Strategies to Overcome Obstacles to Successful Immunotherapy of Melanoma

Abstract

The immunogenicity of malignant melanomas has been recognized by the observed recruitment of tumor-specific cytotoxic T-cells (CTL), leading to the identification of several melanoma associated antigen (MAA). However, numerous strategies to treat melanoma with immunotherapy have resulted in only partial success. In this editorial, we discuss recent data related to the ability of tumors to elude immune responses. We therefore discuss different strategies to induce a clinically effective immune response. These approaches include 1) immunostimulation: including peptide/protein based vaccines, dendritic cell vaccines, and adoptive cell transfer; and 2) overcoming immunosuppression, including targeting of checkpoint molecules such as CTLA-4, circumventing the activity of Tregs, and assuring antigen expression by tumor cells (thwarting antigen silencing). Finally, we discuss recent advances in gene therapy, including adoptive therapy with engineered T cell receptors (TCRs). These issues lead to the conclusion that successful immunotherapy in malignant melanoma requires a combination of strategies aimed at both inducing immunostimulation and blocking immunosuppression.Melanoma, a highly malignant tumor of the pigmented cells, is a significant worldwide health concern. The 5-year survival for patients with involvement of regional lymph nodes is 35%, with fewer than 2% of patients with visceral metastatic disease alive at 5 years. Therapy with interferon alpha-2b (IFNalpha-2b), the only agent approved in the United States for adjuvant use in high-risk melanoma patients, has not shown consistent overall survival benefit in randomized trials and is associated with considerable toxicity. Conventional chemotherapy for unresectable metastatic disease does not improve survival, while patients with completely resected metastatic disease have a median survival of <20 months. Since there is clearly a need for more effective therapies in these high-risk patients and because steps towards new effective therapies against melanoma are currently being taken, we will focus on melanoma therapies to highlight the new immunotherapy strategies.While there is good reason to question the effectiveness of the host response against spontaneously arising tumors, there is clear evidence that specific immune cells are recruited to tumor sites. In fact, lymphocytic infiltration of tumors was first observed by Rudolf Virchow in 1863, before

Depletion of endogenous tumor-associated regulatory T cells improves the efficacy of adoptive cytotoxic T-cell immunotherapy in murine acute myeloid leukemia

“…[46][47][48] Little progress has been made in achieving long-term survival in advanced disease settings. Enhancement of cancer immunotherapy by depletion of regulatory T cells has been well studied and characterized as prophylaxis in tumor models.…”

Melanoma Immunomodulation: A War of Attrition

“…Surprisingly, melanoma tumors represent immunogenic cancers with various activation of antitumor immunity, yet the natural immune responses are incapable of eradicating the tumor, the reason for which is not fully understood (Pandolfi et al, 2008). A contributing factor to this is the previously mentioned immunosuppressive microenvironment and the altered Ag processing and presentation in melanoma that can stimulate T cells, but not in the same way as APCs which would drive a strong immune response against the tumor.…”

Mast Cells and Arachidonic Acid Cascade in Inflammation

“…However, other cells might also be involved in this immediate response such as macrophages, eosinophils, and platelets; while late-phase reactions appear to be a consequence of infiltration with neutrophils, eosinophils, and macrophages. These cells are recruited and activated either by mast cellassociated chemotactic non-specific factors such as LTB4, PAF, the eosinophil chemotactic factor of anaphylaxis (ECF-A), and chemotactic specific factors: chemokines (44)(45)(46). These compounds also participate in the late phase reactions six hours subsequent to the exposure to the allergen (47).…”