRs) with picomolar affinities for their antigen. Using targeted mutagenesis and phage display, we have generated a number of soluble, high affinity mTCRs specific for several reported tumour-associated antigens. Through mTCR fusion to an anti-CD3 single chain variable fragment (scfv), we produced bifunctional proteins that redirect T cell immune specificity. These novel proteins are termed ImmTACs (Immune-mobilising mTCRs Against Cancer). We present data demonstrating the potential of two such ImmTAC molecules, NY-ESO-ImmTAC and MAGE-A3-ImmTAC, to treat certain cancers. NY-ESO1 and MAGE-A3 are both cancer testes antigens and therefore represent potentially very clean molecular targets. We demonstrate that both NY-ESO-ImmTAC and MAGE-A3-ImmTAC are capable of potently redirecting unstimulated peripheral blood mononuclear cells (PBMC) or CD8+ T cells against multiple myeloma, colorectal carcinoma and non-small cell lung cancer cell lines despite the presentation of extremely low antigen numbers (&lt;100 epitopes/cell) on the surface of these cells. ImmTAC-redirected T cells respond with multiple effector functions including the production of granzyme B, IFNγ and IL-2, resulting in a high level of antigen-specific cancer cell killing over the course of 24 hours. The mechanism of killing is at least partly contributed by the caspase-3/7 apoptotic pathway. We also show that NY-ESO-ImmTAC and MAGE-A3-ImmTAC were inert by all our measures in the presence of normal primary cells including melanocytes, hepatocytes and astrocytes. Thus both MAGE-A3 and NY-ESO-ImmTACs possess the potential to be highly specific, potent cancer immunotherapies offering a targeting and therapeutic approach distinct from any other biologic in development.

Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5616.