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Hodi F.S.,Dana-Farber Cancer Institute | O'Day S.J.,Angeles Clinic and Research Institute | McDermott D.F.,Beth Israel Deaconess Medical Center | Weber R.W.,St Marys Medical Center | And 25 more authors.
New England Journal of Medicine | Year: 2010

Background: An improvement in overall survival among patients with metastatic melanoma has been an elusive goal. In this phase 3 study, ipilimumab - which blocks cytotoxic T-lymphocyte-associated antigen 4 to potentiate an antitumor T-cell response - administered with or without a glycoprotein 100 (gp100) peptide vaccine was compared with gp100 alone in patients with previously treated metastatic melanoma. Methods: A total of 676 HLA-A*0201-positive patients with unresectable stage III or IV melanoma, whose disease had progressed while they were receiving therapy for metastatic disease, were randomly assigned, in a 3:1:1 ratio, to receive ipilimumab plus gp100 (403 patients), ipilimumab alone (137), or gp100 alone (136). Ipilimumab, at a dose of 3 mg per kilogram of body weight, was administered with or without gp100 every 3 weeks for up to four treatments (induction). Eligible patients could receive reinduction therapy. The primary end point was overall survival. Results: The median overall survival was 10.0 months among patients receiving ipilimumab plus gp100, as compared with 6.4 months among patients receiving gp100 alone (hazard ratio for death, 0.68; P<0.001). The median overall survival with ipilimumab alone was 10.1 months (hazard ratio for death in the comparison with gp100 alone, 0.66; P=0.003). No difference in overall survival was detected between the ipilimumab groups (hazard ratio with ipilimumab plus gp100, 1.04; P=0.76). Grade 3 or 4 immune-related adverse events occurred in 10 to 15% of patients treated with ipilimumab and in 3% treated with gp100 alone. There were 14 deaths related to the study drugs (2.1%), and 7 were associated with immune-related adverse events. Conclusions: Ipilimumab, with or without a gp100 peptide vaccine, as compared with gp100 alone, improved overall survival in patients with previously treated metastatic melanoma. Adverse events can be severe, long-lasting, or both, but most are reversible with appropriate treatment. (Funded by Medarex and Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00094653.) Copyright © 2010 Massachusetts Medical Society.


Wolchok J.D.,Sloan Kettering Cancer Center | Neyns B.,Universitair Ziekenhuis | Linette G.,University of Washington | Negrier S.,Center Leon Berard | And 12 more authors.
The Lancet Oncology | Year: 2010

Background: Ipilimumab is a human monoclonal antibody that blocks cytotoxic T-lymphocyte antigen 4 and has shown promising activity in advanced melanoma. We aimed to ascertain the antitumour efficacy of ipilimumab in patients with advanced melanoma. Methods: We undertook a randomised, double-blind, phase 2 trial in 66 centres from 12 countries. 217 patients with previously treated stage III (unresectable) or stage IV melanoma were randomly assigned a fixed dose of ipilimumab of either 10 mg/kg (n=73), 3 mg/kg (n=72), or 0·3 mg/kg (n=72) every 3 weeks for four cycles (induction) followed by maintenance therapy every 3 months. Randomisation was done with a permuted block procedure, stratified on the basis of type of previous treatment. The primary endpoint was best overall response rate (the proportion of patients with a complete or partial response, according to modified WHO criteria). Efficacy analyses were done by intention to treat, whereas safety analyses included patients who received at least one dose of ipilimumab. This study is registered with ClinicalTrials.gov, number NCT00289640. Findings: The best overall response rate was 11·1% (95% CI 4·9-20·7) for 10 mg/kg, 4·2% (0·9-11·7) for 3 mg/kg, and 0% (0·0-4·9) for 0·3 mg/kg (p=0·0015; trend test). Immune-related adverse events of any grade arose in 50 of 71, 46 of 71, and 19 of 72 patients at doses of 10 mg/kg, 3 mg/kg, and 0·3 mg/kg, respectively; the most common grade 3-4 adverse events were gastrointestinal immune-related events (11 in the 10 mg/kg group, two in the 3 mg/kg group, none in the 0·3 mg/kg group) and diarrhoea (ten in the 10 mg/kg group, one in the 3 mg/kg group, none in the 0·3 mg/kg group). Interpretation: Ipilimumab elicited a dose-dependent effect on efficacy and safety measures in pretreated patients with advanced melanoma, lending support to further studies at a dose of 10 mg/kg. Funding: Bristol-Myers Squibb. © 2010 Elsevier Ltd. All rights reserved.


PubMed | Washington University in St. Louis, University of Michigan, Mount Sinai Comprehensive Cancer Center, University of Chicago and 10 more.
Type: Journal Article | Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2017

CRA9003 Background: Gq/11 mutations are early oncogenic events in UM resulting in MAPK pathway activation. We demonstrated decreased viability in UM cell lines harboring Gq/11 mut with sel, a small molecule inhibitor of MEK1/2 (Ambrosini, CCR 2012).We conducted a 16 center randomized phase II study of hyd-sulfate sel 75 mg BID vs TMZ 150 mg/m80 pts were randomized. Sel (n=39): median age 66 (range 32-86), 54% male, 54% G11 mut, median ECOG PS 0 (range 0-1), 97% M1c, median prior tx 0 (range 0-2). TMZ (n=41): median age 60 (range 34-81), 63% male, 58% G11 mut, median ECOG PS 0 (range 0-1), 93% M1c, median prior tx 0 (range 0-2). 11/39 (28%) pts on sel experienced grade (gr) 3 toxicity (tox) manageable with dose modification (5 CPK elevation, 3 LFT elevation, 1 rash, 1 lymphopenia, 1 edema). 1/41 (2%) pt on TMZ experienced gr 3 tox (neutropenia). No gr 4/5 tox occurred. 28 pts on sel underwent paired tumor biopsies with inhibition of pERK and cyclinD1 observed by Western blot at day 14. At interim analysis (9/25/12), 55 pts were evaluable with 45 progression events and 16 deaths. Sel (n=27): median PFS 16 wks (95% CI 8-30.9), RR 11%, median OS 11.8 months (95% CI 4.8-not reached). TMZ (n=28): median PFS 4 wks (95% CI 3.7-15), RR 0%, median OS 4.7 months (95% CI 4.3-14.3). TMZsel (n=25): median PFS 8.1 wks (95% CI 7-15), RR 0%.Sel is the first drug to ever show improved clinical activity in UM relative to TMZ. Sustained target inhibition is observed with sel. Final results will be presented.NCT01143402.


Soares H.P.,Mount Sinai Medical Center | Lutzky J.,Mount Sinai Comprehensive Cancer Center
Expert Opinion on Biological Therapy | Year: 2010

Importance of the field: Immunotherapy for cancer has been investigated for several decades, achieving limited success. The development of effective new immunotherapeutic agents has reignited interest in the filed. Intralesional injection of plasmids in order to transfect genes capable of stimulating or augmenting immune recognition and destruction of tumors is a relatively new approach. Areas covered in this review: Our objective is to discuss the role velimogene aliplasmid (Allovectin-7®, Vical Incorporated), a plasmidlipid complex containing the DNA sequences encoding HLA-B7 and β2 microglobulin, as an immunotherapeutic agent. What the reader will gain: Intralesional velimogene aliplasmid induces anti-tumor responses in a proportion of melanoma patients with locoregional and limited distant metastases. Preclinical data and the results of Phase I, II and III clinical trials with this drug are reviewed. The limited data in other malignancies is also reviewed. Velimogene aliplasmid in humans appears safe, with minimal drug-related adverse events. Take home message: Velimogene aliplasmid has activity in melanoma with local and limited distant disease associated with an excellent safety profile. The activity of this approach is also being investigated in other malignancies. © 2010 Informa UK Ltd.


Akbari M.R.,University of Toronto | Donenberg T.,University of Miami | Lunn J.,Doctors Hospital | Curling D.,Princess Margaret Hospital | And 5 more authors.
Clinical Genetics | Year: 2014

We sought to identify the full range of founder mutations in BRCA1 and BRCA2 in the Bahamas and to estimate the proportion of all BRCA1 and BRCA2 mutations that are accounted for by founder mutations. We studied 214 Bahamian women with invasive breast cancer, unselected for age or family history. A founder mutation had previously been identified in 49 patients. We conducted full sequencing of the BRCA1 and BRCA2 genes and multiplex ligation-dependent probe amplification (MLPA) for 156 patients. A novel founder mutation in BRCA2 (exon 17 818delA) was seen in four different patients and five other unique mutations in BRCA1 and BRCA2, including a large deletion (exons 8-9) in BRCA1. In total, a mutation was seen in 58 of the 214 patients (27%); 92% of carriers carried one of the seven founder mutations. Approximately 27% of unselected cases of breast cancer in the Bahamian population are attributable to a mutation in BRCA1 or BRCA2, a prevalence which far exceeds that of any other country. The majority of women who carry a mutation in the Bahamas, carry one of the seven founder mutations, making it possible to offer genetic testing to all women at risk for breast cancer in the Bahamas. © 2013 John Wiley & Sons A/S.


Chistiakov D.A.,Mount Sinai Comprehensive Cancer Center | Chistiakov D.A.,Research Center for Childrens Health | Orekhov A.N.,Russian Academy of Sciences | Bobryshev Y.V.,University of New South Wales | Bobryshev Y.V.,University of Western Sydney
Cellular and Molecular Life Sciences | Year: 2015

Circulating extracellular vesicles (EVs) comprise a heterogeneous population of vesicular structures. According to the current paradigm, there are three types of EVs, including exosomes, microvesicles and apoptotic bodies, that are differentiated in their size, formation, and release mechanisms. EVs were shown to act as a 'post service' that serves a long-distance delivery of complex cellular messages. The cargo of EVs consists of a variety of biomolecules including proteins, DNA, mRNA, and non-coding RNA. In normal or pathological conditions, EVs deliver various molecules to the recipient cells. Those molecules greatly vary depending on the microenvironmental stimuli. In proinflammatory conditions such as atherosclerosis and other cardiovascular diseases, EVs derived from vascular endothelial cells, vascular smooth muscle cells, macrophages, and other circulating immune cells mainly possess proinflammatory properties. However, the capacity of circulating EVs to stably maintain and deliver a variety of biomolecules makes these microparticles to be a promising therapeutic tool for treatment of cardiovascular pathology. To date, circulating EVs were evaluated to be as a source of valuable diagnostic and prognostic biomarkers such as microRNA. Circulating EVs keep a great therapeutic potential to serve as vehicles for targeted therapy of cardiovascular diseases. © 2015 Springer Basel.


Bobryshev Y.V.,University of New South Wales | Orekhov A.N.,Russian Academy of Sciences | Chistiakov D.A.,Mount Sinai Comprehensive Cancer Center
Cell and Tissue Research | Year: 2015

Stem/progenitor cells residing in the vascular wall of post-natal vessels play a crucial role in angiogenesis and vascular regeneration after damage. There are four major populations of vascular-resident stem/progenitor cells with differentiated clonogenic and proliferative potential, namely mesenchymal stem cells, pericytes, endothelial progenitor cells, and smooth muscle progenitor cells. These progenitors reside in vascular stem cell niches, which are more likely to be in the adventitia, a vascular wall layer in which increased concentration of stem cell surface markers has been shown. Indeed, vascular resident progenitors are not uniformly distributed across the vessel wall and the circulatory system. The heterogeneity of such a distribution could contribute to the differentiated susceptibility of various vessel regions to chronic vascular diseases such as atherosclerosis. In cardiovascular pathology, adult vascular resident progenitors could play either a negative or a positive role. © 2015, Springer-Verlag Berlin Heidelberg.


Lutzky J.,Mount Sinai Comprehensive Cancer Center
Chinese Clinical Oncology | Year: 2014

Advanced malignant melanoma has historically been considered a uniformly lethal disease. Recent scientific strides have led to unprecedented understanding of both the molecular alterations and the mechanisms of immune evasion in this malignancy. The realization that an intense and dynamic interplay of stimulatory and inhibitory signals occurs in the "immune synapses" among T cells, tumor cells and dendritic cells, led to the development and subsequent clinical testing of agonist and antagonist monoclonal antibodies (mAb) that can modulate these signals. The resulting positive outcomes of the clinical trials utilizing CTLA-4, PD-1 and PD-L1 modulating drugs, has catapulted the field of immunotherapy into the realm of standard treatment. In this article we review the most important agents and clinical data feeding the ongoing paradigm change in the treatment of advanced melanoma. © Chinese Clinical Oncology.


Lutzky J.,Mount Sinai Comprehensive Cancer Center
Seminars in Cutaneous Medicine and Surgery | Year: 2010

During the past 3 decades, the incidence, morbidity, and mortality of malignant melanoma have increased dramatically. Advanced melanoma has remained a disease that is for the most part incurable and has challenged all therapeutic efforts to make a dent in its natural history. Recent advances in the understanding of the molecular alterations in melanoma and in the immunologic mechanisms playing a role in this malignancy have brought hope that significant progress can be achieved, as evidenced by early encouraging clinical data. This review will summarize these recent developments and their impact on current clinical practice. © 2010 Elsevier Inc.


Donenberg T.,University of Miami | Lunn J.,Doctors Hospital | Curling D.,Princess Margaret Hospital | Turnquest T.,Princess Margaret Hospital | And 4 more authors.
Breast Cancer Research and Treatment | Year: 2011

The Bahamas is a group of islands in the Caribbean with a high incidence of early onset breast cancer. In isolated populations, the identification of founder mutations in cancer predisposing genes may facilitate genetic testing and counseling. To date, six distinct BRCA1 mutations have been found in patients from cancer families from the Bahamas. The frequencies of these mutant alleles have not been measured in a large series of unselected breast cancer patients from Bahamas. We studied 214 Bahamian women with invasive breast cancer, unselected for age or family history of cancer. All patients were screened for six mutations in the BRCA1 gene that have previously been reported in cancer patients from the Bahamas. A mutation was identified in 49 of the 214 breast cancer patients (23%). The mutation frequency was particularly high in women diagnosed before age 50 (33%) in women with a first-degree relative with breast or ovarian cancer (41%) and in women with bilateral breast cancer (58%). Approximately 23% of unselected cases of breast cancer in the Bahamian population are attributable to a founder mutation in the BRCA1 gene-this is the highest reported mutation prevalence for any country studied to date. Genetic testing for these mutations is advisable for all women diagnosed with breast cancer in the Bahamas. © 2010 Springer Science+Business Media, LLC.

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