Blockade of cytotoxic T-lymphocyte antigen-4 as a new therapeutic approach for advanced melanoma

Abstract

Introduction The incidence of melanoma continues to rise and prognosis in patients with metastatic melanoma remains poor. The cytotoxic T-lymphocyte antigen-4 (CTLA-4) serves as one of the primary immune checkpoints and downregulates T cell activation pathways. Enhancing T cell activation by antibody blockade of the CTLA-4 provides a novel approach to overcome tumor-induced immune tolerance. Recently, anti-CTLA-4 therapy demonstrated significant clinical benefit in patients with metastatic melanoma, which led to the approval of ipilimumab by the Food and Drug Administration in early 2011. Areas covered The fundamental concepts underlying CTLA-4 blockade-potentiated immune activation, the scientific rationale for and the preclinical evidence supporting CTLA-4-targeted cancer immunotherapy are presented. We also provide an update on clinical trials with anti-CTLA-4 inhibitors and discuss the associated autoimmune toxicity. Expert opinion Given that overall survival is the only validated endpoint for the anti-CTLA-4 therapy, the clinical implications of the antigen or tumor-specific immunity in patients remain to be clarified. Additional research is necessary to elucidate the prognostic significance of immune-related side effects and significantly optimize the treatment regimens. An improved understanding of the mechanisms of action of CTLA-4 antibodies may also culminate in wide-ranging clinical applications of this novel therapy for other tumor types.

Evolving Strategies for Therapeutically Targeting Cancer Stem Cells

“…Recent studies indicate a negative correlation between degrees of host immunocompetence and rates of cancer development, indicating that CSCs possess the phenotypic and functional characteristics required to evade host antitumor immunity (Nahas, Patel, Bliss, & Rameshwar, 2012;Schatton & Frank, 2009). Numerous immunosuppressive molecules have been identified including programmed cell death 1 (PD-1), programmed cell death 1 ligand 1 (PD1-L1), transforming growth factor β (TGF-β), cytotoxic T-lymphocyte-associated 4 (CTLA-4), B-and T-lymphocyte attenuator (BTLA) (Santarpia et al, 2015), and CD200 (Kawasaki & Farrar, 2008;Wang & Fisher, 2015;Wang, Zuo, Sarkar, & Fisher, 2011). Immune selection also enhances the growth and stem-like properties of tumor cells (Noh et al, 2012).…”

Association of CTLA-4 gene polymorphisms −318C/T and +49A/G and Hashimoto's thyroidits in Zahedan, Iran

“…It is expressed on the surface of activated T lymphocytes and has an important role in hemostasis and negative regulation of immune responses (18,19).…”

Non-BRAF-targeted therapy, immunotherapy, and combination therapy for melanoma

“…An extremely promising approach used in clinical settings to counteract the immune escape mechanisms mounted by cancer cells is the inhibition of the CTLA-4 ( Figure 3) [147]. CTLA-4 is a key player in establishing immune tolerance and one of the main regulators of T-cell-mediated antitumor immune responses.…”

“…The major function of CTLA-4 is to modulate T cells at the time of their initial response to antigen [148]. In fact, although CTLA-4 is expressed by activated CD8 + effector T cells, its key role relies in the regulation of T CD4 + populations through down modulation of helper T-cell activity and enhancement of regulatory T-cell immunosuppressive function [147,148].…”