New Perspectives for Melanoma Immunotherapy: Role of IL-12

Abstract

Metastatic melanoma is a poor prognosis skin cancer. Since conventional treatments including surgery and chemotherapy often fail, novel therapeutic strategies are needed. In particular, identification of melanoma associated antigen has fostered the progress of both active (vaccines) and adoptive immunotherapy. Some promising results have been obtained, but most melanoma patients are not yet cured possibly because of different immune-escape mechanisms operated by tumor cells. Several studies have addressed the use of interleukin (IL)-12 for melanoma therapy due to its immunoregulatory function and anti-tumor activity mediated by stimulation of T and NK effector cells. Unfortunately, IL-12 has shown considerable toxicity. We [1] have recently demonstrated that IL-12 exerts a direct anti-tumor activity on murine B16 melanoma cells expressing a functional IL-12 receptor (R). In our model low levels of endogenous IL-12 reduced proliferation, increased apoptosis, and defective microvessel formation of tumor cells. This review summarizes information about melanoma immunotherapy and highlights a novel mechanism of IL-12-mediated anti-tumor activity based upon the direct effect of the cytokine on IL-12R(+) tumor cells. In this view, new therapeutic approaches may be planned including: i) pre-screening of melanoma patients for IL-12Rbeta2 expression to identify potential responders, ii) administration of small and less frequent doses of IL-12 to avoid toxicity and iii) targeting of IL-12 to IL-12R(+) tumor cells, such as local administration in patients with skin tumors or injection of IL-12 fused to an antibody specific to tumor cells.

Lack of Interleukin-12 in p40-Deficient Mice Leads to Poor CD8+T-Cell Immunity againstEncephalitozoon cuniculiInfection

“…Furthermore, as stated above, regulation of CD8 ϩ T-cell immunity is not dependent on IFN-␥, as reported for other infections (9,11). Recent studies have suggested that due to its ability to expand the CD8 ϩ T-cell population, IL-12 treatment has a strong therapeutic potential in diseases where these cells are critical for the host defense (3,27). As CD8 ϩ T-cell immunity plays a central role in protection against E. cuniculi challenge (1, 2, 16), the observations described above have strong implications in developing strategies for designing immunotherapeutic agents for HIV-infected and elderly individuals who are prone to this type of infection.…”

Aloe-emodin exerts a potent anticancer and immunomodulatory activity on BRAF-mutated human melanoma cells

“…Since cancers possess several strategies to evade immune surveillance, the application of immunotherapy is of a great importance (Weber, 2011). For example, interleukin(IL)-12 and interferon-γ (IFN-γ) are among the best characterized and most potent antitumor cytokines (Cocco et al, 2009;Balachandran and Adams, 2013).…”

Cancer Electrogene Therapy with Interleukin-12

“…It has profound antitumor efficacy that was demonstrated on a variety of different types of tumors and metastases in preclinical as well as clinical studies. In recent years, several excellent reviews describing the activities of IL-12, the preclinical and clinical use of recombi-nant IL-12 and gene therapy with IL-12 have been published [1,8,11,45,56,57]. On the other hand, 10 years have passed since the first paper on combination of plasmid DNA encoding for IL-12 injected intramuscularly with electroporation was published [39].…”