Nanotechnology in Melanoma Therapy
The use of nanotechnology represents one of the newer alternative therapies employed for treatment of melanoma and is especially gaining interest due to reduced adverse effects in comparison with other conventional treatments for melanoma. Nanotechnology-based drug delivery systems precisely target tumor cells and improve the effect of both the conventional and innovative antineoplastic treatment.27,31 Tumor vasculature differs from normal tissues by being discontinuous and having interspersed small gaps/holes that allow nanoparticles to exit the circulation and enter and accumulate in the tumor tissue, leading to enhanced and targeted release of the antineoplastic drug to tumor cells.32 This mechanism is called the enhanced permeability and retention effect.33
Another mechanism by which nanoparticles work is ligand-based targeting in which ligands such as monoclonal antibodies, peptides, and nucleic acids located on the surface of nanoparticles can bind to receptors on the plasma membrane of tumor cells and lead to targeted delivery of the drug.34 Nanomaterials used for melanoma treatment include vesicular systems such as liposomes and niosomes, polymeric nanoparticles, noble metal-based nanoparticles, carbon nanotubes, dendrimers, solid lipid nanoparticles and nanostructures, lipid carriers, and microneedles. In melanoma, nanoparticles can be used to enhance targeted delivery of drugs, including immune checkpoint inhibitors (ICIs). Cai et al35 described usage of scaffolds in delivery systems. Tumor-associated antigens, adjuvant drugs, and chemical agents that influence the tumor microenvironment can be loaded onto these scaffolding agents. In a study by Zhu et al,36 photosensitizer chlorin e6 and immunoadjuvant aluminum hydroxide were used as a novel nanosystem that effectively destroyed tumor cells and induced a strong systemic antitumor response. IL-2 is a cytokine produced by B or T lymphocytes. Its use in melanoma has been limited by a severe adverse effect profile and lack of complete response in most patients. Cytokine-containing nanogels have been found to selectively release IL-2 in response to activation of T-cell receptors, and a mouse model in melanoma showed better response compared to free IL-1 and no adverse systemic effects.37
Nanovaccines represent another interesting novel immunotherapy modality. A study by Conniot et al38 showed that nanoparticles can be used in the treatment of melanoma. Nanoparticles made of biodegradable polymer were loaded with Melan-A/MART-1 (26–35 A27L) MHC class I-restricted peptide (MHC class I antigen), and the limited peptide MHC class II Melan-A/MART-1 51–73 (MHC class II antigen) and grafted with mannose that was then combined with an anti–PD-L1 antibody and injected into mouse models. This combination resulted in T-cell infiltration at early stages and increased infiltration of myeloid-derived suppressor cells. Ibrutinib, a myeloid-derived suppressor cell inhibitor, was added and demonstrated marked tumor remission and prolonged survival.38
Overexpression of certain microRNAs (miRNAs), especially miR-204-5p and miR-199b-5p, has been shown to inhibit growth of melanoma cells in vitro, both alone and in combination with MAPK inhibitors, but these miRNAs are easily degradable in body fluids. Lipid nanoparticles can bind these miRNAs and have been shown to inhibit tumor cell proliferation and improve efficacy of BRAF and MEK inhibitors.39
Triple-Combination Therapy
Immune checkpoint inhibitors such as anti–PD-1 or anti–CTLA-4 drugs have become the standard of care in treatment of advanced melanoma. Approximately 40% to 50% of cases of melanoma harbor BRAF mutations, and patients with these mutations could benefit from BRAF and MEK inhibitors. Data from clinical trials on BRAF and MEK inhibitors even showed initial high objective response rates, but the response was short-lived, and there was frequent acquired resistance.40 With ICIs, the major limitation was primary resistance, with only 50% of patients initially responding.41 Studies on murine models demonstrated that BRAF-mutated tumors had decreased expression of IFN-γ, tumor necrosis factor α, and CD40 ligand on CD4+ tumor-infiltrating lymphocytes and increased accumulation of regulatory T cells and myeloid-derived suppressor cells, leading to a protumor microenvironment. BRAF and MEK pathway inhibition were found to improve intratumoral CD4+ T-cell activity, leading to improved antitumor T-cell responses.42 Because of this enhanced immune response by BRAF and MEK inhibitors, it was hypothesized and later supported by clinical research that a combination of these targeted treatments and ICIs can have a synergistic effect, leading to increased antitumor activity.43 A randomized phase 2 clinical trial (KEYNOTE-022) in which the treatment group was given pembrolizumab, dabrafenib, and trametinib and the control group was treated with dabrafenib and trametinib showed increased medial OS in the treatment group vs the control group (46.3 months vs 26.3 months) and more frequent complete response in the treatment group vs the control group (20% vs 15%).44 In the IMspire150 phase 3 clinical trial, patients with advanced stage IIIC to IV BRAF-mutant melanoma were treated with either a triple combination of the PDL-1 inhibitor atezolizumab, vemurafenib, and cobimetinib or vemurafenib and cobimetinib. Although the objective response rate was similar in both groups, the median duration of response was longer in the triplet group compared with the doublet group (21 months vs 12.6 months). Given these results, the FDA approved the triple-combination therapy with atezolizumab, vemurafenib, and cobimetinib. Although triple-combination therapy has shown promising results, it is expected that there will be an increase in the frequency of treatment-related adverse effects. In the phase 3 COMBi-I study, patients with advanced stage IIIC to IV BRAF V600E mutant cutaneous melanoma were treated with either a combination of spartalizumab, dabrafenib, and trametinib or just dabrafenib and trametinib. Although the objective response rates were not significantly different (69% vs 64%), there was increased frequency of treatment-related adverse effects in patients receiving triple-combination therapy.43 As more follow-up data come out of these ongoing clinical trials, benefits of triple-combination therapy and its adverse effect profile will be more definitely established.
Challenges and Future Perspectives
One of the major roadblocks in the treatment of melanoma is the failure of response to ICI with CTLA-4 and PD-1/PD-L1 blockade in a large patient population, which has resulted in the need for new biomarkers that can act as potential therapeutic targets. Further, the main underlying factor for both adjuvant and neoadjuvant approaches remains the selection of patients, optimizing therapeutic outcomes while minimizing the number of patients exposed to potentially toxic treatments without gaining clinical benefit. Clinical and pathological factors (eg, Breslow thickness, ulceration, the number of positive lymph nodes) play a role in stratifying patients as per risk of recurrence.45 Similarly, peripheral blood biomarkers have been proposed as prognostic tools for high-risk stage II and III melanoma, including markers of systemic inflammation previously explored in the metastatic setting.46 However, the use of these parameters has not been validated for clinical practice. Currently, despite promising results of BRAF and MEK inhibitors and therapeutic ICIs, as well as IL-2 or interferon alfa, treatment options in metastatic melanoma are limited because of its high heterogeneity, problematic patient stratification, and high genetic mutational rate. Recently, the role of epigenetic modifications andmiRNAs in melanoma progression and metastatic spread has been described. Silencing of CDKN2A locus and encoding for p16INK4A and p14ARF by DNA methylation are noted in 27% and 57% of metastatic melanomas, respectively, which enables melanoma cells to escape from growth arrest and apoptosis generated by Rb protein and p53 pathways.47 Demethylation of these and other tumor suppressor genes with proapoptotic function (eg, RASSF1A and tumor necrosis factor–related apoptosis-inducing ligand) can restore cell death pathways, though future clinical studies in melanoma are warranted.48