Combination Therapy of Immunocytokines with Ipilimumab: A Cure for Melanoma?

This paper summarizes the successful administration of the tumor targeting immunocytokines L19-IL2 and L19-TNF in combination with Ipilimumab (Yervoy) which resulted in the complete regression of the tumor in mice.

Metastatic melanoma is an aggressive form of skin cancer with limited treatment options due to resistance to conventional chemotherapy. Patients also often develop resistance to Vemurafenib (Zelboraf), a recently developed targeted drug for metastatic melanoma with a specific genetic mutation (BRAF positive).  As a result, a number of alternative treatment options were explored in clinical trial settings. The use of cytokine therapies yielded positive results, but was accompanied by severe toxicities in most patients. Another alternative treatment approach is the use of immunological therapies for melanoma (i.e. Ipilimumab), which was shown to increase survival rates in 20% of the patients. Overall, the strongest anti-tumor activity was found in so called “immunocytokines” which are better tolerated by patients than pure cytokine treatments. Cytokines are proteins in the body that stimulate certain immune responses. Immunocytokines are modified cytokines, that can target specific tumor tissues. This way, the immune response is limited to areas of cancer growth, lowering overall toxicity of the treatment. Cancer tissue targeting is achieved with antibodies, which are structures that selectively bind to proteins produced by cancer cells.

This article reports results of a study by Schwager et al. (2012) which assessed the efficacy of a new anti-tumor immunocytokine in mice. This drug contained the cytokine L19-Il2 bound to an antibody against a specific protein, CTLA4. An effective immune response was generated and lead to significant delay in tumor growth in mice. Similar results were obtained for the treatment with L19-Il2 combined with an anti-PD-1 antibody (delay in growth but not complete tumor regression). Complete tumor regression was achieved when combining L19-Il2 with another cytokine, L19-TNF, in a mouse model.

Based on these results, researchers suggest two strategies for the treatment of metastatic melanoma. One option is to combine L19-IL2 with Ipilimumab, while the other involves combining L19-Il2 with L19-TNF.

These are encouraging results and further studies are warranted to characterize the mechanism of action of these immunological treatments. L19-Il2 and Ipilimumab shows significant promise as a melanoma treatment and clinical trials are awaited.