Ella Institute of Melanoma

Tel Aviv, Israel

Ella Institute of Melanoma

Tel Aviv, Israel
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Sapoznik S.,Ella Institute of Melanoma | Ortenberg R.,Ella Institute of Melanoma | Ortenberg R.,Tel Aviv University | Schachter J.,Ella Institute of Melanoma | And 3 more authors.
Current Topics in Medicinal Chemistry | Year: 2012

CEACAM1 adhesion molecule is broadly expressed, participates in pivotal cellular and immunological processes and is involved in cancer. Originally identified as a tumor suppressor, it is now known that in several cancers, including malignant melanoma, CEACAM1 expression correlates with tumor progression and poor survival. Here we review the findings connecting CEACAM1 to malignant melanoma, encompassing in-vitro, in-vivo and patients-derived data. A CEACAM1-mediated mechanism used by melanoma cells to evade immune attack is described in detail. Finally, the potential value of CEACAM1 as a melanoma biomarker and therapeutic target is being discussed. © 2012 Bentham Science Publishers.


Markel G.,Ella Institute of Melanoma | Markel G.,Sheba Medical Center | Markel G.,Tel Aviv University | Imazio M.,Maria Vittoria Hospital | And 4 more authors.
Clinical Cardiology | Year: 2013

The most troublesome complication of acute pericarditis is recurrent pericardial inflammation, which occurs in 15%-32% of cases. The optimal method for prevention has not been fully established; accepted modalities include nonsteroidal anti-inflammatory drugs, corticosteroids, immunosuppressive agents, and pericardiectomy. Over the last years, objective clinical evidence has matured and clearly indicates the important role and beneficial clinical effect of colchicine therapy in preventing recurrent pericarditis caused by various etiologies. Colchicine-treated patients consistently display significantly fewer recurrences and longer symptom-free periods, and even when attacks occur, they are weaker and shorter in nature. Notably, pretreatment with corticosteroids substantially attenuates the efficacy of colchicine, causing significantly more recurrences and longer therapy periods. The safety profile seems superior to other drugs, such as corticosteroids and immunosuppressive drugs. Colchicine is a safe and effective modality for the treatment and prevention of recurrent pericarditis, especially as an adjunct to other modalities, because it provides a sustained benefit, superior to all current modalities. The authors have no funding, financial relationships, or conflicts of interest to disclose. © 2013 Wiley Periodicals, Inc.


Besser M.J.,Ella Institute of Melanoma | Besser M.J.,Tel Aviv University | Shapira-Frommer R.,Sheba Medical Center | Itzhaki O.,Ella Institute of Melanoma | And 18 more authors.
Clinical Cancer Research | Year: 2013

Purpose: Adoptive cell transfer (ACT) using autologous tumor-infiltrating lymphocytes (TIL) was reported to yield objective responses in about 50% of metastatic patients with melanoma. Here, we present the intent-to-treat analysis of TIL ACT and analyze parameters predictive to response as well as the impact of other immunotherapies. Experimental Design: Eighty patients with stage IV melanoma were enrolled, of which 57 were treated with unselected/young TIL and high-dose interleukin-2 (IL-2) following nonmyeloablative lymphodepleting conditioning. Results: TIL cultures were established from 72 of 80 enrolled patients. Altogether 23 patients were withdrawn from the study mainly due to clinical deterioration during TIL preparation. The overall response rate and median survival was 29% and 9.8 months for enrolled patients and 40% and 15.2 months for treated patients. Five patients achieved complete and 18 partial remission. All complete responders are on unmaintained remission after a median follow-up of 28 months and the 3-year survival of responding patients was 78%. Multivariate analysis revealed blood lactate-dehydrogenase levels, gender, days of TIL in culture, and the total number of infused CD8+ cells as independent predictive markers for clinical outcome. Thirty-two patients received the CTLA-4-blocking antibody ipilimumab prior or post TIL infusion. Retrospective analysis revealed that nonresponders to ipilimumab or IL-2 based therapy had the same overall response rate to ACT as other patients receiving TIL. No additional toxicities to TIL therapy occurred following ipilimumab treatment. Conclusion: Adoptive transfer of TIL can yield durable and complete responses in patients with refractory melanoma, even when other immunotherapies have failed. ©2013 AACR.


Greenberg E.,Ella Institute of Melanoma | Greenberg E.,Tel Aviv University | Hajdu S.,Ella Institute of Melanoma | Nemlich Y.,Ella Institute of Melanoma | And 10 more authors.
Open Biology | Year: 2014

The various roles of microRNAs (miRNAs) in controlling the phenotype of cancer cells are the focus of contemporary research efforts. We have recently shown that miR-17 directly targets the ADAR1 gene and thereby enhances melanoma cell aggressiveness. miR-17 and miR-20a belong to the miR-17/92 complex, and their mature forms are identical except for two non-seed nucleotides. Nevertheless, herewe show that these two miRNAs carry markedly different effects on melanoma cells. A strong positive correlation was observed between the expression of miR-17 and miR-20a among various melanoma cultures. Luciferase assays showed that miR-17 but not miR-20a directly targets the 3' untranslated region of the ADAR1 gene. Ectopic expression of these miRNAs in melanoma cells differentially alters the expression of five exemplar TargetScan-predicted target genes: ADAR1, ITGB8, TGFBR2, MMP2 and VEGF-A. Whole-genome expression microarrays confirm a markedly differential effect on the transcriptome. Functionally, over-expression of miR-20a but not of miR-17 in melanoma cells inhibits net proliferation in vitro. The differential functional effect was observed following ectopic expression of the mature miRNA or of the premiRNA sequences. This suggests that the two non-seed nucleotides dictate target sequence recognition and overall functional relevance. These miRNAs are clearly not redundant in melanoma cell biology. © 2014 The Authors.


Gur C.,Hebrew University of Jerusalem | Ibrahim Y.,Hebrew University of Jerusalem | Isaacson B.,Hebrew University of Jerusalem | Yamin R.,Hebrew University of Jerusalem | And 21 more authors.
Immunity | Year: 2015

Bacteria, such as Fusobacterium nucleatum, are present in the tumor microenvironment. However, the immunological consequences of intra-tumoral bacteria remain unclear. Here, we have shown that natural killer (NK) cell killing of various tumors is inhibited in the presence of various F.nucleatum strains. Ourdata support that this F.nucleatum-mediated inhibition is mediated by human, but not by mouse TIGIT, an inhibitory receptor present on all human NK cellsand on various Tcells. Using a library of F.nucleatum mutants, we found that the Fap2 protein of F.nucleatum directly interacted with TIGIT, leading to the inhibition of NK cell cytotoxicity. We have further demonstrated that tumor-infiltrating lymphocytes expressed TIGIT and that Tcell activities were also inhibited by F.nucleatum via Fap2. Our results identify a bacterium-dependent, tumor-immune evasion mechanism in which tumors exploit the Fap2 protein of F.nucleatum to inhibit immune cell activity via TIGIT. © 2015 Elsevier Inc.


Shoshan E.,University of Houston | Mobley A.K.,University of Houston | Braeuer R.R.,University of Houston | Kamiya T.,University of Houston | And 24 more authors.
Nature Cell Biology | Year: 2015

Although recent studies have shown that adenosine-to-inosine (A-to-I) RNA editing occurs in microRNAs (miRNAs), its effects on tumour growth and metastasis are not well understood. We present evidence of CREB-mediated low expression of ADAR1 in metastatic melanoma cell lines and tumour specimens. Re-expression of ADAR1 resulted in the suppression of melanoma growth and metastasis in vivo. Consequently, we identified three miRNAs undergoing A-to-I editing in the weakly metastatic melanoma but not in strongly metastatic cell lines. One of these miRNAs, miR-455-5p, has two A-to-I RNA-editing sites. The biological function of edited miR-455-5p is different from that of the unedited form, as it recognizes a different set of genes. Indeed, wild-type miR-455-5p promotes melanoma metastasis through inhibition of the tumour suppressor gene CPEB1. Moreover, wild-type miR-455 enhances melanoma growth and metastasis in vivo, whereas the edited form inhibits these features. These results demonstrate a previously unrecognized role for RNA editing in melanoma progression. © 2015 Macmillan Publishers Limited.


Greenberg E.,Ella Institute of Melanoma | Greenberg E.,Tel Aviv University | Nemlich Y.,Ella Institute of Melanoma | Markel G.,Ella Institute of Melanoma | And 2 more authors.
Current Pharmaceutical Design | Year: 2014

Melanoma is a high-grade, poorly differentiated malignant tumor of pigment-producing cells (melanocytes), accounting for more than 70% of the skin cancer related deaths. Although new lines of targeted therapy and immunotherapy were introduced lately, durable responses are not common as it is hard to target the elusive metastatic phenotype. microRNAs (miRNAs) are short non-coding RNA molecules that function as specific epigenetic regulators of the transcriptome. miRNAs are involved in a broad spectrum of physiological and pathological processes, including cancer-related functions such as proliferation, cell cycle, migration, invasion, immune evasion and drug resistance. These functions are mostly regulated in melanoma through four molecular deregulated pathways, including the RAS/MAPK pathway, the MITF pathway, the p16INK4A-CDK4-RB pathway and the PI3K-AKT pathway. miRNAs provide a strong platform for delineation of cancer mechanisms. Here we review the diverse roles of miRNAs in melanoma cell biology. Studying miRNA-mediated regulation of aggressive and tumor related features is expected to provide novel mechanistic insights that may pave the way for new diagnostic, prognostic and predictive tools as well as new molecular targets for future therapy. © 2014 Bentham Science Publishers.


Besser M.J.,Ella Institute of Melanoma | Besser M.J.,Tel Aviv University
OncoImmunology | Year: 2013

The adoptive transfer of tumor-infiltrating lymphocytes (TILs) can yield durable responses in patients affected by metastatic melanoma. In particular, we have recently reported an 80% 3 year survival rate among patients who responded to this immunotherapeutic regimen. Of note, overall response rates were equal among ipilimumab-naïve and ipilimumabrefractory patients. Thus, the adoptive transfer of TILs, as a standalone therapeutic intervention or combined with other treatment modalities, bears a high clinical potential that must be optimally employed. © 2013 Landes Bioscience.


Besser M.J.,Ella Institute of Melanoma | Besser M.J.,Tel Aviv University | Hershkovitz L.,Ella Institute of Melanoma | Schachter J.,Ella Institute of Melanoma | Treves A.J.,Sheba Cancer Research Center
Clinical and Developmental Immunology | Year: 2010

Adoptive Cell Transfer (ACT) of Tumor-Infiltrating Lymphocytes (TIL) in combination with lymphodepletion has proven to be an effective treatment for metastatic melanoma patients, with an objective response rate in 50%-70% of the patients. It is based on the ex vivo expansion and activation of tumor-specific T lymphocytes extracted from the tumor and their administration back to the patient. Various TIL-ACT trials, which differ in their TIL generation procedures and patient preconditioning, have been reported. In the latest clinical studies, genetically engineered peripheral T cells were utilized instead of TIL. Further improvement of adoptive T cell transfer depends on new investigations which seek higher TIL quality, increased durable response rates, and aim to treat more patients. Simplifying this therapy may encourage cancer centers worldwide to adopt this promising technology. This paper focuses on the latest progress regarding adoptive T cell transfer, comparing the currently available protocols and discussing their advantages, disadvantages, and implication in the future. © 2010 Liat Hershkovitz et al.


Burazor I.,Clinical Center Nis | Imazio M.,Maria Vittoria Hospital | Markel G.,Ella Institute of Melanoma | Markel G.,Sheba Medical Center | And 3 more authors.
Cardiology (Switzerland) | Year: 2013

Malignant pericardial effusion is a common and serious manifestation in malignancies. The origins of the malignant process include solid tumors or hematological malignancies, while primary neoplasms of the pericardium are less common. In the oncological patient, pericardial effusion may develop by several different mechanisms, namely by direct or metastatic spread of the primary process or as a complication of antineoplastic therapies. In some cases, pericardial effusion may be the first manifestation of the disease, and that is why malignancy must be excluded in every case of an acute pericardial disease with cardiac tamponade at presentation, rapidly increasing pericardial effusion and an incessant or recurrent course. Thus, the definite differentiation of malignant pericardial effusion and rapid diagnosis are of particular therapeutic and prognostic importance. Management of these patients is multidisciplinary and requires team work, but at present there is a need for further research. An individual treatment plan should be established, taking into account cancer stage, the patient's prognosis, local availability and experience. In emergency cases with cardiac tamponade or significant effusion, initial relief can be obtained with pericardiocentesis. Despite the magnitude of this serious problem, little progress has been made in the treatment of pericardial effusion secondary to malignant disease. © 2013 S. Karger AG, Basel.

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