CTLA-4 blockade may induce antitumor responses by sustaining the activation of tumor-specific T cells [76]. 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. Jasmonic acid == 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. Keywords:cytotoxic T-lymphocyte-associated antigen, CTL-A blockade, T cell activation, tumor immunity, overall survival == 1. Introduction == The incidence of malignant melanoma has been Jasmonic acid steadily increasing for the past 30 years in western countries [1]. The American Cancer Society estimates that about 68,130 new melanomas will be diagnosed in the United States during 2010 (about 38,870 in men and 29,260 in women) [2]. Despite an increasing understanding of the genetic and epigenetic causes of this malignancy, the death rate continues to increase faster than that for most other Jasmonic acid types of cancer [3]. Melanoma is staged 0IV and the survival of patients with melanoma declines dramatically with increasing stage of disease [4]. The prognosis in melanoma patients with distant metastases is poor, and the 5-year survival rate is less than 10 %10 %. Chemotherapy is often used for treatment of melanoma [5,6]. Dacarbazine and Jasmonic acid hydroxyurea are approved by the Food and Drug Administration (FDA) for the treatment of metastatic melanoma. However, chemotherapy is of limited value in most patients with stage III or IV melanoma and a clear survival benefit for chemotherapy has yet to be demonstrated. Recently, the BRAF kinase inhibitor vemurafenib (PLX4032) was shown to dramatically improve progression-free and overall survival in patients with previously untreated melanoma with the BRAF V600E mutation [7]. The final estimate of survival outcomes and durability of the response after the discontinuation of vemurafenib remains to be determined. Currently, there is no standard of care for patients who have progressive disease. Due to the marginal benefits of conventional therapy, there has been considerable interest in the development of other strategies for melanoma treatment. Most of our knowledge-base on human tumor immunology is derived from studies of melanoma. The identification of melanoma-associated antigens resulted in major progress in understanding of the antitumor immune responses [810]. Emerging evidence supports the concept of immunotherapy for the treatment of patients with malignant diseases [11,12]. Indeed, a number of systemic adjuvant therapies using cytokines have been evaluated for melanoma Rabbit Polyclonal to E2F6 patients with a high risk of disease recurrence following surgery [13,14]. High-dose Interferon (IFN)-2b (Intron A; Schering Corporation, Kenilworth, NJ) is the only agent approved by the FDA in the US for the adjuvant therapy of melanoma [15]. IFN- has demonstrated therapeutic effects in the treatment of a variety of hematologic malignancies and solid tumors due to their immunoregulatory and antiproliferative properties [16]. The use of IFN- as an adjuvant therapy for melanoma was based on multiple clinical trials showing a consistent improvement in relapse-free survival of patients with resectable, stage IIB/III melanoma. However, the effect of IFN- therapy on OS remains unclear [15,17,18]. In addition, its high toxicity profile also affects the decision to use IFN- as an adjuvant therapy for melanoma [19]. Cytokine-based therapy with high dose Interleukin-2 (IL-2), a potent immunostimulatory molecule involved in T cell growth and expansion [20], is approved for patients with metastatic melanoma in the US [21]. Overall response rates were documented in 16% of patients, while 6% of patients achieved durable complete responses [22]. However, the serious and toxic side effects caused by high-dose IL-2 treatment represent significant limitations for its clinical applications [23]. Although the moderate success of agents such as IFN- and IL-2 validated the principle of cancer immunotherapy, the overall Jasmonic acid limited efficacy of these agents as indicated by poor overall response rates and a lack of survival benefit for melanoma has prompted scientists to continue searching for novel therapeutic targets capable of potentiating immune activation. Advances in defining the mechanisms involved in regulation of.
