High-Dose Interferon Alfa-2b Does Not Diminish Antibody Response to GM2 Vaccination in Patients With Resected Melanoma: Results of the Multicenter Eastern Cooperative Oncology Group Phase II Trial E2696
High-dose interferon alfa-2b (IFNalpha2b) is the only established adjuvant therapy of resectable high-risk melanoma. GM2-KLH/QS-21 (GMK) is a chemically defined vaccine that is one of the best developed of a range of vaccine candidates for melanoma. A single-institution phase III trial conducted at Memorial Hospital served as the impetus for an intergroup adjuvant E1694/S9512/C509801 trial, which recently completed enrollment of 880 patients. To build on the apparent benefit of IFNalpha2b in resectable high-risk American Joint Committee on Cancer (AJCC) stage IIB or III melanoma, this phase II study was designed to evaluate the combination of GMK and IFNalpha2b. The E2696 trial was undertaken to evaluate the toxicity and other effects of the established adjuvant high-dose IFNalpha2b regimen in relation to immune responses to GMK and to evaluate the potential clinical and immunologic effects of the combined therapies.
This trial enrolled 107 patients with resectable high- or very high-risk melanoma (AJCC stages IIB, III, and IV).
The results demonstrate that IFNalpha2b does not significantly inhibit immunoglobulin M or G serologic responses to the vaccine and that the combination of high-dose IFNalpha2b and GMK is well tolerated in this patient population.
Cox analysis of the results of the combination with IFNalpha2b show improvement in the relapse-free survival of patients with very high-risk melanoma (including those with resectable M1 disease).
"Melanoma is a solid tumor that is well known to elicit a strong immune response and as such, has been the focus of multiple therapies designed to improve the antitumor immune response through vaccines, adoptive transfer of tumor-reactive lymphocytes , cytokines and monoclonal antibodies designed to manipulate immune checkpoints [4,5]. The role of vaccination with proteins and peptides has been an area of intense interest [6-8], however many of these studies have been hampered by modest clinical benefits despite initially promising results [7,9,10]. One of the mechanisms involved in immune escape by melanoma cells involves down regulation of the proinflammatory microenvironment by regulatory T cells (Treg) via the release of immunosuppressive cytokines such as IL-10 and TGF-β, among several other immune suppressive mechanisms [9,11]. "
[Show abstract][Hide abstract] ABSTRACT: E1694 tested GM2-KLH-QS21 vaccine versus high-dose interferon-alpha2b (HDI) as adjuvant therapy for operable stage IIB-III melanoma. We tested banked serum specimens from patients in the vaccine arm of E1694 for prognostic biomarkers.
Aushon Multiplex Platform was used to quantitate baseline serum levels of 115 analytes from 40 patients. Least absolute shrinkage and selection operator proportional hazard regression (Lasso PH) was used to select markers that are most informative for relapse-free survival (RFS) and overall survival (OS). Regular Cox PH models were then fit with the markers selected by the Lasso PH. Survival receiver operating characteristic (ROC) analysis was used to evaluate the ability of the models to predict 1-year RFS and 5-year OS.
Four markers that include Tumor Necrosis Factor alpha Receptor II (TNF-RII), Transforming Growth Factor alpha (TGF-alpha), Tissue Inhibitor of Metalloproteinases 1 (TIMP-1), and C-reactive protein (CRP) were found to be most informative for the prediction of OS (high levels correlate with worse prognosis). The dichotomized risk score based on the four markers could significantly separate the OS curves (p = 0.0005). When using the four-marker PH model to predict 5-year OS, we achieved an area under the curve (AUC) of 89% (cross validated AUC = 72%). High baseline TNF-RII was also significantly associated with worse RFS. The RFS with high (above median) TNF-RII was significantly lower than low TNF-RII (p = 0.01).
The biomarker signature consisting of TNFR-II, TGF-alpha, TIMP-1 and CRP is significantly prognostic of survival in patients with high-risk melanoma and warrants further investigation.
Journal of Translational Medicine 01/2014; 12(1):19. DOI:10.1186/1479-5876-12-19 · 3.93 Impact Factor
"E2696 was an ECOG-sponsored randomized, phase II trial that enrolled 107 patients with resected stage IIB, stage III, and stage IV disease (including patients with resectable intransit metastases or extracapsular extension of nodal disease [formerly AJCC designated stage IV, M1 disease but currently classified as AJCC stage IIIC disease]) . The trial comprised 3 treatment arms—arm A (GMK plus concurrent HDI), arm B (GMK plus sequential HDI), and arm C (GMK alone). "
[Show abstract][Hide abstract] ABSTRACT: With an incidence that is increasing at 2-5% per year, cutaneous melanoma is an international scourge that disproportionately targets young individuals. Despite much research, the treatment of advanced disease is still quite challenging. Immunotherapy with high-dose interferon-α2b or interleukin-2 benefits a select group of patients in the adjuvant and metastatic settings, respectively, with significant attendant toxicity. Advances in the biology of malignant melanoma and the role of immunomodulatory therapy have produced advances that have stunned the field. In this paper, we review the data for the use of interferon-α2b in various dosing ranges, vaccine therapy, and the role of radiotherapy in the adjuvant setting for malignant melanoma. Recent trials in the metastatic setting using anticytoxic T-lymphocyte antigen-4 (anti-CTLA-4) monoclonal antibody therapy and BRAF inhibitor therapy have demonstrated clear benefit with prolongation of survival. Trials investigating combinations of these novel agents with existing immunomodulators are at present underway.
"We have chosen this cancer model because melanoma is a very aggressive cancer, and one of the therapeutic agents frequently used in the treatment of melanoma is IFN-α. Significant improvements in relapse-free and overall survival, with postoperative adjuvant IFN-α therapy, have been reported by large and randomized studies [63–65]. However, the beneficial effect of IFN-α was only obtained when the patients received high doses (20 MIU/m2 intravenously five times per week). "
[Show abstract][Hide abstract] ABSTRACT: The discovery of the interferon-lambda (IFN-λ) family has considerably contributed to our understanding of the role of interferon not only in viral infections but also in cancer. IFN-λ proteins belong to the new type III IFN group. Type III IFN is structurally similar to type II IFN (IFN-γ) but functionally identical to type I IFN (IFN-α/β). However, in contrast to type I or type II IFNs, the response to type III IFN is highly cell-type specific. Only epithelial-like cells and to a lesser extent some immune cells respond to IFN-λ. This particular pattern of response is controlled by the differential expression of the IFN-λ receptor, which, in contrast to IFN-α, should result in limited side effects in patients. Recently, we and other groups have shown in several animal models a potent antitumor role of IFN-λ that will open a new challenging era for the current IFN therapy.
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