Clinical results

In total, 41 patients were treated with interferon alpha and T cell therapy, either derived from blood, or from their tumour tissue. Of them, 34 patients with progressive stage IV metastatic melanoma received the full treatment cycle and are therefore evaluable for safety/toxicity, clinical response according to RECIST and immunological parameters.

First of all, the T cell treatment in combination with interferon alpha was safe and well tolerated. 2 patients had a complete response, 1 had a partial response and 7 displayed a prolonged stable disease. Thus, 10 out of 34 (29,4%) of the treated patients achieved clinical benefit from treatment (responders). Patients were treated in different dose cohorts but the responses were distributed among all doses.

Interestingly, 6 out of 14 (42.8%) patients who did not previous receive immune (checkpoint) therapy showed clinical benefit, whereas 4 out of 20 (20%) patients who received prior checkpoint therapy still responded to T cell treatment with interferon alpha.

The overall survival of responder and non-responder patients was respectively 90% versus 28.6% at 1 year, and 46.7% versus 0% at 3 years follow-up. Median survival was 36 versus 7 months, respectively. Overall, non-responding patients more often received 3 or more systemic therapies, when compared with patients who responded, 40% vs 14%, respectively. Finally, 4 patients with the longest survival for which an autologous tumour cell line was available had T cell responses specific to unique mutation-derived neoantigens expressed by their tumour.

Value

Immune therapy has revolutionised melanoma treatment. In particular through the discovery of the checkpoint blockers. Still, the majority of patients are refractory or relapse. This recently published trial shows that 20% of the patients that experience no (more) benefit from checkpoint blockers can have a clinical benefit from autologous adoptive T cell therapy with interferon alpha. Clinical benefit is defined as patients with complete response (CR), partial response (PR) or durable (≥ 6 months) stable disease (SD) according to RECIST.

Moreover, the responders also contained (few) patients with brain metastasis. A population that usually has a very grim prognosis.

What’s next?

Based on the obtained results, the research group is already recruiting in a follow-up trial, ACTME (NCT03638375), where patients will earlier on receive tumour derived T cells in combination with checkpoint blockers (anti-PD-1, nivolumab) to explore whether this combination is safe. If so, interferon alpha will be added as well and after safety of the total combination is established it will be evaluated whether this approach further optimises the treatment.

In parallel, the group searches for funding to explore the feasibility to enrich selected tumour-specific T cells in each particular patient and whether this T cell product would enhance the benefit for patients.

Contribution of the Anticancer Fund

In 2012, the Anticancer Fund supported the preclinical work of Els Verdegaal from the group of Sjoerd van der Burg from LUMC, Leiden, The Netherlands with 147 000 euro to test whether enrichment of tumour-specific peripheral blood T cells was feasible with autologous melanoma cell lines. The data gathered allowed this research group to find additional funding, eventually leading to this clinical trial. Part of the patients were treated with blood derived T cell therapy expanded by this approach.

Furthermore, the technique to generate autologous cell lines allowed to test whether a T cell response specific to the patients tumour was present.