Immtacs: Bi-Specific Tcr-Anti-Cd3 Fusions For Potent Re-Directed Killing Of Cancer Cells

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Immunotherapeutic strategies that are able to drive activation of T cells, and in particular CD8+ cells, possess significant potential to eradicate tumors. Although it is well-established that CD8+ T cells can mediate potent destruction of tumor tissue, the immunosuppressive tumor microenvironment and thymic selection serve to limit the availability and effectiveness of tumor-specific T cells. These factors typically prevent an effective immune response in cancer patients. Despite some successful attempts to counter immune-suppression using bi-specific, immune-activating antibodies, the paucity of tumor-specific antibody targets limits this approach. ImmTACs (immune mobilising monoclonal TCRs against cancer) are a new class of soluble bi-specific molecules comprising, pico-molar affinity T cell receptors (TCRs) fused to an anti-CD3 specific scFv. Unlike antibodies, TCRs target peptide epitopes, derived from intracellular antigens, and presented on the cell surface by Class I MHC, thus providing access to a large pool of tumor-associated antigens. The high affinity recognition mediated by the engineered TCR portion of ImmTACs overcomes the problems posed by thymic selection, as well as HLA down-regulation on tumor cells, while the anti-CD3 moiety re-directs T cells to mediate a potent anti-tumor response. The most advanced ImmTAC reagent to-date, IMCgp100, targets the HLA-A2 presented gp100280-288 epitope. This reagent represents a first-in-class treatment for malignant melanoma, and is currently in Phase I clinical testing, with maximum tolerated dose having been established. Here we examine the processes which underpin the mechanism of action of IMCgp100, as well as the broader ImmTAC platform. These studies demonstrate that IMCgp100 is able to redirect T cells from healthy donors and from melanoma patients to destroy cancer cells with low cell-surface epitope densities (25 to 70 epitopes per cell), and to secrete a range of inflammatory cytokines. Effector and central memory cells in the CD8+ and CD4+ repertoire rapidly respond to ImmTAC engagement on melanoma cells, while the naive cells provide a slower but nonetheless potent response. ImmTACs can induce an anti-tumor T cell response despite the presence of immunosuppressive regulatory T cells and expression of inhibitory molecules such as PD-L1. In addition, ImmTAC activated cytotoxic T cells are capable of serially killing a number of target cells. Finally, we have been able to demonstrate that IMCgp100 can trigger DC X presentation of melanoma associated antigens providing a potential mechanism for inducing a long-term self-sustained anti-cancer response. Taken together these data demonstrate the potential of the ImmTAC platform for targeted cancer therapy. Citation Format: Giovanna Bossi, Debbie Baker, Katherine Adams, Jane Harper, Joseph Dukes, Nathaniel Liddy, Samantha Paston, Yvonne McGrath, Tara Mahon, Pater Molloy, Malkit Sami, Emma Baston, Brian Cameron, Andrew Johnson, Annelise Vuidepot, Namir Hassan, Bent Jakobsen. ImmTACs: Bi-specific TCR-anti-CD3 fusions for potent re-directed killing of cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 670. doi:10.1158/1538-7445.AM2014-670