Metastatic melanoma has limited treatment options, but advances in the understanding of the oncogenic mutations that drive this cancer and how the immune system can be better modulated to fight melanoma provide a new generation of active approaches for patients. Targeting c-kit and BRAF-activating gene mutations with orally available specific inhibitors, like imatinib and PLX4032, has resulted in a high frequency of objective tumor responses. The use of antibodies that modulate costimulatory signaling, like anti-CTLA4 or anti-PD-1, result in reproducible durable tumor responses, although this occurs in only a small subset of patients. The response rates are higher when using adoptive cell transfer therapies. Therefore, novel advances arising from basic research knowledge are resulting in active treatments in the clinical setting and are reviewed here.
Most patients with advanced melanoma have poor outcomes with current therapeutic approaches. Neither of the only 2 agents approved by the US Food and Drug Administration (FDA) for the treatment of Stage IV melanoma, the chemotherapy drug dacarbazine and the immunotherapy cytokine interleukin-2 (IL-2), has demonstrated an impact on patient survival in a clinical trial compared with a placebo control group.1
The past 20 years have provided plenty of examples of novel approaches and experimental drugs that have failed to improve on the low performance of standard-of-care therapies for melanoma in randomized clinical trials. Some examples include multiagent chemotherapy (ie, the Dartmouth regimen), combination of chemotherapy and immunotherapy in the so-called biochemotherapy regimens, vaccines (dendritic cells, vitespen [Oncophage]), the antisense bcl-2 oligonucleotide oblimersen (Genasense), the multitargeted tyrosine kinase inhibitor (TKI) sorafenib (Nexavar), the reactive-oxide species inhibitor elesclomol, among a long list of agents.1-4
These numerous negative randomized clinical trials have given melanoma the reputation of being a graveyard for drug development.
Two main approaches are posed to change this grim picture; one based on immunotherapy with immune-activating antibodies or with adoptive cell transfer (ACT) therapy, and another based on small molecule–targeted therapies that specifically block pathways activated by oncogenes. Antigen-specific T cells reactive to infectious pathogens and tumor antigens generated in vitro and adoptively transferred to patients can provide clinical benefi t.5-7
Response rates up to 70% have been achieved with an optimized combination of ex vivo, clonally expanded, tumor infiltrating lymphocytes (TILs), lymphodepletion, and IL-2 helper cytokine administration.8-11
To make this approach more widely applicable and to avoid the long time required to expand antigen-specific cells ex vivo, T-cell receptor (TCR) engineering has been developed and tested in humans.12
In addition, the improved knowledge of oncogenic events in melanoma has led to the development of specific oncogenic inhibitors and their very successful initial testing in clinical trials.13-15ADVANCES IN IMMUNOTHERAPY FOR MELANOMA
The 2 major areas of progress in immunotherapy for melanoma are the clinical development of a series of immune-stimulating antibodies, which provide evidence that modulating the immune system can lead to objective and durable tumor responses, and the ex vivo generation of large quantities of tumor antigen–specific lymphocytes that have powerful antitumor activity when given in repeated infusions to patients with metastatic melanoma.CTLA4-Blocking Antibodies