Melanoma accounts for one-third of all malignant skin tumors (approximately 6.8–20.0%). Globally, the incidence and mortality rates of melanoma are increasing.[1] For early-stage (I–II) melanoma, extended resection shows a better survival advantage. Once melanoma metastasizes, it can lead to poor prognosis.[2] Melanoma with strong immunogenicity is an excellent immunotherapy research object.[3] Immunotherapy drugs for melanoma have developed rapidly in the last 20 years. The clinical benefits of these drugs are apparent,[4,5] which provides better treatment options for most patients with melanoma. Here, we reviewed the current progress in immunotherapy for melanoma.
Cytokine. Cytokines are a class of small molecular proteins with extensive biological activities that are synthesized and secreted by immune cells and some non-immune cells (endothelial cells, epidermal cells, fibroblasts, etc.) after stimulation.
The response rate of high-dose interleukin 2 (HD IL-2) monotherapy to melanoma is about 15–28%,[6,7] but can maintain long-term remission.[8] High-dose interferon α-2b (HD IFNα-2b) therapy for high-risk melanoma can have significant and lasting effects on recurrence-free survival (RFS).[9] Tsavaris et al[10] evaluated the response rate of dose-increasing IFNα-2b in the treatment of multiple malignant tumors. The results showed that in 14 melanoma cases, five patients (35%) achieved partial remission (PR), and the other nine patients developed disease progression.
Melanoma Vaccine. Dendritic cells (DCs) are the most effective antigen-presenting cells (APCs) in the immune system, activating the initial T cells and providing strong security.[11] The number of CD8+ tumor-infiltrating lymphocytes (TIL) increased significantly after DC vaccination and affected the tumor microenvironment of melanoma.[12] A IIb clinical trial compared DC vaccine therapy with placebo in patients with stage III–IV melanoma after surgery. The study found that in per-treatment (PT) analysis, the 2-year disease-free survival (DFS) in the DC group was significantly improved (62% vs. 34%, P = 0.041).[13]
Adoptive Cell Therapy (ACT). ACT can kill tumor cells by collecting patient autoimmune cells, amplifying or enhancing their targeting effect in vitro, and transporting them back to the patients. TIL are considered an alternative treatment for patients with stage IV melanoma and are a reliable method for treating metastatic malignant melanoma, which can mediate tumor regression in most patients.[14,15] In a phase II clinical trial comparing the efficacy of TIL alone or combined with DC vaccine, the results showed that the objective response rate (ORR) of the TIL + DC group was higher (50% vs. 30%), although the difference did not reach statistical significance.[16]
Oncolytic Virus. An oncolytic virus is a novel cancer treatment that promotes anti-tumor immunity by selectively replicating and lysing tumor cells. Talimogene laherparepvec (T-Vec) was the first oncolytic drug approved by the U.S. Food and Drug Administration (FDA). Tumor regression of the injected lesions was induced by direct tumor lysis, and tumor regression of the uninjected lesions was induced by systemic antitumor immunity. A stage III clinical trial showed that T-Vec reduced tumor volume in 64% of injected lesions (N = 2116), 34% of un-injected non-visceral lesions (N = 981), and 15% of visceral lesions (N = 177).[17]
Immune Checkpoint Inhibitors (ICIs). The revolutionary efficacy of ICIs makes them a commonly used treatment for many solid malignant tumors,[18] especially targeting cytotoxic T lymphocyte-associated protein-4 (CTLA-4) or programed cell death protein-1 (PD-1). The clinical application of ICIs has completely changed the treatment of advanced melanoma.
CTLA-4 is a receptor expressed on the surface of activated T cells. It can interact with CD80 (B7-1) and CD86 (B7-2) on APC and downregulate T cell immune responses.
Ipilimumab (Ipi) is the first immunotherapeutic drug approved by the FDA and has proven beneficial for progression-free survival (PFS) and OS in melanoma patients.[19–21] A phase III study compared different dose regimens of Ipi. It confirmed that patients receiving 10 mg/kg had improved OS (15.7 months vs. 11.5 months) when compared with patients receiving 3 mg/kg. In this study, the optimal dose of Ipi was determined to be 10 mg/kg.[22]
A preliminary study of tremelimumab showed sustainable regression in the treatment of metastatic melanoma.[23] The Camacho et al[24] study found that the optimal dose of tremelimumab in clinical trials was 15 mg/kg every 3 months.
Melanoma cells express programed cell death receptor ligand 1 (PD-L1), which can trigger programed cell death of T cells after binding to PD-1 on the T cell surface, resulting in decreased cellular immune activity and immune escape. Pembrolizumab monoclonal antibody targets the PD-1/PD-L1 pathway. A phase Ib study by Yamazaki et al[25] assessed the safety and antitumor activity of pembrolizumab. Among the 37 advanced melanoma patients, the ORR of cutaneous melanoma was 24% (95% CI: 10 – 43%), and the 12-month OSR was 82%.
Nivolumab (Nivo) can produce a sustained response in melanoma patients. A phase II non-randomized prospective trial showed that the PFS was 67% after 12 months of Nivo treatment and follow-up.[26]
Currently, available anti-PD-L1 drugs (atezolizumab, avelumab, durvalumab, and cemiplimap) are still in the experimental stage. Durvalumab combined with targeted drugs can observe tumor immune infiltration and objective clinical responses in biopsy pathological sites.[27,28]
The degree of malignancy of melanoma is high, and the prognosis of recurrence or distant metastasis is poor. Compared to conventional therapy, immunotherapy has great development potential and brings new hope to patients.
Cytokines such as IL-2 and IFNα-2b are commonly used in the early treatment of melanoma; however, the incidence of severe adverse events (AEs) is high.[29] ICIs can be used alone or in combination with other therapies such as radiation therapy, oncolytic viruses, and ACT to synergistically inhibit tumor activity.[30] Selecting the best combination, predicting and managing the toxic effects of different combinations, screening tumor markers with high sensitivity and specificity, and improving patients' 5-year survival rates remain major challenges for melanoma treatment. Although the immune system is highly complex, further research on the interaction mechanism between the immune system and tumors will eventually bring revolutionary achievements in melanoma treatment.
Funding
This study was supported by grants from 1·3·5 project for disciplines of excellence, West China Hospital, Sichuan University (Nos. ZYPY20001 and ZYPY20002).
Conflicts of interest
None.
References
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