Combining Immunotherapy with Oncogene-Targeted Therapy: A New Road for Melanoma Treatment

Abstract

Cutaneous melanoma arises from the malignant transformation of skin melanocytes; its incidence and mortality have been increasing steadily over the last 50 years, now representing 3% of total tumors. Once melanoma metastasizes, prognosis is somber and therapeutic options are limited. However, the discovery of prevalent BRAF mutations in at least 50% of melanoma tumors led to development of BRAF-inhibitors, and other drugs targeting the MAPK pathway including MEK-inhibitors, are changing this reality. These recently approved treatments for metastatic melanoma have made a significant impact on patient survival; though the results are shadowed by the appearance of drug-resistance. Combination therapies provide a rational strategy to potentiate efficacy and potentially overcome resistance. Undoubtedly, the last decade has also born a renaissance of immunotherapy, and encouraging advances in metastatic melanoma treatment are illuminating the road. Immune checkpoint blockades, such as CTLA-4 antagonist-antibodies, and multiple cancer vaccines are now invaluable arms of anti-tumor therapy. Recent work has brought to light the delicate relationship between tumor biology and the immune system. Host immunity contributes to the anti-tumor activity of oncogene-targeted inhibitors within a complex network of cytokines and chemokines. Therefore, combining immunotherapy with oncogene-targeted drugs may be the key to melanoma control. Here, we review ongoing clinical studies of combination therapies using both oncogene inhibitors and immunotherapeutic strategies in melanoma patients. We will revisit the preclinical evidence that tested sequential and concurrent schemes in suitable animal models and formed the basis for the current trials. Finally, we will discuss potential future directions of the field.

Myeloid Cells That Impair Immunotherapy Are Restored in Melanomas with Acquired Resistance to BRAF Inhibitors

“…While the first trial combining BRAFi with anti-CTLA-4 (ipiliumimab) was terminated due to hepatotoxicity (13), new trials combining BRAFi and MEKi, with anti-CTLA-4, anti-PD-1, and other immunotherapies, are currently underway (14). In preclinical studies, the efficacy of BRAF-inhibitors is enhanced by immunotherapies including anti-CSF-1R (15), anti-PD-1 (16), and adoptive T cell therapy (17).…”

The Immune System in Cancer Pathogenesis: Potential Therapeutic Approaches

“…Notably, Ipilimumab is also known to inhibit the immunosuppressive function of Tregs [54]. Similarly, IgG4 monoclonal antibody against PD-1 (Keytruda) has been on the market for treatment of melanoma patients (Figure 3) [61]. PD-1 is expressed on T cells and plays a role in immune-suppression by repressing T cell activation.…”

“…PD-1 is expressed on T cells and plays a role in immune-suppression by repressing T cell activation. However treatment with Keytruda prevents the inhibitory effects of PD-1 on T cells, thereby, allowing activation of T cells and immune responses against melanoma [61]. Similarly, Nivolumab is an FDA approved IgG4 monoclonal antibody that targets anti-PD1 in melanoma and squamous non-small-cell lung cancer patients [61].…”

“…Similarly, Nivolumab is an FDA approved IgG4 monoclonal antibody that targets anti-PD1 in melanoma and squamous non-small-cell lung cancer patients [61]. It functions in the same manner as Keytruda [61]. Both of these anti-PD1 immunotherapies can also facilitate ADCC and result in cancer cell death [39].…”

Case report on the role of radiofrequency-assisted spleen-preserving surgery for splenic metastasis in the era of check-point inhibitors

“…[1,2] The programmed cell death 1 receptor (PD-1), an inhibitory receptor present on the activated T cells, binds to its ligand (PD-L1) present on the tumor cells and downregulates the activated T cell to produce an effective immune response. [3] Thus antibodies directed against PD-1 (nivolumab, pembrolizumab) or the PD-L1 ligand may restore or augment the antitumor immune response making it able to suppress the cancerous melanoma cells.…”