Novel bi-specific TCR-based reagents for targeted cancer immunotherapy

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Published: 27 Apr 2017
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Dr Joseph Dukes - Immunocore Limited, Abingdon, UK

Dr Dukes speaks with ecancer at the 1st Cancer Research @ Bath Symposium about ImmTac, a bi-specific T cell platform that targets uveal melanoma.

He describes the CD3 targetting of ImmTac to attract T cells to attack tumours, and introduces dose escalation studies leading to upcoming phase II trials, including combination with other immunotherapies.

Dr Dukes considers the function of other T cell platforms, including those against CD19, and looks forward to presenting trial data soon.

The ImmTac is what’s called a bi-specific drug so it has two recognition ends, one is a T-cell receptor so this recognises specific peptides that we choose to target that are specifically expressed in cancer, so for targets that are restricted to cancer and not normal cells typically. The TCR end binds to this peptide presented by what’s called an HLA molecule on the surface. On the other end of the molecule is what’s called an SCFE2-CD3, so this is like an antibody fragment that recognises CD3 which is present on most T-cells. So when the TCR end binds to the peptide HLA complex on the cancer cell it can then decorate this cancer cell with this anti-CD3 end which can then in turn recruit T-cells in the vicinity to kill that target cell. That’s, very briefly, our ImmTac technology.
Have there been any successful models or trials so far?
Yes, we are currently in a phase II pivotal study in uveal melanoma with our lead molecule which is called IMCgp100. We’ve seen signs of safety in our dose escalation study; we’ve established a maximum tolerated dose and a recommended phase II dose. In that phase II uveal melanoma study that we’re at now previously we’ve seen clinical responses, we’ve seen durable responses, patients responding for upwards of two years and these are end-stage patients with metastatic melanoma. We’ve seen a number of responses on that trial so very encouraging results there and that’s why we have identified this uveal melanoma subset to focus on our phase II pivotal study with because we’ve seen good responses in uveal melanoma. We’ve also seen responses in cutaneous skin melanoma and we are in trials with those with combining with other immunotherapy agents such as the checkpoint inhibitor molecules.
We’re not really working in this, using CD19 as a targeting modality for malignant B-cells, so lymphomas and leukaemias, is something that other similar approaches are being used for that are antibody approaches, so targeting the CD19 such as BiTEs which also use CD3 on the other end to recruit T-cells against the over-expressing CD19 positive leukaemia cells. What we’re also looking at is to combine with other immune modulatory agents, so using our same format of ImmTac and maybe combine it with something like a TGF-β inhibitor, combining with various other agents that are starting to get out there that could have potential synergistic effects with what our molecule does, maybe make them perform better than they already do.
When can we expect results?
Over the next year or so we hope to develop the full results, maybe by the end of 2018, beginning of 2019. We should hopefully at some of the usual ASCO and AACR clinical conferences present some initial findings from those which are looking promising. So look out for those abstracts to come out