Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study

The Society for Immunotherapy of Cancer consensus statement on tumour immunotherapy for the treatment of cutaneous melanoma

“…Ipilimumab has been evaluated in several phase I and II clinical trials and demonstrated an improvement in overall survival in patients with metastatic melanoma in two large prospective randomized phase III trials. 5,9,44,45 In a double-blind, randomized phase III trial, 676 patients with advanced-stage melanoma who expressed the HLA-A2 haplotype were treated with ipilimumab (3 mg/kg), ipilimumab (3 mg/kg) and an HLA-A2-restricted modified gp100 peptide vaccine, or vaccine alone. Patients who received ipilimumab in either treatment arm had improved overall survival compared to patients receiving vaccine alone (10 months versus 6 months; P = 0.0026).…”

GITR engagement in combination with CTLA-4 blockade completely abrogates immunosuppression mediated by human liver tumor-derived regulatory T cellsex vivo

“…36 Recent studies have demonstrated that anti-CTLA-4 mAb administration augments clinical antitumor responses and improves survival in patients with metastatic melanoma 18,37 resulting in FDA approval of Ipilimumab, an anti-CTLA-4 antibody, for the treatment of unresectable or metastatic melanoma. The promising clinical activity of anti-CTLA-4 mAb in melanoma encourages to explore its therapeutic applicability in other malignancies, especially because it does not require specific targets expressed on tumor cells.…”

“…However, therapy with anti-CTLA-4 mAb ipilimumab has induced life-threatening adverse events, 17,38,39 which is a major limitation in exploring higher doses for the treatment. The current clinically approved dosing for anti-CTLA-4 antibody (Ipilimumab) is 3 mg/kg which results in a steady state serum concentration (Cmin) of about 10 mg/mL, 18,40 and an overall response rate of 4% in patients with advanced melanoma with 3% of patients experiencing severe immune-related adverse events. A higher dose of Ipilimumab of 10 mg/kg (Cmin 32 mg/mL) showed a better response rate of 11% but also higher frequency (15%) of severe adverse events.…”

“…A higher dose of Ipilimumab of 10 mg/kg (Cmin 32 mg/mL) showed a better response rate of 11% but also higher frequency (15%) of severe adverse events. 18 Based upon results from murine models, it has previously been suggested that GITR stimulation and CTLA-4 inhibition can be combined to enhance the induction of immune responses and might even work synergistically. 41 Importantly, combination of low doses of anti-CTLA-4 antibody and GITRL resulted in a complete recovery of in vitro T cell proliferation and TNFa production.…”

“…Abrogation of Ti-Treg function may allow the induction of antitumor immunity at the tumor site and improve the outcome of immunotherapy aimed to activate antitumor responses. In advanced melanoma, CTLA-4-blocking has demonstrated a survival advantage 17,18 and CTLA-4-blockade was shown to induce antiviral immunity in HCC-patients infected with hepatitis C virus (HCV). 19 However, only limited tumor-responses were reported, emphasizing the need to improve this strategy.…”