Abstract 5616: Soluble, high affinity TCRs fused to anti-CD3 redirect T cells to kill cancer cells presenting MAGE-A3 and NY-ESO antigens

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 (