New Treatment for Skin Cancer - Skin Cancer Vaccine (Part Two)

    1. Melanoma

    Melanoma is the most aggressive malignant tumor in skin cancer. In the past 20 years, the incidence rate worldwide has risen sharply, increasing at a rate of 3.1% per year. The incidence rate in China is relatively low, but in recent years, the growth has accelerated, with about 20,000 new cases each year. In situ melanoma with a thickness < 1 mm has a 5-year survival rate of over 95%. Despite this, 20% progressed to metastatic melanoma. Once metastasis occurs, the prognosis is extremely poor, with a 5-year survival rate of less than 10%. Metastatic melanoma is not sensitive to radiotherapy and chemotherapy and is one of the most difficult tumors to be effectively treated. Melanoma is highly immunogenic and immunotherapy is the most promising treatment. In recent years, breakthroughs have been made in immunotherapy, especially immunomodulatory antibodies. Develop specificity for cancer development vaccines and cancer, providing great potential for the treatment of cancer patients. CTLA-4 monoclonal antibody Ipilimumab was used to treat metastatic melanoma, and overall survival (OS) was significantly benefited. It was approved by the US FDA on March 25, 2011.

    2.1. Cytokines

    Cytokines, a class of immunomodulatory small molecule proteins secreted by immune cells, enhance antitumor immune responses by inducing activation and proliferation of immune cells. Cytokines for the treatment of melanoma mainly include interleukins and interferon alpha.

    1. 1.1. Interleukin

    High-dose IL-2 is the first immunization drug approved by the US FDA for inoperable or metastatic melanoma. The objective response rate (ORR) of IL-2 treatment is low, but recent studies suggest that IL-2 can be used as an immunoadjuvant to enhance the efficacy of specific immunotherapy. Phase III clinical trials showed a significant increase in ORR (16% vs 6%) and a benefit from progression-free survival (PFS) in combination with high-dose IL-2/gp100 compared with high-dose IL-2 (2. February vs 1. June, P=0.008); The median OS has an extended trend (17 August vs 11. January, P=0.06). Another characteristic of high-dose IL-2 is severe adverse reactions and high mortality. It is limited to patients with good organ function in experienced specialists in experienced treatment facilities. The main causes of adverse reactions were "cytokine storm" and "systemic autophagy syndrome." Animal model studies have found that the combination of IL-2 and autophagy inhibitors can limit adverse reactions and prolong antitumor effects. Clinical studies have found that melanoma intra-injection of IL-2 has a high ORR (> 60%) and a moderate adverse effect. More interestingly, after intratumoral injection of IL-2 recurrence, chemotherapy was still effective (effective 36.7%). Thus, IL-2 combination therapy has the advantage of improving the remission rate and reducing adverse reactions, and becomes the main treatment for melanoma.

    2.1. 2. Interferon alpha (IFNα)

    IFNα, the only effective drug for melanoma adjuvant therapy. The two commonly used subtypes, FNα-2α and IFNα-2b, differ only in two amino acids. There is almost no difference between the two, in terms of binding receptors, mode of action, and adverse reactions. IFNα is mainly used for adjuvant treatment of high-risk patients after melanoma surgery, and is rarely used for metastatic melanoma. A large number of clinical studies have shown that IFNα can prolong disease-free survival (DFS), but has no advantage in improving survival rate, and serious adverse reactions. Polyethylene glycol IFNα-2b (IFNα-2b, Sylatron), modified IFNα, long half-life (40-60 hours). Phase III clinical trial (EORTC 18991) found that Sylatron significantly improved postoperative relapse-free survival (RFS) for stage III melanoma, with an average of 34.8%. Therefore, on March 29, 2011, the FDA approved Sylatron for the adjuvant treatment of melanoma with microscopic or gross lymph node metastasis within 84 days of postoperative (including lymph node dissection). Subgroup analysis showed that Sylatron reduced the risk of recurrence, distant metastasis, and death in patients with microscopic lymph node involvement and primary ulcer.

    2.2. Vaccine

    Sipuleucel-T (Provenge), an autologous dendritic cell vaccine, was approved by the US FDA in April 2011 for the treatment of hormone-resistant asymptomatic or metastatic prostate cancer patients. Provenge's success marks a new era in vaccine treatment. Melanoma is highly immunogenic and its associated antigen-targeted vaccine is a valuable study. At present, melanoma therapeutic vaccines mainly include protein/polypeptide vaccines, recombinant vector vaccines, whole-cell vaccines, and dendritic cell vaccines.

    To be continued in Part Three…