Metastatic Melanoma in the Older Patient

Immunologic Insights and Treatment Outcomes

Upendra P Hegde; Nitya Chakraborty; Bijay Mukherji; Jane M Grant Kels

Disclosures

Expert Rev Pharmacoeconomics Outcomes Res. 2011;11(2):185-193. 

In This Article

Case for Immune-based Treatment of MM: New Advances

Melanoma is recognized as an ideal tumor model for developing immune-based treatment strategies. A number of melanoma-associated tumor epitopes have been identified and sequenced.[21] The early studies targeted anti-melanoma immunity via peptide vaccination or dendritic cell-based melanoma vaccination.[22] A number of adjuvants have been used to enhance the anti-melanoma immunity. The proof of concept has been unequivocally confirmed but the results have not been consistent and are often unpredictable in patients. Although the innate and adaptive immune systems coordinate to generate an anti-tumor response, the T cell is the centerpiece of anti-tumor immunity. Important components of the anti-tumor immune system include tumor antigen, antigen-presenting cells (APCs), effector or cytotoxic T lymphocytes (CTLs; CD8+ cells), helper T lymphocytes (CD4+ cells) and regulatory T lymphocytes (Tregs; CD4+, CD25+ and foxp3+). The cytokines that are generated either by the tumor cells or secreted by the components of the immune system during the process of generating an anti-melanoma immune response include either facilitatory inflammatory cytokines, such as IFN-γ, IL-2 and TNF-α, or inhibitory anti-inflammatory cytokines, such as IL-10 or TGF-β. Although critical to maintaining immune homeostasis in health, Tregs have been increasingly recognized for their negative impact on anticancer immune responses.[23] Chakraborty et al. have reported severe obliteration of Mart-1 antigen-specific effector T-cell responses by induced Tregs mediated through the secretion of inhibitory cytokines such as IL-10 and TGF-β.[24] Recent advances in melanoma treatment have focused on adaptive immune therapies that consist of administration of in vitro-expanded autologous melanoma-infiltrating lymphocytes in large numbers, targeting the tumor in vivo in patients. The success of this strategy has been linked to innovative ways of expanding anti-tumor T lymphocytes in vitro and creating immunologic space for lymphocytes to reside in vivo as they fight the tumor. This strategy has been reported to be successful in a significant proportion of eligible patients. The ability to engineer lymphocytes with tumor-avid T-cell receptors has enhanced the successful clinical application of this technology in patients.[25] Finally, clinically relevant anti-melanoma immune responses were generated, targeting regulatory pathways by successful use of a fully human monoclonal antibody ipilimumab, designed to block cytotoxic T lymphocyte antigen-4 in a randomized multi-institutional Phase III clinical trial. The study demonstrated a statistically significant overall survival advantage and durable responses in patients with MM.[26] The field of immune-based treatment approaches to melanoma has thus become very promising, providing hope for patients with MM.

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