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Melanoma: HELP
Articles by Philip A. Friedlander
Based on 13 articles published since 2009
(Why 13 articles?)
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Between 2009 and 2019, Philip Friedlander wrote the following 13 articles about Melanoma.
 
+ Citations + Abstracts
1 Review Advances in targeted therapy for melanoma. 2010

Friedlander, Philip / Hodi, F Stephen. ·Instructor of Medicine, Department of Medical Oncology at Dana Farber Cancer Institute in Boston, Massachusetts 02115, USA. pfriedlander@partners.org ·Clin Adv Hematol Oncol · Pubmed #21157411.

ABSTRACT: Metastatic melanoma remains an aggressive malignancy conferring a very poor prognosis, and standard chemotherapeutic and immunologic treatments have not demonstrated an overall survival benefit. No molecularly targeted therapy is approved for the treatment of advanced melanoma. Melanoma is a molecularly heterogeneous malignancy, and optimal treatment in a given patient is likely to depend on the presence of specific molecular abnormalities. Aberrations in components of signal transduction pathways have been identified that modulate melanoma proliferation and survival. Mutations that activate the mitogen activated protein kinase (MAPK) pathway via BRAF or NRAS are present in the majority of melanomas arising on skin intermittently exposed to the sun. Mutations that activate the KIT oncogene are more commonly present in melanomas arising from mucosal, acral, or chronic sun-damaged sites. Inhibitors of the MAPK pathway and of KIT are currently undergoing clinical investigation. In this article, we review advances in targeted strategies to treat different subgroups of patients with melanoma.

2 Clinical Trial Whole-blood RNA transcript-based models can predict clinical response in two large independent clinical studies of patients with advanced melanoma treated with the checkpoint inhibitor, tremelimumab. 2017

Friedlander, Philip / Wassmann, Karl / Christenfeld, Alan M / Fisher, David / Kyi, Chrisann / Kirkwood, John M / Bhardwaj, Nina / Oh, William K. ·Division of Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, Mount Sinai Hospital, New York, NY, USA. philip.friedlander@mssm.edu. · CPS Companion Diagnostics, Cambridge, MA, USA. · Department of Dermatology, Harvard Medical School, Boston, MA, USA. · Division of Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, Mount Sinai Hospital, New York, NY, USA. · Departments of Medicine, Dermatology and Translational Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. · Parker Institute of Cancer Immunotherapy, San Francisco, CA, USA. ·J Immunother Cancer · Pubmed #28807052.

ABSTRACT: BACKGROUND: Tremelimumab is an antibody that blocks CTLA-4 and demonstrates clinical efficacy in a subset of advanced melanoma patients. An unmet clinical need exists for blood-based response-predictive gene signatures to facilitate clinically effective and cost-efficient use of such immunotherapeutic interventions. METHODS: Peripheral blood samples were collected in PAXgene® tubes from 210 treatment-naïve melanoma patients receiving tremelimumab in a worldwide, multicenter phase III study (discovery dataset). A central panel of radiologists determined objective response using RECIST criteria. Gene expression for 169 mRNA transcripts was measured using quantitative PCR. A 15-gene pre-treatment response-predictive classifier model was identified. An independent population (N = 150) of refractory melanoma patients receiving tremelimumab after chemotherapy enrolled in a worldwide phase II study (validation dataset). The classifier model, using the same genes, coefficients and constants for objective response and one-year survival after treatment, was applied to the validation dataset. RESULTS: A 15-gene pre-treatment classifier model (containing ADAM17, CDK2, CDKN2A, DPP4, ERBB2, HLA-DRA, ICOS, ITGA4, LARGE, MYC, NAB2, NRAS, RHOC, TGFB1, and TIMP1) achieved an area under the curve (AUC) of 0.86 (95% confidence interval 0.81 to 0.91, p < 0.0001) for objective response and 0.6 (95% confidence interval 0.54 to 0.67, p = 0.0066) for one-year survival in the discovery set. This model was validated in the validation set with AUCs of 0.62 (95% confidence interval 0.54 to 0.70 p = 0.0455) for objective response and 0.68 for one-year survival (95% confidence interval 0.59 to 0.75 p = 0.0002). CONCLUSIONS: To our knowledge, this is the largest blood-based biomarker study of a checkpoint inhibitor, tremelimumab, which demonstrates a validated pre-treatment mRNA classifier model that predicts clinical response. The data suggest that the model captures a biological signature representative of genes needed for a robust anti-cancer immune response. It also identifies non-responders to tremelimumab at baseline prior to treatment.

3 Clinical Trial Adoptive Transfer of Invariant NKT Cells as Immunotherapy for Advanced Melanoma: A Phase I Clinical Trial. 2017

Exley, Mark A / Friedlander, Phillip / Alatrakchi, Nadia / Vriend, Lianne / Yue, Simon / Sasada, Tetsuro / Zeng, Wanyong / Mizukami, Yo / Clark, Justice / Nemer, David / LeClair, Kenneth / Canning, Christine / Daley, Heather / Dranoff, Glenn / Giobbie-Hurder, Anita / Hodi, F Stephen / Ritz, Jerome / Balk, Steven P. ·Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts. mexley@partners.org sbalk@bidmc.harvard.edu. · Gastroenterology, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts. · University of Manchester, Manchester, United Kingdom. · Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. · Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts. · Cancer Vaccine Center, Dana-Farber Cancer Institute, Boston, Massachusetts. · Biostatistics & Computational Biology, Dana Farber Cancer Institute, Harvard School of Public Health, Boston, Massachusetts. ·Clin Cancer Res · Pubmed #28193627.

ABSTRACT:

4 Clinical Trial Bevacizumab plus ipilimumab in patients with metastatic melanoma. 2014

Hodi, F Stephen / Lawrence, Donald / Lezcano, Cecilia / Wu, Xinqi / Zhou, Jun / Sasada, Tetsuro / Zeng, Wanyong / Giobbie-Hurder, Anita / Atkins, Michael B / Ibrahim, Nageatte / Friedlander, Philip / Flaherty, Keith T / Murphy, George F / Rodig, Scott / Velazquez, Elsa F / Mihm, Martin C / Russell, Sara / DiPiro, Pamela J / Yap, Jeffrey T / Ramaiya, Nikhil / Van den Abbeele, Annick D / Gargano, Maria / McDermott, David. ·Authors' Affiliations: Departments of Medical Oncology, Stephen_Hodi@dfci.harvard.edu. · Massachusetts General Hospital Cancer Center; Departments of. · University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania; · Authors' Affiliations: Departments of Medical Oncology. · Biostatistics, and. · Lombardi Cancer Center Georgetown University, Washington, District of Columbia; and. · Mount Sinai Medical Center, New York, New York. · Pathology and. · Tufts University; Miraca Life Sciences, Newton, Massachusetts; · Surgery, Brigham and Women's Hospital; · Imaging, Dana-Farber Cancer Institute; · Beth Israel-Deaconess Medical Center, Boston; ·Cancer Immunol Res · Pubmed #24838938.

ABSTRACT: Ipilimumab improves survival in advanced melanoma and can induce immune-mediated tumor vasculopathy. Besides promoting angiogenesis, vascular endothelial growth factor (VEGF) suppresses dendritic cell maturation and modulates lymphocyte endothelial trafficking. This study investigated the combination of CTLA4 blockade with ipilimumab and VEGF inhibition with bevacizumab. Patients with metastatic melanoma were treated in four dosing cohorts of ipilimumab (3 or 10 mg/kg) with four doses at 3-week intervals and then every 12 weeks, and bevacizumab (7.5 or 15 mg/kg) every 3 weeks. Forty-six patients were treated. Inflammatory events included giant cell arteritis (n = 1), hepatitis (n = 2), and uveitis (n = 2). On-treatment tumor biopsies revealed activated vessel endothelium with extensive CD8(+) and macrophage cell infiltration. Peripheral blood analyses demonstrated increases in CCR7(+/-)/CD45RO(+) cells and anti-galectin antibodies. Best overall response included 8 partial responses, 22 instances of stable disease, and a disease-control rate of 67.4%. Median survival was 25.1 months. Bevacizumab influences changes in tumor vasculature and immune responses with ipilimumab administration. The combination of bevacizumab and ipilimumab can be safely administered and reveals VEGF-A blockade influences on inflammation, lymphocyte trafficking, and immune regulation. These findings provide a basis for further investigating the dual roles of angiogenic factors in blood vessel formation and immune regulation, as well as future combinations of antiangiogenesis agents and immune checkpoint blockade.

5 Clinical Trial Blood mRNA expression profiling predicts survival in patients treated with tremelimumab. 2014

Saenger, Yvonne / Magidson, Jay / Liaw, Bobby / de Moll, Ellen / Harcharik, Sara / Fu, Yichun / Wassmann, Karl / Fisher, David / Kirkwood, John / Oh, William K / Friedlander, Philip. ·Authors' Affiliations: Division of Hematology and Oncology, Tisch Cancer Institute, Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York; Statistical Innovations, Belmont; Department of Dermatology, Harvard Medical School, Boston, Massachusetts; Departments of Medicine, Dermatology and Translational Sciences, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; and Gene News, Ontario, CanadaAuthors' Affiliations: Division of Hematology and Oncology, Tisch Cancer Institute, Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York; Statistical Innovations, Belmont; Department of Dermatology, Harvard Medical School, Boston, Massachusetts; Departments of Medicine, Dermatology and Translational Sciences, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; and Gene News, Ontario, Canada yvonne.saenger@mssm.edu. · Authors' Affiliations: Division of Hematology and Oncology, Tisch Cancer Institute, Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York; Statistical Innovations, Belmont; Department of Dermatology, Harvard Medical School, Boston, Massachusetts; Departments of Medicine, Dermatology and Translational Sciences, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; and Gene News, Ontario, Canada. · Authors' Affiliations: Division of Hematology and Oncology, Tisch Cancer Institute, Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York; Statistical Innovations, Belmont; Department of Dermatology, Harvard Medical School, Boston, Massachusetts; Departments of Medicine, Dermatology and Translational Sciences, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; and Gene News, Ontario, CanadaAuthors' Affiliations: Division of Hematology and Oncology, Tisch Cancer Institute, Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York; Statistical Innovations, Belmont; Department of Dermatology, Harvard Medical School, Boston, Massachusetts; Departments of Medicine, Dermatology and Translational Sciences, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; and Gene News, Ontario, Canada. ·Clin Cancer Res · Pubmed #24721645.

ABSTRACT: PURPOSE: Tremelimumab (ticilimumab, Pfizer), is a monoclonal antibody (mAb) targeting cytotoxic T lymphocyte-associated antigen-4 (CTLA-4). Ipilimumab (Yervoy, BMS), another anti-CTLA-4 antibody, is approved by the U.S. Federal Drug Administration (FDA). Biomarkers are needed to identify the subset of patients who will achieve tumor control with CTLA-4 blockade. EXPERIMENTAL DESIGN: Pretreatment peripheral blood samples from 218 patients with melanoma who were refractory to prior therapy and receiving tremelimumab in a multicenter phase II study were measured for 169 mRNA transcripts using reverse transcription polymerase chain reaction (RT-PCR). A two-class latent model yielded a risk score based on four genes that were highly predictive of survival (P < 0.001). This signature was validated in an independent population of 260 treatment-naïve patients with melanoma enrolled in a multicenter phase III study of tremelimumab. RESULTS: Median follow-up was 297 days for the training population and 386 days for the test population. Expression levels of the 169 genes were closely correlated across the two populations (r = 0.9939). A four-gene model, including cathepsin D (CTSD), phopholipase A2 group VII (PLA2G7), thioredoxin reductase 1 (TXNRD1), and interleukin 1 receptor-associated kinase 3 (IRAK3), predicted survival in the test population (P = 0.001 by log-rank test). This four-gene model added to the predictive value of clinical predictors (P < 0.0001). CONCLUSIONS: Expression levels of CTSD, PLA2G7, TXNRD1, and IRAK3 in peripheral blood are predictive of survival in patients with melanoma treated with tremelimumab. Blood mRNA signatures should be further explored to define patient subsets likely to benefit from immunotherapy.

6 Clinical Trial Imatinib for melanomas harboring mutationally activated or amplified KIT arising on mucosal, acral, and chronically sun-damaged skin. 2013

Hodi, F Stephen / Corless, Christopher L / Giobbie-Hurder, Anita / Fletcher, Jonathan A / Zhu, Meijun / Marino-Enriquez, Adrian / Friedlander, Philip / Gonzalez, Rene / Weber, Jeffrey S / Gajewski, Thomas F / O'Day, Steven J / Kim, Kevin B / Lawrence, Donald / Flaherty, Keith T / Luke, Jason J / Collichio, Frances A / Ernstoff, Marc S / Heinrich, Michael C / Beadling, Carol / Zukotynski, Katherine A / Yap, Jeffrey T / Van den Abbeele, Annick D / Demetri, George D / Fisher, David E. ·F. Stephen Hodi, Anita Giobbie-Hurder, Philip Friedlander, Jason J. Luke, Katherine A. Zukotynski, Jeffrey T. Yap, Annick D. Van den Abbeele, and George D. Demetri, Dana-Farber Cancer Institute · Jonathan A. Fletcher, Meijun Zhu, and Adrian Marino-Enriquez, Brigham and Women's Hospital · Donald Lawrence, Keith T. Flaherty, and David E. Fisher, Massachusetts General Hospital, Boston, MA · Christopher L. Corless, Michael C. Heinrich, and Carol Beadling, Portland Veterans Administration Medical Center and Oregon Health & Science University, Portland, OR · Philip Friedlander, Mount Sinai Medical Center, New York, NY · Rene Gonzalez, University of Colorado Cancer Center, Aurora, CO · Jeffrey S. Weber, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL · Thomas F. Gajewski, University of Chicago, Chicago, IL · Steven J. O'Day, Beverly Hills Cancer Center, Beverly Hills, CA · Kevin B. Kim, The University of Texas MD Anderson Cancer Center, Houston, TX · Frances A. Collichio, The University of North Carolina at Chapel Hill, Chapel Hill, NC · and Marc S. Ernstoff, Geisel School of Medicine and Norris Cotton Cancer Center, Hanover, NH. ·J Clin Oncol · Pubmed #23775962.

ABSTRACT: PURPOSE: Amplifications and mutations in the KIT proto-oncogene in subsets of melanomas provide therapeutic opportunities. PATIENTS AND METHODS: We conducted a multicenter phase II trial of imatinib in metastatic mucosal, acral, or chronically sun-damaged (CSD) melanoma with KIT amplifications and/or mutations. Patients received imatinib 400 mg once per day or 400 mg twice per day if there was no initial response. Dose reductions were permitted for treatment-related toxicities. Additional oncogene mutation screening was performed by mass spectroscopy. RESULTS: Twenty-five patients were enrolled (24 evaluable). Eight patients (33%) had tumors with KIT mutations, 11 (46%) with KIT amplifications, and five (21%) with both. Median follow-up was 10.6 months (range, 3.7 to 27.1 months). Best overall response rate (BORR) was 29% (21% excluding nonconfirmed responses) with a two-stage 95% CI of 13% to 51%. BORR was significantly greater than the hypothesized null of 5% and statistically significantly different by mutation status (7 of 13 or 54% KIT mutated v 0% KIT amplified only). There were no statistical differences in rates of progression or survival by mutation status or by melanoma site. The overall disease control rate was 50% but varied significantly by KIT mutation status (77% mutated v 18% amplified). Four patients harbored pretreatment NRAS mutations, and one patient acquired increased KIT amplification after treatment. CONCLUSION: Melanomas that arise on mucosal, acral, or CSD skin should be assessed for KIT mutations. Imatinib can be effective when tumors harbor KIT mutations, but not if KIT is amplified only. NRAS mutations and KIT copy number gain may be mechanisms of therapeutic resistance to imatinib.

7 Clinical Trial Final results of phase III SYMMETRY study: randomized, double-blind trial of elesclomol plus paclitaxel versus paclitaxel alone as treatment for chemotherapy-naive patients with advanced melanoma. 2013

O'Day, Steven J / Eggermont, Alexander M M / Chiarion-Sileni, Vanna / Kefford, Richard / Grob, Jean Jacques / Mortier, Laurent / Robert, Caroline / Schachter, Jacob / Testori, Alessandro / Mackiewicz, Jacek / Friedlander, Philip / Garbe, Claus / Ugurel, Selma / Collichio, Frances / Guo, Wei / Lufkin, Joelle / Bahcall, Safi / Vukovic, Vojo / Hauschild, Axel. ·Los Angeles Skin Cancer Institute, The Beverly Hills Cancer Center, 8900 Wilshire Blvd, Beverly Hills, CA 90211, USA. stevenjoday@gmail.com ·J Clin Oncol · Pubmed #23401447.

ABSTRACT: PURPOSE: Elesclomol, an investigational first-in-class compound, induces oxidative stress, triggers mitochondrial-induced apoptosis in cancer cells, and shows synergy with taxanes in tumor models. Following completion of a phase II trial of elesclomol in combination with paclitaxel that met its primary end point of progression-free survival (PFS), this randomized, double-blind, controlled phase III study was conducted to confirm the efficacy and tolerability of elesclomol in combination with paclitaxel versus paclitaxel alone in patients with advanced melanoma. PATIENTS AND METHODS: Patients with stage IV chemotherapy-naive melanoma (n = 651) were randomly assigned 1:1 to paclitaxel 80 mg/m(2) either alone or in combination with elesclomol 213 mg/m(2) administered weekly for 3 weeks of a 4-week cycle. Patients were stratified by prior systemic treatment, M1 subclass, and baseline lactate dehydrogenase (LDH) levels. The primary end point was PFS. RESULTS: The study did not achieve its PFS end point (hazard ratio, 0.89; P = .23). The study was stopped when an early overall survival data analysis indicated an imbalance in total deaths favoring paclitaxel, predominantly in patients with high LDH levels. A prospectively defined subgroup analysis revealed a statistically significant improvement in median PFS for the combination in patients with normal baseline LDH. CONCLUSION: The addition of elesclomol to paclitaxel did not significantly improve PFS in unselected patients with advanced melanoma. The association between baseline LDH and clinical outcomes suggests that LDH may be a predictive factor for treatment with this combination, consistent with recent findings on the association between elesclomol anticancer activity and cellular metabolic state.

8 Clinical Trial Establishment of antitumor memory in humans using in vitro-educated CD8+ T cells. 2011

Butler, Marcus O / Friedlander, Philip / Milstein, Matthew I / Mooney, Mary M / Metzler, Genita / Murray, Andrew P / Tanaka, Makito / Berezovskaya, Alla / Imataki, Osamu / Drury, Linda / Brennan, Lisa / Flavin, Marisa / Neuberg, Donna / Stevenson, Kristen / Lawrence, Donald / Hodi, F Stephen / Velazquez, Elsa F / Jaklitsch, Michael T / Russell, Sara E / Mihm, Martin / Nadler, Lee M / Hirano, Naoto. ·Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA. marcus_butler@dfci.harvard.edu ·Sci Transl Med · Pubmed #21525398.

ABSTRACT: Although advanced-stage melanoma patients have a median survival of less than a year, adoptive T cell therapy can induce durable clinical responses in some patients. Successful adoptive T cell therapy to treat cancer requires engraftment of antitumor T lymphocytes that not only retain specificity and function in vivo but also display an intrinsic capacity to survive. To date, adoptively transferred antitumor CD8(+) T lymphocytes (CTLs) have had limited life spans unless the host has been manipulated. To generate CTLs that have an intrinsic capacity to persist in vivo, we developed a human artificial antigen-presenting cell system that can educate antitumor CTLs to acquire both a central memory and an effector memory phenotype as well as the capacity to survive in culture for prolonged periods of time. We examined whether antitumor CTLs generated using this system could function and persist in patients. We showed that MART1-specific CTLs, educated and expanded using our artificial antigen-presenting cell system, could survive for prolonged periods in advanced-stage melanoma patients without previous conditioning or cytokine treatment. Moreover, these CTLs trafficked to the tumor, mediated biological and clinical responses, and established antitumor immunologic memory. Therefore, this approach may broaden the availability of adoptive cell therapy to patients both alone and in combination with other therapeutic modalities.

9 Article Randomized, Open-Label Phase II Study Evaluating the Efficacy and Safety of Talimogene Laherparepvec in Combination With Ipilimumab Versus Ipilimumab Alone in Patients With Advanced, Unresectable Melanoma. 2018

Chesney, Jason / Puzanov, Igor / Collichio, Frances / Singh, Parminder / Milhem, Mohammed M / Glaspy, John / Hamid, Omid / Ross, Merrick / Friedlander, Philip / Garbe, Claus / Logan, Theodore F / Hauschild, Axel / Lebbé, Celeste / Chen, Lisa / Kim, Jenny J / Gansert, Jennifer / Andtbacka, Robert H I / Kaufman, Howard L. ·Jason Chesney, J. Graham Brown Cancer Center, University of Louisville, Louisville, KY · Igor Puzanov, Roswell Park Cancer Institute, Buffalo · Philip Friedlander, Mt Sinai School of Medicine, New York, NY · Frances Collichio, The University of North Carolina at Chapel Hill, Chapel Hill, NC · Parminder Singh, Mayo Clinic, Phoenix, AZ · Mohammed M. Milhem, University of Iowa Hospitals and Clinics, Iowa City, IA · John Glaspy, University of California Los Angeles School of Medicine · Omid Hamid, The Angeles Clinic and Research Institute, Los Angeles · Lisa Chen, Jenny J. Kim, and Jennifer Gansert, Amgen, Thousand Oaks, CA · Merrick Ross, MD Anderson Cancer Center, Houston, TX · Claus Garbe, University Hospital Tuebingen, Tuebingen · Axel Hauschild, University of Kiel, Kiel, Germany · Theodore F. Logan, Indiana University Simon Cancer Center, Indianapolis, IN · Celeste Lebbé, Assistance Publique-Hôpital De Paris Dermatology and CIC Hôpital Saint Louis University Paris Diderot Sorbonne, Institut National de la Santé et de la Recherche Médicale U976, Paris, France · Robert H.I. Andtbacka, University of Utah, Salt Lake City, UT · and Howard L. Kaufman, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ. ·J Clin Oncol · Pubmed #28981385.

ABSTRACT: Purpose We evaluated the combination of talimogene laherparepvec plus ipilimumab versus ipilimumab alone in patients with advanced melanoma in a phase II study. To our knowledge, this was the first randomized trial to evaluate addition of an oncolytic virus to a checkpoint inhibitor. Methods Patients with unresectable stages IIIB to IV melanoma, with no more than one prior therapy if BRAF wild-type, no more than two prior therapies if BRAF mutant, measurable/injectable disease, and without symptomatic autoimmunity or clinically significant immunosuppression were randomly assigned 1:1 to receive talimogene laherparepvec plus ipilimumab or ipilimumab alone. Talimogene laherparepvec treatment began in week 1 (first dose, ≤ 4 mL × 10

10 Article Development of Bell's Palsy After Treatment With Ipilimumab and Nivolumab for Metastatic Melanoma: A Case Report. 2018

Zecchini, Julia M / Kim, Sara / Yum, Kendra / Friedlander, Philip. ·Department of Pharmacy. · Division of Hematology/Oncology, Tisch Cancer Institute, One Gustave L. Levy Place, New York, NY. ·J Immunother · Pubmed #28926356.

ABSTRACT: Ipilimumab is a human monoclonal antibody that targets cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), and it is FDA approved for the treatment of unresectable or metastatic melanoma. Immune-related adverse events (irAEs) of gastrointestinal, dermatologic, and endocrine origin are commonly seen, ranging between 18% and 44%, with immune checkpoint inhibitors (anti-CTLA-4 and anti-PD-1/PD-L1). Rare irAEs include neurological, renal, and hematologic toxicities. Bell's palsy is a form of neurological toxicity that presents as an idiopathic paralysis of the muscles on one side of the face. We report a case of Bell's palsy in a 45-year-old male patient who received 1 dose of both ipilimumab and nivolumab for the treatment of metastatic melanoma. After the resolution of symptoms, ipilimumab was permanently discontinued and single-agent nivolumab administered. The patient has remained free of neurological symptoms. This case suggests that Bell's palsy is an irAE induced by ipilimumab.

11 Article Dissection of immune gene networks in primary melanoma tumors critical for antitumor surveillance of patients with stage II-III resectable disease. 2014

Sivendran, Shanthi / Chang, Rui / Pham, Lisa / Phelps, Robert G / Harcharik, Sara T / Hall, Lawrence D / Bernardo, Sebastian G / Moskalenko, Marina M / Sivendran, Meera / Fu, Yichun / de Moll, Ellen H / Pan, Michael / Moon, Jee Young / Arora, Sonali / Cohain, Ariella / DiFeo, Analisa / Ferringer, Tammie C / Tismenetsky, Mikhail / Tsui, Cindy L / Friedlander, Philip A / Parides, Michael K / Banchereau, Jacques / Chaussabel, Damien / Lebwohl, Mark G / Wolchok, Jedd D / Bhardwaj, Nina / Burakoff, Steven J / Oh, William K / Palucka, Karolina / Merad, Miriam / Schadt, Eric E / Saenger, Yvonne M. ·Division of Hematology and Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA; Hematology/Oncology Medical Specialists, Lancaster General Health, Lancaster, Pennsylvania, USA. · Department of Genetics and Genomic Science, Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York, USA. Electronic address: rui.r.chang@mssm.edu. · Department of Genetics and Genomic Science, Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York, USA. · Department of Dermatology, Tisch Cancer Center, Icahn School of Medicine at Mount Sinai, New York, New York, USA; Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York, USA. · Department of Dermatology, Tisch Cancer Center, Icahn School of Medicine at Mount Sinai, New York, New York, USA. · Department of Dermatology, Geisinger Health Systems, Dermatology Woodbine Danville, Danville, Pennsylvania, USA. · Division of Hematology and Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA. · Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, USA. · Department of Pathology, Geisinger Health Systems, Danville, Pennsylvania, USA. · Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York, USA; Department of Pathology, Englewood Hospital and Medical Center, Englewood, New Jersey, USA. · Center for Biostatistics, Icahn School of Medicine at Mount Sinai, New York, New York, USA. · Department of Clinical Immunology, Icahn School of Medicine at Mount Sinai, New York, New York, USA. · Benaroya Research Institute at Virginia Mason, Seattle, Washington, USA. · Ludwig Center for Cancer Immunotherapy, Memorial Sloan-Kettering Cancer Center, New York, New York, USA. · Division of Hematology and Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA; Department of Pathology, New York University, New York, New York, USA; Department of Dermatology, New York University, New York, New York, USA. · Division of Hematology and Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA; Baylor Institute for Immunology Research, Dallas, Texas, USA. · Division of Hematology and Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA. · Division of Hematology and Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA; Department of Dermatology, Tisch Cancer Center, Icahn School of Medicine at Mount Sinai, New York, New York, USA. Electronic address: yvonne.saenger@mssm.edu. ·J Invest Dermatol · Pubmed #24522433.

ABSTRACT: Patients with resected stage II-III cutaneous melanomas remain at high risk for metastasis and death. Biomarker development has been limited by the challenge of isolating high-quality RNA for transcriptome-wide profiling from formalin-fixed and paraffin-embedded (FFPE) primary tumor specimens. Using NanoString technology, RNA from 40 stage II-III FFPE primary melanomas was analyzed and a 53-immune-gene panel predictive of non-progression (area under the curve (AUC)=0.920) was defined. The signature predicted disease-specific survival (DSS P<0.001) and recurrence-free survival (RFS P<0.001). CD2, the most differentially expressed gene in the training set, also predicted non-progression (P<0.001). Using publicly available microarray data from 46 primary human melanomas (GSE15605), a coexpression module enriched for the 53-gene panel was then identified using unbiased methods. A Bayesian network of signaling pathways based on this data identified driver genes. Finally, the proposed 53-gene panel was confirmed in an independent test population of 48 patients (AUC=0.787). The gene signature was an independent predictor of non-progression (P<0.001), RFS (P<0.001), and DSS (P=0.024) in the test population. The identified driver genes are potential therapeutic targets, and the 53-gene panel should be tested for clinical application using a larger data set annotated on the basis of prospectively gathered data.

12 Article Sweet's syndrome in a patient with metastatic melanoma after ipilimumab therapy. 2013

Pintova, Sofya / Sidhu, Harleen / Friedlander, Philip A / Holcombe, Randall F. ·Departments of aHematology and Medical Oncology bPathology, Mount Sinai School of Medicine, New York, New York, USA. ·Melanoma Res · Pubmed #24113862.

ABSTRACT: Sweet's syndrome, a neutrophilic dermatosis, is a known paraneoplastic complication occurring with various malignancies. It has been infrequently reported in association with melanoma. Ipilimumab is an antibody against an inhibitory cytotoxic T-lymphocyte-associated antigen 4 receptor on T cells. It is associated with a range of immune-related toxicities. Sweet's syndrome in association with ipilimumab has been reported only briefly in the literature. However, neutrophilic infiltration has been seen in biopsies of patients with ipilimumab-associated enterocolitis. We report, in detail, the case of a woman with metastatic melanoma undergoing ipilimumab therapy. After the second cycle of immunotherapy, the patient presented with high-grade fever followed by a rash on her hands. No infectious etiology was elucidated after an extensive workup. Pathologic examination of the skin biopsy from the hands confirmed neutrophilic dermatosis. The patient was treated with systemic steroids achieving complete remission of the skin lesions. Physicians should be aware of Sweet's syndrome as a possible cutaneous side effect of ipilimumab therapy and be familiar with its management.

13 Article Elevated rates of transaminitis during ipilimumab therapy for metastatic melanoma. 2013

Bernardo, Sebastian G / Moskalenko, Marina / Pan, Michael / Shah, Shaily / Sidhu, Harleen K / Sicular, Serge / Harcharik, Sara / Chang, Rui / Friedlander, Philip / Saenger, Yvonne M. ·Departments of Dermatology, Mount Sinai School of Medicine, New York, New York 10029, USA. ·Melanoma Res · Pubmed #23262440.

ABSTRACT: Melanoma is the deadliest form of skin cancer. Ipilimumab, a novel immunotherapy, is the first treatment shown to improve survival in patients with metastatic melanoma in large randomized controlled studies. The most concerning side effects reported in clinical studies of ipilimumab fall into the category of immune-related adverse events, which include enterocolitis, dermatitis, thyroiditis, hepatitis, hypophysitis, uveitis, and others. During the course of routine clinical care at Mount Sinai Medical Center, frequent hepatotoxicity was noted when ipilimumab was administered at a dose of 3 mg/kg according to Food and Drug Administration (FDA) guidelines. To better characterize these adverse events, we conducted a retrospective review of the first 11 patients with metastatic melanoma treated with ipilimumab at the Mount Sinai Medical Center after FDA approval. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) elevation, as defined by the National Cancer Institute's Common Terminology Criteria for Adverse Events, each occurred in six of 11 cases (≥grade 1), a notably higher frequency than could be expected on the basis of the FDA licensing study where elevations were reported in 0.8 and 1.5% of patients for AST and ALT, respectively. Grade 3 elevations in AST occurred in three of 11 patients as compared with 0% in the licensing trial. All cases of transaminitis resolved when ipilimumab was temporarily withheld without administration of immunosuppressive medication. During routine clinical care of late-stage melanoma patients with ipilimumab, physicians should monitor patients closely for hepatotoxicity and be aware that toxicity rates may differ across populations during ipilimumab therapy.