Melanoma Immunotherapy

Abstract

Melanoma immunotherapy has been an area of intense research for decades, and this work is now yielding more tangible results for patients. Work has focused on 4 main areas: cytokine therapy, administration of immune-modulating antibodies, adoptive T-cell therapy, and vaccines. Cytokine therapy is an established treatment for advanced melanoma, and immune-modulating antibodies have recently emerged as an exciting new area of drug development with efficacy now established in a phase III trial. Adoptive T-cell therapy provides the proof of principle that T cells can attack and eliminate tumors. It has been challenging, however, to adapt this treatment for widespread use. Vaccines have generally yielded poor results, but intratumor pathogen-based strategies have shown encouraging results in recent trials, perhaps due to stronger immune stimulation. A review of the field of melanoma immunotherapy is provided here, with emphasis on those agents that have reached clinical testing. Novel strategies to induce the immune system to attack melanomas are reviewed. In the future, it is envisioned that immunotherapy will have further application in combination with cytotoxic and targeted therapies.

Melanoma Immunomodulation: A War of Attrition

“…This section will briefly highlight some of the successes and issues with current immunotherapy, and try to determine how these deficiencies may be overcome. A more complete review of melanoma immunotherapy strategies can also be found from Sivendran et al (Sivendran et al, 2010 (Fang et al, 2008). IL-2 therapy remains the only immunotherapy strategy for late stage melanoma but significant issues remain with its use.…”

“…Cytokines like IL-15, IL-7, and IL-21 could prove more beneficial in stimulating antitumor immune cells during chemotherapy, with reduced toxicity when compared to IL-2 or IFN (Epardaud et al, 2008;Ribas, 2006). IL-21 has the added benefit of more selective T cell expansion versus IL-2, in which Tregs are not responsive to IL-21 stimulation (Sivendran et al, 2010). Currently IL-21 is being tested in phase I/II clinical trials displaying promising results (Sivendran et al, 2010).…”

“…IL-21 has the added benefit of more selective T cell expansion versus IL-2, in which Tregs are not responsive to IL-21 stimulation (Sivendran et al, 2010). Currently IL-21 is being tested in phase I/II clinical trials displaying promising results (Sivendran et al, 2010). IL-15 shares similarity with IL-2 through a shared receptor subunit, but IL-15 has been shown to enhance both ACT and chemotherapy strategies in mouse models with almost no cytokine associated toxicity (Epardaud et al, 2008).…”

“…A larger phase III comparison study using DTIC ± ipilimumab involving more than 500 patients has been performed, the results of which led to the approval of Ipilimumab in the treatment of advanced melanoma on March 25, 2011. Ipilimumab, like any other treatment, is not without issue, as patients undergoing treatment have experienced immune-induced side effects including dermatitis, enterocolitis, hepatitis, and most significantly diarrhea (Sivendran et al, 2010). Some interesting treatment effects have also been observed in a number of patients treated with ipilimumab which will require close attention in determining the best treatment protocol.…”

“…New immune criteria for the judgment of drug efficacy should be included in determining the best course of patient treatment to avoid issues like these, particularly as ipilimumab has great potential as a combined agent with vaccination and cytotoxic drug therapy, and most interestingly with ACT. Ipilimumab is not the only mAb targeting advanced disease receiving clinical attention; anti-PD-1, anti-CD137, and anti-CD40 are all undergoing clinical investigation (Sivendran et al, 2010). Anti-PD-1 has shown promise in melanoma cell lines and small phase I/II clinical trials displayed immune activity without major drug associated toxicity, opening the door for its use in combination with other mAb and immunotherapeutic strategies (Brahmer et al, 2010).…”