Ella Lemelbaum Institute for Melanoma

Tel Aviv, Israel

Ella Lemelbaum Institute for Melanoma

Tel Aviv, Israel
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Schachter J.,Ella Lemelbaum Institute for Melanoma | Ribas A.,University of California at Los Angeles | Long G.V.,University of Sydney | Arance A.,Hospital Clinic Of Barcelona | And 16 more authors.
The Lancet | Year: 2017

Background: Interim analyses of the phase 3 KEYNOTE-006 study showed superior overall and progression-free survival of pembrolizumab versus ipilimumab in patients with advanced melanoma. We present the final protocol-specified survival analysis. Methods: In this multicentre, open-label, randomised, phase 3 trial, we recruited patients from 87 academic institutions, hospitals, and cancer centres in 16 countries (Australia, Austria, Belgium, Canada, Chile, Colombia, France, Germany, Israel, Netherlands, New Zealand, Norway, Spain, Sweden, UK, and USA). We randomly assigned participants (1:1:1) to one of two dose regimens of pembrolizumab, or one regimen of ipilimumab, using a centralised, computer-generated allocation schedule. Treatment assignments used blocked randomisation within strata. Eligible patients were at least 18 years old, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, at least one measurable lesion per Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1), unresectable stage III or IV melanoma (excluding ocular melanoma), and up to one previous systemic therapy (excluding anti-CTLA-4, PD-1, or PD-L1 agents). Secondary eligibility criteria are described later. Patients were excluded if they had active brain metastases or active autoimmune disease requiring systemic steroids. The primary outcome was overall survival (defined as the time from randomisation to death from any cause). Response was assessed per RECIST v1.1 by independent central review at week 12, then every 6 weeks up to week 48, and then every 12 weeks thereafter. Survival was assessed every 12 weeks, and final analysis occurred after all patients were followed up for at least 21 months. Primary analysis was done on the intention-to-treat population (all randomly assigned patients) and safety analyses were done in the treated population (all randomly assigned patients who received at least one dose of study treatment). Data cutoff date for this analysis was Dec 3, 2015. This study was registered with ClinicalTrials.gov, number NCT01866319. Findings: Between Sept 18, 2013, and March 3, 2014, 834 patients with advanced melanoma were enrolled and randomly assigned to receive intravenous pembrolizumab every 2 weeks (n=279), intravenous pembrolizumab every 3 weeks (n=277), or intravenous ipilimumab every 3 weeks (ipilimumab for four doses; n=278). One patient in the pembrolizumab 2 week group and 22 patients in the ipilimumab group withdrew consent and did not receive treatment. A total of 811 patients received at least one dose of study treatment. Median follow-up was 22·9 months; 383 patients died. Median overall survival was not reached in either pembrolizumab group and was 16·0 months with ipilimumab (hazard ratio [HR] 0·68, 95% CI 0·53-0·87 for pembrolizumab every 2 weeks vs ipilimumab; p=0·0009 and 0·68, 0·53-0·86 for pembrolizumab every 3 weeks vs ipilimumab; p=0·0008). 24-month overall survival rate was 55% in the 2-week group, 55% in the 3-week group, and 43% in the ipilimumab group. Interpretation: Substantiating the results of the interim analyses of KEYNOTE-006, pembrolizumab continued to provide superior overall survival versus ipilimumab, with no difference between pembrolizumab dosing schedules. These conclusions further support the use of pembrolizumab as a standard of care for advanced melanoma. Funding: Merck & Co. © 2017 Elsevier Ltd.

Robert C.,University Paris - Sud | Robert C.,University of Sydney | Schachter J.,Ella Lemelbaum Institute for Melanoma | Schachter J.,University of Sydney | And 25 more authors.
New England Journal of Medicine | Year: 2015

Background The immune checkpoint inhibitor ipilimumab is the standard-of-care treatment for patients with advanced melanoma. Pembrolizumab inhibits the programmed cell death 1 (PD-1) immune checkpoint and has antitumor activity in patients with advanced melanoma. Methods In this randomized, controlled, phase 3 study, we assigned 834 patients with advanced melanoma in a 1:1:1 ratio to receive pembrolizumab (at a dose of 10 mg per kilogram of body weight) every 2 weeks or every 3 weeks or four doses of ipilimumab (at 3 mg per kilogram) every 3 weeks. Primary end points were progression-free and overall survival. Results The estimated 6-month progression-free-survival rates were 47.3% for pembrolizumab every 2 weeks, 46.4% for pembrolizumab every 3 weeks, and 26.5% for ipilimumab (hazard ratio for disease progression, 0.58; P<0.001 for both pembrolizumab regimens versus ipilimumab; 95% confidence intervals [CIs], 0.46 to 0.72 and 0.47 to 0.72, respectively). Estimated 12-month survival rates were 74.1%, 68.4%, and 58.2%, respectively (hazard ratio for death for pembrolizumab every 2 weeks, 0.63; 95% CI, 0.47 to 0.83; P = 0.0005; hazard ratio for pembrolizumab every 3 weeks, 0.69; 95% CI, 0.52 to 0.90; P = 0.0036). The response rate was improved with pembrolizumab administered every 2 weeks (33.7%) and every 3 weeks (32.9%), as compared with ipilimumab (11.9%) (P<0.001 for both comparisons). Responses were ongoing in 89.4%, 96.7%, and 87.9% of patients, respectively, after a median follow-up of 7.9 months. Efficacy was similar in the two pembrolizumab groups. Rates of treatment-related adverse events of grade 3 to 5 severity were lower in the pembrolizumab groups (13.3% and 10.1%) than in the ipilimumab group (19.9%). Conclusions The anti-PD-1 antibody pembrolizumab prolonged progression-free survival and overall survival and had less high-grade toxicity than did ipilimumab in patients with advanced melanoma. © 2015 Massachusetts Medical Society.

Ortenberg R.,Ella Lemelbaum Institute for Melanoma | Sapoznik S.,Ella Lemelbaum Institute for Melanoma | Zippel D.,Ella Lemelbaum Institute for Melanoma | Shapira-Frommer R.,Ella Lemelbaum Institute for Melanoma | And 9 more authors.
Journal of Immunology Research | Year: 2015

Malignant melanoma is a devastating disease whose incidences are continuously rising. The recently approved antimelanoma therapies carry new hope for metastatic patients for the first time in decades. However, the clinical management of melanoma is severely hampered by the absence of effective screening tools. The expression of the CEACAM1 adhesion molecule on melanoma cells is a strong predictor of poor prognosis. Interestingly, a melanoma-secreted form of CEACAM1 (sCEACAM1) has recently emerged as a potential tumor biomarker. Here we add novel evidences supporting the prognostic role of serum CEACAM1 by using a mice xenograft model of human melanoma and showing a correlation between serum CEACAM1 and tumor burden. Moreover, we demonstrate that serum CEACAM1 is elevated over time in progressive melanoma patients who fail to respond to immunotherapy as opposed to responders and stable disease patients, thus proving a correlation between sCEACAM1, response to treatment, and clinical deterioration. © 2015 R. Ortenberg et al.

Weinstein-Marom H.,MIGAL Galilee Research Institute | Weinstein-Marom H.,Hebrew University of Jerusalem | Pato A.,MIGAL Galilee Research Institute | Pato A.,Hebrew University of Jerusalem | And 12 more authors.
Journal of Immunotherapy | Year: 2016

Proinflammatory cytokines are widely explored in different adoptive cell therapy protocols for enhancing survival and function of the transferred T cells, but their systemic administration is often associated with severe toxicity which limits their clinical use. To confine cytokine availability to the therapeutic T cells, we expressed 3 key cytokines, IL-2, IL-12, and IL-15, as integral T-cell membrane proteins. To prevent permanent activation of growth signaling pathways, we delivered these genes to T cells through mRNA electroporation. The engineered cytokines could be detected on the surface of mRNA-transfected cells and binding to their cell-surface receptors mainly occurred in cis. The 3 human cytokines supported the ex vivo growth of activated human CD8 and CD4 T cells for at least 6 days posttransfection, comparably to high-dose soluble IL-2. Similarly, membrane IL-2, membrane IL-12, and, to a lesser extent, membrane IL-15, were comparable with their soluble counterparts in supporting proliferation of splenic mouse CD8 T cells. Following electroporation of human CD8 T cells and antimelanoma tumor-infiltrating lymphocytes, membrane cytokines synergized with constitutively active toll-like receptor 4 in inducing interferon-g secretion. Efficient cooperation with TLR4 was also evident in the upregulation of the activation molecules CD25, CD69, CD137 (4-1BB), and CD134 (OX40). Taken together, membrane cytokines expressed through mRNA transfection emerge as effective tools for enhancing T-cell proliferation and function and may have potential use in adoptive T-cell therapy. Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.

Zikich D.,Ella Lemelbaum Institute for Melanoma | Schachter J.,Ella Lemelbaum Institute for Melanoma | Besser M.J.,Ella Lemelbaum Institute for Melanoma | Besser M.J.,Tel Aviv University
Immunotherapy | Year: 2016

In the past decades, the increasing knowledge in cellular immunology and tumor-host immune interactions, led to the development of immunotherapy approaches. Immunotherapy, based on adoptive cell transfer of ex vivo activated and expanded tumor-infiltrating T lymphocytes (TILs), has shown promising clinical results in patients with metastatic melanoma. TIL therapy yields response rates of around 50% and significant survival benefit in refractory melanoma patients, even after failing other immunotherapies, such as checkpoint inhibitors or cytokine-based therapy. Identifying predictors of TIL efficacy and detection of TIL subsets with specific reactivity against the patient's tumor might be an important milestone toward further improvement of clinical responses and prolonged survival. © 2016 Future Medicine Ltd.

Besser M.J.,Ella Lemelbaum Institute for Melanoma | Besser M.J.,Tel Aviv University | Shapira-Frommer R.,Ella Lemelbaum Institute for Melanoma | Schachter J.,Ella Lemelbaum Institute for Melanoma
Cancer Journal (United States) | Year: 2015

Adoptive cell therapy (ACT) with tumor-infiltrating lymphocytes (TILs) in combination with lymphodepletion and high-dose interleukin 2 has shown reproducible objective response rates of approximately 50% in patients with highly advanced, refractory metastatic melanoma. As confirmed by different clinical centers, TIL ACT can yield durable responses especially in patients with complete regression, who are mostly disease-free many years after treatment, suggesting the possibility of cure. Most TIL ACT trials have been conducted as salvage therapy for patients with multiple metastases, frequently in visceral organs and even brain, and who failed numerous treatments, including checkpoint inhibitors, which underlines the value of the treatment. Recent developments in the identification and selection of tumor-specific T-cell populations have facilitated the implementation of TIL ACTalso in nonmelanoma malignancies. We summarize the clinical experience of TIL ACT in melanoma, briefly discuss new directions for further improvement of this promising therapy, and present the latest clinical results in nonmelanoma cancers. © 2015 Wolters Kluwer Health, Inc. All rights reserved.

Plotnikov A.,Weizmann Institute of Science | Flores K.,Weizmann Institute of Science | Maik-Rachline G.,Weizmann Institute of Science | Zehorai E.,Weizmann Institute of Science | And 6 more authors.
Nature Communications | Year: 2015

A hallmark of the ERK1/2 functioning is their nuclear translocation, which is mainly required for the induction of proliferation. Activated ERK1/2 molecules that remain in the cytoplasm initiate other activities, including immediate feedback loops. Prevention of the nuclear translocation should therefore inhibit proliferation, without affecting cytoplasm-induced cellular processes. Here we present an NTS-derived myristoylated phosphomimetic peptide, which blocks the interaction of importin7 and ERK1/2, and consequently the nuclear translocation of the latter. In culture, the peptide induces apoptosis of melanoma cells inhibits the viability of other cancer cells, but has no effect on non-transformed, immortalized cells. It even inhibits the viability of PLX4032- and U0126-resistant melanoma cells. In xenograft models, the peptide inhibits several cancers, and acts much better than PLX4032 in preventing melanoma recurrence. This study provides a proof of concept for using the nuclear translocation of ERK1/2 as a drug target for the combat of various ERK1/2-related cancers. © 2015 Macmillan Publishers Limited. All rights reserved.

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