The background of IMA203, it’s known as Anzu-cel, the idea was if you could target a cold tumour micro-environment with a T-cell receptor against a highly expressed protein or a peptide, would this actually be a strategy to develop an immune response? So in this cohort we looked at the uveal melanoma patients. Uveal melanoma is the most common adult cancer of the eye. It’s the second most common type of melanoma outside the skin, but it meets the WHO and National Cancer Institute definitions for rare cancer. It only affects 0.6-0.7 per 100,000, so that’s 6-7 persons per million in the general population. So it’s a rare cancer, despite being the most common adult eye cancer. The dilemma in uveal melanoma is that half of patients will metastasise and usually die from their metastasis. It predominantly involves the liver, so death is liver failure, and despite having 15 years of advancements in skin melanoma, most of these treatments were neither tested nor effective in uveal melanoma, so we need therapies that really work in this particular disease.

What was the study design?

So IMA203, Anzu-cel, targets PRAME. PRAME is a peptide, a protein, highly expressed in cancer. In uveal melanoma we think it’s expressed in more than 90% of metastatic tumours. PRAME is processed into different peptide fragments and then carried to the tumour cell surface in the context of an HLA molecule. So Anzu-cel, IMA203, is the investigational product that is transduced with a T-cell receptor that recognises the specific HLA-PRAME complex. Patients are tested for HLA in their blood, their tumour is tested for PRAME expression, and if both of those are positive then they undergo leukapheresis. Anzu-cel is then manufactured from their white blood cells to be transduced to recognise this HLA-PRAME complex, and then the patients receive some lymphodepleting chemotherapy, Anzu-cel one-off infusion and ten days of low-dose interleukin-2.

What have the findings been so far?

So this was a phase I study, the primary objective of phase I studies are typically safety and determining the recommended phase II dose, RP2D. In this study we found that the IMA203, Anzu-cel, is quite safe to administer but there are some expected toxicities to be aware of. In most cell therapies there are toxicities from the lymphodepleting chemotherapy, and that’s what we saw. Most patients had some degree of cytopenia, neutropenia, anaemia etc. Those are transient and very self-limiting. All patients experienced cytokine release syndrome; the median onset was day 1, median duration was nine days, and there were no patients with long-term side effects or cytokine-release syndrome. Importantly, there were no deaths from the Anzu-cel treatment, and that’s in the 16 patients with uveal melanoma but also in the totality of the 74 patients treated in the phase I study.

As far as efficacy, which is a secondary outcome, all 16 patients with uveal melanoma had some reduction in their tumours, so this is pretty remarkable, to see all patients getting some benefit. 66% of patients had a confirmed response, so that means a response that was then maintained for at least four weeks, and over 80% of patients had some benefit in terms of disease control rate, so stability or a response for at least six weeks.

What are the next steps?

So the next steps off of these data, 16 patients with uveal melanoma, we’re very excited to say that this will be confirmed in a phase II trial. Uveal melanoma is a rare disease and we understand we don’t always know what to randomise against, but still we do believe that this cohort is important. The fact that all 16 patients had a reduction in their tumour burden means we want to see if this holds up as we enrol more patients in a phase II study.

What are the potential implications of these findings?

So Anzu-cel is being also studied in a phase III randomised trial in cutaneous melanoma, so we have hopes that it will be effective there because skin melanoma also has a high expression rate of PRAME. There’s this phase II in uveal melanoma that’s hopefully a confirmatory trial of these phase I results. We actually think mucosal melanoma has a high PRAME expression rate as well as many, many other solid tumours. So really we hope that we’re proving the point that what works in this cold tumour, such as uveal melanoma, typically not immune responsive, if you target a highly expressed protein with a specific T-cell receptor, you might be able to engender some clinical benefit and PRAME might just be the target and Anzu-cel might just be the drug.