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Melanoma: HELP
Articles by Ronnie Shapira-Frommer
Based on 15 articles published since 2010
(Why 15 articles?)
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Between 2010 and 2020, Ronnie Shapira-Frommer wrote the following 15 articles about Melanoma.
 
+ Citations + Abstracts
1 Review Adoptive immunotherapy of advanced melanoma. 2012

Shapira-Frommer, Ronnie / Schachter, Jacob. ·Ella Institute for the Treatment and Research of Melanoma, Sheba Medical Center, Ramat-Gan, 52621, Israel. roni.shapira@sheba.health.gov.il ·Curr Treat Options Oncol · Pubmed #22864561.

ABSTRACT: Adoptive cell therapy (ACT) has emerged as an effective therapy for patients with metastatic melanoma. Since the first introduction of the protocol in 1988 [1], major improvements have been achieved with response rates of 40%-72% among patients who were resistant to previous treatment lines. Both cell product and conditioning regimen are major determinants of treatment efficacy; therefore, developing ACT protocols explore diverse ways to establish autologous intra-tumoral lymphocyte cultures or peripheral effector cells as well as different lymphodepleting regimens. While a proof of feasibility and a proof of concept had been established with previous published results, ACT will need to move beyond single-center experiences, to confirmatory, multi-center studies. If ACT is to move into widespread practice, it will be necessary to develop reproducible high quality cell production methods and accepted lymphodepleting regimen. Two new drugs, ipilimumab (Yervoy, Bristol-Myers Squibb) and vemurafenib (Zelboraf, Roche), were approved in 2011 for the treatment of metastatic melanoma based on positive phase III trials. Both drugs show a clear overall survival benefit, so the timing of when to use ACT will need to be carefully thought out. In contrast to these 2 new, commercially available outpatient treatments, ACT is a personally-specified product and labor-intensive therapy that demands both acquisition of high standard laboratory procedures and close clinical inpatient monitoring during treatment. It is unique among other anti-melanoma treatments, providing the potential for a durable response following a single, self-limited treatment. This perspective drives the efforts to make this protocol accessible for more patients and to explore modifications that may optimize treatment results.

2 Clinical Trial Development of MK-8353, an orally administered ERK1/2 inhibitor, in patients with advanced solid tumors. 2018

Moschos, Stergios J / Sullivan, Ryan J / Hwu, Wen-Jen / Ramanathan, Ramesh K / Adjei, Alex A / Fong, Peter C / Shapira-Frommer, Ronnie / Tawbi, Hussein A / Rubino, Joseph / Rush, Thomas S / Zhang, Da / Miselis, Nathan R / Samatar, Ahmed A / Chun, Patrick / Rubin, Eric H / Schiller, James / Long, Brian J / Dayananth, Priya / Carr, Donna / Kirschmeier, Paul / Bishop, W Robert / Deng, Yongqi / Cooper, Alan / Shipps, Gerald W / Moreno, Blanca Homet / Robert, Lidia / Ribas, Antoni / Flaherty, Keith T. ·Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. · Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA. · Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. · Translational Genomics Research Institute, Phoenix, Arizona, USA; Virginia G. Piper Cancer Center, Scottsdale, Arizona, USA. · Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York, USA. · The University of Auckland and Auckland City Hospital, Auckland, New Zealand. · Department of International Medicine, Chaim Sheba Medical Center, Tel-HaShomer, Israel. · University of Pittsburgh School of Medicine, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, USA. · Merck & Co. Inc., Kenilworth, New Jersey, USA. · Jonsson Comprehensive Cancer Center at UCLA, University of California Los Angeles, Los Angeles, California, USA. ·JCI Insight · Pubmed #29467321.

ABSTRACT: BACKGROUND: Constitutive activation of ERK1/2 occurs in various cancers, and its reactivation is a well-described resistance mechanism to MAPK inhibitors. ERK inhibitors may overcome the limitations of MAPK inhibitor blockade. The dual mechanism inhibitor SCH772984 has shown promising preclinical activity across various BRAFV600/RAS-mutant cancer cell lines and human cancer xenografts. METHODS: We have developed an orally bioavailable ERK inhibitor, MK-8353; conducted preclinical studies to demonstrate activity, pharmacodynamic endpoints, dosing, and schedule; completed a study in healthy volunteers (P07652); and subsequently performed a phase I clinical trial in patients with advanced solid tumors (MK-8353-001). In the P07652 study, MK-8353 was administered as a single dose in 10- to 400-mg dose cohorts, whereas in the MK-8353-001 study, MK-8353 was administered in 100- to 800-mg dose cohorts orally twice daily. Safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity were analyzed. RESULTS: MK-8353 exhibited comparable potency with SCH772984 across various preclinical cancer models. Forty-eight patients were enrolled in the P07652 study, and twenty-six patients were enrolled in the MK-8353-001 study. Adverse events included diarrhea (44%), fatigue (40%), nausea (32%), and rash (28%). Dose-limiting toxicity was observed in the 400-mg and 800-mg dose cohorts. Sufficient exposure to MK-8353 was noted that correlated with biological activity in preclinical data. Three of fifteen patients evaluable for treatment response in the MK-8353-001 study had partial response, all with BRAFV600-mutant melanomas. CONCLUSION: MK-8353 was well tolerated up to 400 mg twice daily and exhibited antitumor activity in patients with BRAFV600-mutant melanoma. However, antitumor activity was not particularly correlated with pharmacodynamic parameters. TRIAL REGISTRATION: ClinicalTrials.gov NCT01358331. FUNDING: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co. Inc., and NIH (P01 CA168585 and R35 CA197633).

3 Clinical Trial Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. 2015

Ribas, Antoni / Puzanov, Igor / Dummer, Reinhard / Schadendorf, Dirk / Hamid, Omid / Robert, Caroline / Hodi, F Stephen / Schachter, Jacob / Pavlick, Anna C / Lewis, Karl D / Cranmer, Lee D / Blank, Christian U / O'Day, Steven J / Ascierto, Paolo A / Salama, April K S / Margolin, Kim A / Loquai, Carmen / Eigentler, Thomas K / Gangadhar, Tara C / Carlino, Matteo S / Agarwala, Sanjiv S / Moschos, Stergios J / Sosman, Jeffrey A / Goldinger, Simone M / Shapira-Frommer, Ronnie / Gonzalez, Rene / Kirkwood, John M / Wolchok, Jedd D / Eggermont, Alexander / Li, Xiaoyun Nicole / Zhou, Wei / Zernhelt, Adriane M / Lis, Joy / Ebbinghaus, Scot / Kang, S Peter / Daud, Adil. ·University of California, Los Angeles, Los Angeles, CA, USA. Electronic address: aribas@mednet.ucla.edu. · Vanderbilt-Ingram Cancer Center, Nashville, TN, USA. · University of Zürich, Zürich, Switzerland. · University Hospital Essen, Essen, Germany. · The Angeles Clinic and Research Institute, Los Angeles, CA, USA. · Gustave Roussy and Paris-Sud University, Villejuif, France. · Dana-Farber Cancer Institute, Boston, MA, USA. · Sheba Medical Center, Tel Hashomer, Israel. · New York University Cancer Institute, New York, NY, USA. · University of Colorado Denver, Aurora, CO, USA. · University of Arizona Cancer Center, Tucson, AZ, USA. · Netherlands Cancer Institute, Amsterdam, Netherlands. · Beverly Hills Cancer Center, Beverly Hills, CA, USA. · Istituto Nazionale Tumori Fondazione G. Pascale, Napoli, Italy. · Duke Cancer Institute, Durham, NC, USA. · Seattle Cancer Care Alliance/University of Washington, Seattle, WA, USA. · University Medical Center, Mainz, Germany. · Universitätsklinikum Tübingen, Tübingen, Germany. · Abramson Cancer Center of the University of Pennsylvania, Philadelphia, PA, USA. · Crown Princess Mary Cancer Centre, Westmead and Blacktown Hospitals, and Melanoma Institute Australia, Westmead, NSW, Australia. · St Luke's Cancer Center, Bethlehem, PA, USA; Temple University, Philadelphia, PA, USA. · University of North Carolina, Chapel Hill, NC, USA. · University of Pittsburgh, Pittsburgh, PA, USA. · Memorial Sloan Kettering Cancer Center, New York, NY, USA. · Merck & Co, Kenilworth, NJ, USA. · University of California, San Francisco, San Francisco, CA, USA. ·Lancet Oncol · Pubmed #26115796.

ABSTRACT: BACKGROUND: Patients with melanoma that progresses on ipilimumab and, if BRAF(V600) mutant-positive, a BRAF or MEK inhibitor or both, have few treatment options. We assessed the efficacy and safety of two pembrolizumab doses versus investigator-choice chemotherapy in patients with ipilimumab-refractory melanoma. METHODS: We carried out a randomised phase 2 trial of patients aged 18 years or older from 73 hospitals, clinics, and academic medical centres in 12 countries who had confirmed progressive disease within 24 weeks after two or more ipilimumab doses and, if BRAF(V600) mutant-positive, previous treatment with a BRAF or MEK inhibitor or both. Patients had to have resolution of all ipilimumab-related adverse events to grade 0-1 and prednisone 10 mg/day or less for at least 2 weeks, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and at least one measurable lesion to be eligible. Using a centralised interactive voice response system, we randomly assigned (1:1:1) patients in a block size of six to receive intravenous pembrolizumab 2 mg/kg or 10 mg/kg every 3 weeks or investigator-choice chemotherapy (paclitaxel plus carboplatin, paclitaxel, carboplatin, dacarbazine, or oral temozolomide). Randomisation was stratified by ECOG performance status, lactate dehydrogenase concentration, and BRAF(V600) mutation status. Individual treatment assignment between pembrolizumab and chemotherapy was open label, but investigators and patients were masked to assignment of the dose of pembrolizumab. We present the primary endpoint at the prespecified second interim analysis of progression-free survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01704287. The study is closed to enrolment but continues to follow up and treat patients. FINDINGS: Between Nov 30, 2012, and Nov 13, 2013, we enrolled 540 patients: 180 patients were randomly assigned to receive pembrolizumab 2 mg/kg, 181 to receive pembrolizumab 10 mg/kg, and 179 to receive chemotherapy. Based on 410 progression-free survival events, progression-free survival was improved in patients assigned to pembrolizumab 2 mg/kg (HR 0·57, 95% CI 0·45-0·73; p<0·0001) and those assigned to pembrolizumab 10 mg/kg (0·50, 0·39-0·64; p<0·0001) compared with those assigned to chemotherapy. 6-month progression-free survival was 34% (95% CI 27-41) in the pembrolizumab 2 mg/kg group, 38% (31-45) in the 10 mg/kg group, and 16% (10-22) in the chemotherapy group. Treatment-related grade 3-4 adverse events occurred in 20 (11%) patients in the pembrolizumab 2 mg/kg group, 25 (14%) in the pembrolizumab 10 mg/kg group, and 45 (26%) in the chemotherapy group. The most common treatment-related grade 3-4 adverse event in the pembrolizumab groups was fatigue (two [1%] of 178 patients in the 2 mg/kg group and one [<1%] of 179 patients in the 10 mg/kg group, compared with eight [5%] of 171 in the chemotherapy group). Other treatment-related grade 3-4 adverse events include generalised oedema and myalgia (each in two [1%] patients) in those given pembrolizumab 2 mg/kg; hypopituitarism, colitis, diarrhoea, decreased appetite, hyponatremia, and pneumonitis (each in two [1%]) in those given pembrolizumab 10 mg/kg; and anaemia (nine [5%]), fatigue (eight [5%]), neutropenia (six [4%]), and leucopenia (six [4%]) in those assigned to chemotherapy. INTERPRETATION: These findings establish pembrolizumab as a new standard of care for the treatment of ipilimumab-refractory melanoma. FUNDING: Merck Sharp & Dohme.

4 Clinical Trial Pembrolizumab versus Ipilimumab in Advanced Melanoma. 2015

Robert, Caroline / Schachter, Jacob / Long, Georgina V / Arance, Ana / Grob, Jean Jacques / Mortier, Laurent / Daud, Adil / Carlino, Matteo S / McNeil, Catriona / Lotem, Michal / Larkin, James / Lorigan, Paul / Neyns, Bart / Blank, Christian U / Hamid, Omid / Mateus, Christine / Shapira-Frommer, Ronnie / Kosh, Michele / Zhou, Honghong / Ibrahim, Nageatte / Ebbinghaus, Scot / Ribas, Antoni / Anonymous4340827. ·The authors' affiliations are listed in the Appendix. ·N Engl J Med · Pubmed #25891173.

ABSTRACT: 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. (Funded by Merck Sharp & Dohme; KEYNOTE-006 ClinicalTrials.gov number, NCT01866319.).

5 Clinical Trial Adoptive transfer of tumor-infiltrating lymphocytes in patients with metastatic melanoma: intent-to-treat analysis and efficacy after failure to prior immunotherapies. 2013

Besser, Michal J / Shapira-Frommer, Ronnie / Itzhaki, Orit / Treves, Avraham J / Zippel, Douglas B / Levy, Daphna / Kubi, Adva / Shoshani, Noa / Zikich, Dragoslav / Ohayon, Yaara / Ohayon, Daniel / Shalmon, Bruria / Markel, Gal / Yerushalmi, Ronit / Apter, Sara / Ben-Nun, Alon / Ben-Ami, Eytan / Shimoni, Avichai / Nagler, Arnon / Schachter, Jacob. ·Ella Institute of Melanoma, Department of Surgical Oncology, Sheba Medical Center, Ramat Gan, Israel. michal.besser@sheba.health.gov.il ·Clin Cancer Res · Pubmed #23690483.

ABSTRACT: 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.

6 Clinical Trial Clinical responses in a phase II study using adoptive transfer of short-term cultured tumor infiltration lymphocytes in metastatic melanoma patients. 2010

Besser, Michal J / Shapira-Frommer, Ronnie / Treves, Avraham J / Zippel, Dov / Itzhaki, Orit / Hershkovitz, Liat / Levy, Daphna / Kubi, Adva / Hovav, Einat / Chermoshniuk, Natalia / Shalmon, Bruria / Hardan, Izhar / Catane, Raphael / Markel, Gal / Apter, Sara / Ben-Nun, Alon / Kuchuk, Iryna / Shimoni, Avichai / Nagler, Arnon / Schachter, Jacob. ·Ella Institute of Melanoma, Sheba Medical Center, Tel-Hashomer, Israel. michal.besser@sheba.health.gov.il ·Clin Cancer Res · Pubmed #20406835.

ABSTRACT: PURPOSE: Adoptive cell therapy with autologous tumor-infiltrating lymphocytes (TIL) has shown promising results in metastatic melanoma patients. Although objective response rates of over 50% have been reported, disadvantages of this approach are the labor-intensive TIL production and a very high drop-out rate of enrolled patients, limiting its widespread applicability. Previous studies showed a clear correlation between short TIL culture periods and clinical response. Therefore, we used a new TIL production technique using unselected, minimally cultured, bulk TIL (Young-TIL). The use of Young-TIL is not restricted to human leukocyte antigen (HLA)-A2 patients. The purpose of this study is to explore the efficacy and toxicity of adoptively transferred Young-TIL following lympho-depleting chemotherapy in metastatic melanoma patients, refractory to interleukin-2 and chemotherapy. EXPERIMENTAL DESIGN: Young-TIL cultures for 90% of the patients were successfully generated, enabling the treatment of most enrolled patients. We report here the results of 20 evaluated patients. RESULTS: Fifty percent of the patients achieved an objective clinical response according to the Response Evaluation Criteria in Solid Tumors, including two ongoing complete remissions (20+, 4+ months) and eight partial responses (progression-free survival: 18+, 13+, 10+, 9, 6+, 4, 3+, and 3 months). All responders are currently alive. Four additional patients showed disease stabilization. Side effects were transient and manageable. CONCLUSION: We showed that lympho-depleting chemotherapy followed by transfer of short-term cultured TIL can mediate tumor regression in 50% of metastatic melanoma with manageable toxicity. The convincing clinical results combined with the simplification of the process may thus have a major effect on cell therapy of cancer.

7 Article TNFSF4 (OX40L) expression and survival in locally advanced and metastatic melanoma. 2019

Roszik, Jason / Markovits, Ettai / Dobosz, Paula / Layani, Adi / Slabodnik-Kaner, Keren / Baruch, Erez N / Ben-Betzalel, Guy / Grimm, Elizabeth / Berger, Raanan / Sidi, Yehezkel / Schachter, Jacob / Shapira-Frommer, Ronnie / Avni, Dror / Markel, Gal / Leibowitz-Amit, Raya. ·Departments of Melanoma Medical Oncology and Genomic Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA. · Ella Lemelbaum Institute for Immuno-Oncology, Sheba Medical Center-Tel Hashomer, 2 Sheba Road, 5266202, Ramat Gan, Israel. · Department of Clinical Microbiology and Immunology, Sackler Faculty of Medicine, Tel Aviv University, 6997801, Tel Aviv, Israel. · Lab of Molecular Cancer Research, Sheba Medical Center-Tel Hashomer, 2 Sheba Road, 5266202, Ramat Gan, Israel. · Department of Oncology, Sackler Faculty of Medicine, Tel Aviv University, 6997801, Tel Aviv, Israel. · Division of Oncology, Sheba Medical Center-Tel Hashomer, 2 Sheba Road, 5266202, Ramat Gan, Israel. · Oncology Institute and Cancer Research Center, Sheba Medical Center-Tel Hashomer, 2 Sheba Road, 5266202, Ramat Gan, Israel. · Ella Lemelbaum Institute for Immuno-Oncology, Sheba Medical Center-Tel Hashomer, 2 Sheba Road, 5266202, Ramat Gan, Israel. gal.markel@sheba.health.gov.il. · Department of Clinical Microbiology and Immunology, Sackler Faculty of Medicine, Tel Aviv University, 6997801, Tel Aviv, Israel. gal.markel@sheba.health.gov.il. · Department of Oncology, Sackler Faculty of Medicine, Tel Aviv University, 6997801, Tel Aviv, Israel. Raya.leibowitz-amit@sheba.health.gov.il. · Division of Oncology, Sheba Medical Center-Tel Hashomer, 2 Sheba Road, 5266202, Ramat Gan, Israel. Raya.leibowitz-amit@sheba.health.gov.il. · Oncology Institute and Cancer Research Center, Sheba Medical Center-Tel Hashomer, 2 Sheba Road, 5266202, Ramat Gan, Israel. Raya.leibowitz-amit@sheba.health.gov.il. ·Cancer Immunol Immunother · Pubmed #31501955.

ABSTRACT: Immunotherapy with checkpoint inhibitors revolutionized melanoma treatment in both the adjuvant and metastatic setting, yet not all metastatic patients respond, and metastatic disease still often recurs among immunotherapy-treated patients with locally advanced disease. TNFSF4 is a co-stimulatory checkpoint protein expressed by several types of immune and non-immune cells, and was shown in the past to enhance the anti-neoplastic activity of T cells. Here, we assessed its expression in melanoma and its association with outcome in locally advanced and metastatic disease. We used publicly available data from The Cancer Genome Atlas (TCGA) and the Cancer Cell Line Encyclopedia (CCLE), and RNA sequencing data from anti-PD1-treated patients at Sheba medical center. TNFSF4 mRNA is expressed in melanoma cell lines and melanoma samples, including those with low lymphocytic infiltrates, and is not associated with the ulceration status of the primary tumor. Low expression of TNFSF4 mRNA is associated with worse prognosis in all melanoma patients and in the cohorts of stage III and stage IIIc-IV patients. Low expression of TNFSF4 mRNAs is also associated with worse prognosis in the subgroup of patients with low lymphocytic infiltrates, suggesting that tumoral TNFSF4 is associated with outcome. TNFSF4 expression was not correlated with the expression of other known checkpoint mRNAs. Last, metastatic patients with TNFSF4 mRNA expression within the lowest quartile have significantly worse outcome on anti-PD1 treatment, and a significantly lower response rate to these agents. Our current work points to TNFSF4 expression in melanoma as a potential determinant of prognosis, and warrants further translational and clinical research.

8 Article Immunotherapy comes of age in octagenarian and nonagenarian metastatic melanoma patients. 2019

Ben-Betzalel, Guy / Steinberg-Silman, Yael / Stoff, Ronen / Asher, Nethanel / Shapira-Frommer, Ronnie / Schachter, Jacob / Markel, Gal. ·The Ella Lemelbaum Institute for Immuno-Oncology, Sheba Medical Center, Tel-HaShomer, Israel. Electronic address: Guy.Ben-Betzalel@sheba.health.gov.il. · The Ella Lemelbaum Institute for Immuno-Oncology, Sheba Medical Center, Tel-HaShomer, Israel. · The Ella Lemelbaum Institute for Immuno-Oncology, Sheba Medical Center, Tel-HaShomer, Israel; Sackler Faculty of Medicine, Tel Aviv University, Israel. · The Ella Lemelbaum Institute for Immuno-Oncology, Sheba Medical Center, Tel-HaShomer, Israel; Department of Clinical Immunology and Microbiology, Sackler Faculty of Medicine, Tel Aviv University, Israel. Electronic address: Gal.markel@sheba.health.gov.il. ·Eur J Cancer · Pubmed #30648631.

ABSTRACT: Immunotherapy with anti-programmed cell death-1 (PD-1) agents is an effective treatment for metastatic melanoma. Recent data hint at better response to therapy for patients over age 65 years. Patients with metastatic melanoma in their 80's and 90's pose a clinical challenge. We describe a cohort of 144 patients ≥65 years and analyse the efficacy and toxicity of anti-PD-1 therapy in ages 80-100 years compared with ages 65-79 years. Records of metastatic melanoma patients aged 65-100 years treated with anti-PD-1 were collected retrospectively. Baseline parameters, response rate (overall response rate [ORR]), best response, progression-free survival (PFS) and overall survival (OS) and immune-related adverse events were analysed. Cox regression, t test, and chi-square test were used for statistical analysis. Five hundred patients were treated with anti-PD-1 agents between 2013 and 2018.Eighty-two patients were aged 65-79 years (group A, median 71.5 years), and 62 patients were aged 80-100 years (group B, median 84 years, range 80-97 years). Baseline parameters were comparable except for worse PS in group B (p = 0.001). One hundred twenty-four patients were evaluable for analysis of response (76 group A, 48 group B). A trend was noted for higher ORR in the older group with 62.3% for group A and 73.9% for group B (p = 0.09). Complete response was significantly higher in group B versus group A (47.9% versus 20%, p = 0.001). No significant difference was found in PFS or OS between the groups. Toxicity for all patients was similar at 22.8%-25.6% G2-4 adverse events. Elderly patients show enhanced response to anti-PD-1 therapy. Increasing age within the elderly patients group may predict an even better response to therapy and comparable survival in patients of very old age.

9 Article Clinical Significance of Pancreatic Atrophy Induced by Immune-Checkpoint Inhibitors: A Case-Control Study. 2018

Eshet, Yael / Baruch, Erez Nissim / Shapira-Frommer, Ronnie / Steinberg-Silman, Yael / Kuznetsov, Teodor / Ben-Betzalel, Guy / Daher, Sameh / Gluck, Iris / Asher, Nethanel / Apter, Sara / Schachter, Jacob / Bar, Jair / Boursi, Ben / Markel, Gal. ·Department of Nuclear Medicine, Sheba Medical Center, Tel-HaShomer, Israel. · Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. · Department of Clinical Immunology and Microbiology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. · The Ella Lemelbaum Institute for Immuno-Oncology, Sheba Medical Center, Tel-HaShomer, Israel. · Division of Oncology, Sheba Medical Center, Tal-HaShomer, Israel. · Department of Clinical Immunology and Microbiology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. Gal.markel@sheba.health.gov.il. · Talpiot Medical Leadership Program, Sheba Medical Center, Tel-HaShomer, Israel. ·Cancer Immunol Res · Pubmed #30275274.

ABSTRACT: Immune-checkpoint inhibitor (ICI)-related diarrhea is attributed to inflammatory colitis, with no other drug-related differential diagnosis. Here, we investigated the occurrence of pancreatic atrophy (PA) in ICI-treated cancer patients and its correlation to exocrine pancreatic insufficiency (EPI). Metastatic melanoma, non-small cell lung carcinoma, and head and neck squamous cell carcinoma patients (

10 Article Possible immune adverse events as predictors of durable response to BRAF inhibitors in patients with BRAF V600-mutant metastatic melanoma. 2018

Ben-Betzalel, Guy / Baruch, Erez N / Boursi, Ben / Steinberg-Silman, Yael / Asher, Nethanel / Shapira-Frommer, Ronnie / Schachter, Jacob / Markel, Gal. ·Ella Lemelbaum Institute for Immuno-Oncology, Sheba Medical Center, Ramat-Gan, Israel. Electronic address: Guy.ben-betzalel@sheba.health.gov.il. · Ella Lemelbaum Institute for Immuno-Oncology, Sheba Medical Center, Ramat-Gan, Israel; Department of Clinical Microbiology and Immunology, Sackler Faculty of Medicine, Tel Aviv University, Israel. · Division of Oncology, Sheba Medical Center, Ramat-Gan, Israel. · Ella Lemelbaum Institute for Immuno-Oncology, Sheba Medical Center, Ramat-Gan, Israel. · Ella Lemelbaum Institute for Immuno-Oncology, Sheba Medical Center, Ramat-Gan, Israel; Department of Oncology, Sackler Faculty of Medicine, Tel Aviv University, Israel. · Ella Lemelbaum Institute for Immuno-Oncology, Sheba Medical Center, Ramat-Gan, Israel; Department of Clinical Microbiology and Immunology, Sackler Faculty of Medicine, Tel Aviv University, Israel; Talpiot Medical Leadership Program, Sheba Medical Center, Ramat-Gan, Israel. ·Eur J Cancer · Pubmed #30096703.

ABSTRACT: BRAF inhibitors (BRAFi) and MEK inhibitors (MEKi) are among the cornerstones of metastatic melanoma therapy demonstrating excellent response rates with duration of 7-12 m. Long-term benefit from these agents was reported in patients with normal lactate dehydrogenase (LDH) and less than three disease sites. However, a treatment-dependent marker for long-term efficacy is lacking. Data suggest that immune-related adverse events (irAEs) are associated with clinical benefit in patients treated with immunotherapy and that response to BRAF/MEK therapy may have an underlying immune mechanism. We hypothesised that AEs with an underlying immune mechanism may be associated with a durable response to targeted therapy. We retrospectively identified a cohort of 78 BRAF V600-mutant metastatic melanoma patients treated with BRAFi or BRAFi + MEKi between November 2010 and November 2013. Four treatment-related AEs including vitiligo, uveitis, erythema nodosum and keratitis sicca were defined as irAEs of interest. Retrospective analysis of AEs in relationship to progression-free survival (PFS), disease burden and LDH levels was performed. Median PFS (mPFS) for all patients was 7.5 months with responses ongoing in eight patients as of April 2017. Ten patients were identified with the AEs defined previously. Cox regression analysis revealed a very strong association between those AEs and PFS; mPFS was 42.8 m in patients with at least one AE versus 6.1 m in those without an AE (hazard ratio [HR] 0.22, p = 0.002). This association was independent of LDH levels and disease burden (HR 0.24, p = 0.035). This analysis demonstrates a strong association between immune AEs and durable response to targeted therapy and may provide a treatment-related biomarker to estimate the outcome of therapy.

11 Article CT halo sign as an imaging marker for response to adoptive cell therapy in metastatic melanoma with pulmonary metastases. 2014

Shrot, Shai / Schachter, Jacob / Shapira-Frommer, Ronnie / Besser, Michal J / Apter, Sara. ·Department of Diagnostic Imaging, Sheba Medical Center, Tel-Hashomer, 2 Sheba Rd, Tel Hashomer 52621, Israel, affiliated to Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel, shaishrot@gmail.com. ·Eur Radiol · Pubmed #24663820.

ABSTRACT: OBJECTIVES: The halo sign refers to a zone of ground-glass attenuation surrounding a pulmonary nodule. Pulmonary metastatic nodules exhibiting a halo sign are seen mainly in hypervascular tumours. We describe the appearance of a halo sign following treatment of adoptive transfer of autologous tumour-infiltrating lymphocytes (TIL) to melanoma patients with lung metastases. METHODS: The study included 29 melanoma patients with pulmonary metastases who received TIL therapy. Pre- and post-treatment chest CTs were retrospectively reviewed for the presence of a halo sign and its correlation with therapeutic response. RESULTS: A pulmonary halo sign was not seen in any pre-treatment CT. It was observed in four of 12 patients who responded to the therapy but not in those who failed to respond. Significant differences were found between response ratio in patients in whom post-TIL halo sign appeared compared with those without the halo sign (p = 0.02). CONCLUSIONS: The appearance of a CT halo sign in melanoma with lung metastases following TIL therapy may indicate antitumoral effect and a good response to therapy. Our findings emphasize the importance of applying new assessment criteria for immunological anticancer therapies. KEY POINTS: Tumour-infiltrating lymphocytes (TIL) in melanoma patients is a promising novel immunotherapy. Post-therapy pulmonary halo sign appeared in one-third of TIL responders . Pulmonary halo sign may serve as an imaging marker for antitumoral activity.

12 Article A comparative analysis of total serum miRNA profiles identifies novel signature that is highly indicative of metastatic melanoma: a pilot study. 2013

Greenberg, Eyal / Besser, Michal J / Ben-Ami, Eytan / Shapira-Frommer, Ronnie / Itzhaki, Orit / Zikich, Dragoslav / Levy, Daphna / Kubi, Adva / Eyal, Eran / Onn, Amir / Cohen, Yehudit / Barshack, Iris / Schachter, Jacob / Markel, Gal. ·Ella Institute of Melanoma, Sheba Medical Center , Ramat-Gan , Israel . ·Biomarkers · Pubmed #23902289.

ABSTRACT: CONTEXT: Quantification of circulating microRNAs (miRNAs) has recently become feasible and reliable, with most efforts focusing on miRNAs overexpressed by cancer cells. OBJECTIVE: Identification of a characteristic circulating miRNAs profile in melanoma patients. METHODS: We conducted a pilot study comprised of unbiased qPCR comparison of serum miRNA profiles between metastatic melanoma patients and healthy donors. RESULTS: Loss of two normal serum-miRNAs, miR-29c and miR-324-3p, is highly indicative of metastatic melanoma. Hierarchical clustering analysis supported the results and clearly distinguished melanoma patients from healthy donors, metastatic colon and renal cancer patients. DISCUSSION AND CONCLUSIONS: This approach is independent of tumor heterogeneity and is expected to have superior biomarker performances.

13 Article Tumor lysis syndrome and malignant melanoma. 2013

Mouallem, Meir / Zemer-Wassercug, Noa / Kugler, Eitan / Sahar, Nadav / Shapira-Frommer, Ronnie / Schiby, Ginette. ·Department of Medicine E, Sheba Medical Center and Sackler School of Medicine, Tel-Aviv University, Tel-Hashomer 52621, Israel. mouallem@post.tau.ac.il ·Med Oncol · Pubmed #23673985.

ABSTRACT: Tumor lysis syndrome (TLS) is an oncological emergency that results from massive cytolysis of malignant cells with a sudden release of their contents into the systemic circulation. TLS was rarely described in patients with malignant melanoma. In this article, we describe two patients with malignant melanoma who developed this syndrome. In one of them, the syndrome occurred spontaneously, and this is the second description of spontaneous tumor lysis in a patient with melanoma. We reviewed the previous patients with melanoma-induced TLS and discussed the manifestations and the pathophysiology of the syndrome in our patients.

14 Article Nicotinamide inhibits vasculogenic mimicry, an alternative vascularization pathway observed in highly aggressive melanoma. 2013

Itzhaki, Orit / Greenberg, Eyal / Shalmon, Bruria / Kubi, Adva / Treves, Avraham J / Shapira-Frommer, Ronnie / Avivi, Camilla / Ortenberg, Rona / Ben-Ami, Eytan / Schachter, Jacob / Besser, Michal J / Markel, Gal. ·Ella Institute of Melanoma, Sheba Medical Center, Ramat-Gan, Israel. ·PLoS One · Pubmed #23451174.

ABSTRACT: Vasculogenic mimicry (VM) describes functional vascular channels composed only of tumor cells and its presence predicts poor prognosis in melanoma patients. Inhibition of this alternative vascularization pathway might be of clinical importance, especially as several anti-angiogenic therapies targeting endothelial cells are largely ineffective in melanoma. We show the presence of VM structures histologically in a series of human melanoma lesions and demonstrate that cell cultures derived from these lesions form tubes in 3D cultures ex vivo. We tested the ability of nicotinamide, the amide form of vitamin B3 (niacin), which acts as an epigenetic gene regulator through unique cellular pathways, to modify VM. Nicotinamide effectively inhibited the formation of VM structures and destroyed already formed ones, in a dose-dependent manner. Remarkably, VM formation capacity remained suppressed even one month after the complete withdrawal of Nicotimamid. The inhibitory effect of nicotinamide on VM formation could be at least partially explained by a nicotinamide-driven downregulation of vascular endothelial cadherin (VE-Cadherin), which is known to have a central role in VM. Further major changes in the expression profile of hundreds of genes, most of them clustered in biologically-relevant clusters, were observed. In addition, nicotinamide significantly inhibited melanoma cell proliferation, but had an opposite effect on their invasion capacity. Cell cycle analysis indicated moderate changes in apoptotic indices. Therefore, nicotinamide could be further used to unravel new biological mechanisms that drive VM and tumor progression. Targeting VM, especially in combination with anti-angiogenic strategies, is expected to be synergistic and might yield substantial anti neoplastic effects in a variety of malignancies.

15 Article Establishment and large-scale expansion of minimally cultured "young" tumor infiltrating lymphocytes for adoptive transfer therapy. 2011

Itzhaki, Orit / Hovav, Einat / Ziporen, Yaara / Levy, Daphna / Kubi, Adva / Zikich, Dragoslav / Hershkovitz, Liat / Treves, Avraham J / Shalmon, Bruria / Zippel, Douglas / Markel, Gal / Shapira-Frommer, Ronnie / Schachter, Jacob / Besser, Michal J. ·Ella Institute for Treatment and Research of Melanoma, Sheba Medical Center, Tel-Hashomer, Israel. ·J Immunother · Pubmed #21304398.

ABSTRACT: Treatment of metastatic melanoma patients with adoptively transferred tumor infiltrating lymphocytes (TIL) has developed into an effective therapy. Various studies reported objective responses of 50% and more. The use of unselected, minimally cultured, bulk TIL (Young-TIL) has simplified the TIL production process and may therefore, allow the accessibility of this approach to cancer centers worldwide. This article describes the precise process leading to the large-scale production of Young-TIL for therapy. We have enrolled 55 melanoma patients and optimized their Young-TIL generation process. Young-TIL cultures were successfully established for 51 of 55 (93%) patients in 16.7 ± 5.5 days. In a large-scale expansion procedure Young-TIL of 32 patients were further expanded to treatment levels, resulting in a final number of 4.5 x 10¹⁰ ± 2.0 x 10¹⁰ TIL. Fifteen of 31 (48%) patients, who were evaluated, achieved a clinical response, including 4 complete and 11 partial responses. We confirmed the significant correlation between short culture duration, high number of infused cells, and tumor regression. A high percentage of CD8 T cells in the infusion product was beneficial to achieve an objective response. All responding patients were treated with Young-TIL cultures established in < 20 days. In summary, we describe here an efficient and reliable method to generate Young-TIL for adoptive transfer therapy, which may easily be adopted by other cancer centers and can lead to objective responses in 50% of refractory melanoma patients. In the future this approach may be used also in other types of malignancies.