Evaluating targeted and immunomodulatory therapies for melanoma

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Melanoma therapy has changed rapidly due to the emergence of new therapies: MAPK-pathway targeted drugs and immunomodulatory agents. Given the relative success of these new individual drugs, this work set out to evaluate and develop effective melanoma treatments using combination therapies in a preclinical trial models. Therapies tested include BRAF kinase inhibition in combination with: immune checkpoint inhibitors anti-CTLA4, anti-PDL1, and with the topical TLR7/8 agonist imiquimod. Drugs efficacies were tested in established melanomas in a conditional inducible mouse melanoma model based on activation of Braf and beta catenin and loss of Pten. BRAF inhibition in combination with anti-CTLA-4/anti-PD-L1 was not more effective than BRAF inhibition alone in retarding tumor growth or prolonging survival in these studies. Treatment with imiquimod significantly retarded tumor growth and increased survival. Imiquimod-treated tumors show increased macrophage infiltration, but not increased intratumoral T lymphocytes. Further work remains to identify effective, synergistic drug combinations in preclinical trial models.

Melanoma, a cancer that arises from melanocytes, among the skin cancer possesses the highest morbidity and mortality. In the United States, it is estimated that 76,690 cases of melanoma and 9,480 deaths due to melanoma occurred in 2013. Melanoma incidence predominates in countries with conjunction of fair-skinned ethnic populations and high UV light exposure, and global incidence of melanoma continues to rise : 132,00 new cases are diagnosed world-wide and an estimated 48,000 persons die from advanced melanoma across the globe each year. From 1950 to 2000, a national cancer database documented increases of 619 percent in annual diagnoses of cutaneous melanoma and 165 percent in annual mortality from 1950 to 2000.

At the initial diagnosis of a primary melanoma, the depth of the primary lesion is used to predict patient survival. For instance, survival at 10 years for a melanoma less than 1.00 mm in depth is greater than 90%. However, once melanoma has metastasized, the standard of care treatments offer little in the way of long term benefit: a 2009 report estimated one-year survival based on location of melanoma spread as high as 62% and as low as 33%. Thus, high mortality rates associated with unresectable or metastatic melanoma persists, and given the high mortality rates and the relatively young age at which disease often that resistance to BRAF/MEK inhibition occurs in the nearly all cases, indicating that this approach will not cure a significant proportion of melanoma patients.