2. 2. 1. Protein/ Petide-based vaccine

The protein/polypeptide vaccine alone lacks obvious immunogenicity and cannot induce a strong anti-tumor immune response. Therefore, the combination of non-specific immunological adjuvants has been widely studied. MAGE-A3 vaccine combined with immune-adjuvant AS02B and AS15, gp100 combined with high dose IL-2 has different degrees of clinical benefit in the treatment of metastatic melanoma. Recent studies have reported that peptide vaccine combined with Tolllike receptor 9 (TLR9) agonist PF-3512676 and GMCSF in the treatment of stage IV melanoma, with low remission rate, only partial remission in 2 cases (n = 20), but 45% in An ELSPOT positive reaction occurred after 50 days or 90 days. It can be seen that the vaccine combined with immunological adjuvant can enhance the anti-tumor activity of the vaccine, but there is no evidence of OS benefit. Moreover, protein/polypeptide vaccines have certain limitations, and antigen-matched HLA haplotypes must be selected.

2.2. 2. Recombinant vector-based vaccine

Unlike polypeptide/protein vaccines, recombinant vectors provide a platform for expression of one or more gene segments. The advantage is that it is easy to produce and return; if the body has a strong immune response to the vector, it can additionally provide adjuvant treatment for non-specific immunity. The Allovectin-7 vaccine is a complex formed by a DNA plasmid encoding HLA-B7 and β2-microglobulin and a liposome. Phase II clinical studies found that only 15 patients with intratumoral injection of Allocectin-7 had objective remission (n = 133), 2 patients had complete pathological remission, and the mean remission time was 13.8 months. Based on the above clinical benefits, Phase III clinical trials are underway to compare the efficacy of Allocectin-7 and chemotherapy, with primary endpoints of ORR, safety, and OS.

2.2. 3. Whole Cell-based Vaccine

Sources of whole cell vaccines are divided into autologous tumor cells and allogeneic tumor cells or cell lines. CancerVax, an allogeneic whole cell vaccine from three cell lines. Phase II clinical trials of metastatic melanoma, early detection, compared with the untreated group, CancerVax has a significant survival advantage (39% vs 19%); but further studies have shown that the CancerVax / BCG combination group and placebo / BCG There was no significant difference before the group, so the phase III trial was terminated early. M-Vax is an autologous whole-cell melanoma vaccine modified with the hapten dinitrophenyl (DNP). The hapten modification can fully expose tumor-associated antigens and improve immunogenicity. The probability of delayed-type hypersensitivity (DTH) in DNP-modified and unmodified vaccines was 87% and 42%, respectively, and was associated with prolonged survival. Phase III trials of M-Vax in combination with low-dose IL-2 are ongoing.

2.2. 4. Dendritic Cell-based Vaccine

Dendritic cells (DCs), the most powerful antigen presenting cells (APCs), have anti-tumor effects in activating CD8 + cytotoxic T cells (CTLs) and natural killer cells (NK). DC vaccines loaded with tumor antigens induce very short-term anti-tumor responses, but the results of the latest phase II clinical trials are gratifying. Short-term cultured tumor cells (TCs) are rich in tumor stem cells, which are loaded into DCs to prepare DC vaccines. Compared with the TCs vaccine, the DC vaccine had the advantage of prolonging the survival of metastatic melanoma, and the 2-year survival rate was significantly improved (72% vs 31%, P = 0.007). Recent studies have shown that tumor-associated antigen (TAA)-specific CD8 + T cells in skin-infiltrating lymphocytes (SKIL) are associated with prolonged OS, and SKIL detection may become a DC vaccine treatment. Effective sign. Certain Toll-like receptor agonists have a synergistic effect on DCs maturation, but the anti-tumor activity of the combined DC-enhanced DC vaccine has been observed only in animal models. Recent studies have demonstrated that simultaneous activation of TAA-specific CD4 + helper T cells contributes to the enhanced anti-tumor response of TAA-specific CTLs. Recent studies have found that DCs and melanoma cells co-culture, decreased function and activity, but can be reversed by MEK inhibitors U0126 and vemurafenib (BRAFV600E mutant cells). Interestingly, U0126 acts directly on DCs, but inhibits its function and activity; while high dose vemurafenib has no effect on DCs. Therefore, vemurafenib may be the best candidate for DC vaccine combination therapy. Another advancement is plasmacytoid dendritic cells (pDC), intratumoral injection of TAA-loaded pDC for metastatic melanoma, and increased CD4 + T, CD8 + T cell responses in some patients; limited number of pDCs, but each immunotherapy an increase in IFN was observed afterwards. Attempts at pDC have provided a new direction for the study of DC vaccines.

 In the past 10 years, immunotherapy has developed rapidly, bringing a glimmer of hope to patients with skin cancer. However, it still faces a series of challenges. First, the immunotherapeutic kinetics is different from traditional chemotherapy. The anti-tumor effect is often delayed, and the disease progresses after immunotherapy. Whether to continue receiving immunotherapy remains controversial. Therefore, the evaluation criteria for the efficacy of immunotherapy have yet to be proposed. In addition, immunotherapy is different from targeted drugs, and there are currently no sensitive "predictive" biomarkers. Various immunotherapies have their own advantages and disadvantages, such as cytokine, targeted immunomodulatory antibody treatment, low remission rate, but lasting relief; while DC vaccine, TILs, targeted drugs have high remission rate, but the maintenance time is short; joint strategy may have synergistic effect It has the advantages of high efficiency, low toxicity, and prolonged mitigation time, but currently there is no standard joint program. Therefore, how to identify sensitive populations and how to develop a reasonable joint strategy is an important direction for future research on skin cancer immunotherapy.

Reference

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