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Melanoma: HELP
Articles by Jeffrey Weber
Based on 26 articles published since 2009
(Why 26 articles?)

Between 2009 and 2019, Jeffrey Weber wrote the following 26 articles about Melanoma.
+ Citations + Abstracts
Pages: 1 · 2
1 Guideline Melanoma. 2009

Coit, Daniel G / Andtbacka, Robert / Bichakjian, Christopher K / Dilawari, Raza A / Dimaio, Dominick / Guild, Valerie / Halpern, Allan C / Hodi, F Stephen / Kashani-Sabet, Mohammed / Lange, Julie R / Lind, Anne / Martin, Lainie / Martini, Mary C / Pruitt, Scott K / Ross, Merrick I / Sener, Stephen F / Swetter, Susan M / Tanabe, Kenneth K / Thompson, John A / Trisal, Vijay / Urist, Marshall M / Weber, Jeffrey / Wong, Michael K / Anonymous5080627. · ·J Natl Compr Canc Netw · Pubmed #19401060.

ABSTRACT: -- No abstract --

2 Review White paper on adoptive cell therapy for cancer with tumor-infiltrating lymphocytes: a report of the CTEP subcommittee on adoptive cell therapy. 2011

Weber, Jeffrey / Atkins, Michael / Hwu, Patrick / Radvanyi, Laszlo / Sznol, Mario / Yee, Cassian / Anonymous8120686. ·Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA. jeffrey.weber@moffitt.org ·Clin Cancer Res · Pubmed #21325070.

ABSTRACT: Adoptive T-cell therapy (ACT) using expanded autologous tumor-infiltrating lymphocytes (TIL) and tumor antigen-specific T cell expanded from peripheral blood are complex but powerful immunotherapies directed against metastatic melanoma. A number of nonrandomized clinical trials using TIL combined with high-dose interleukin-2 (IL-2) have consistently found clinical response rates of 50% or more in metastatic melanoma patients accompanied by long progression-free survival. Recent studies have also established practical methods for the expansion of TIL from melanoma tumors with high success rates. These results have set the stage for randomized phase II/III clinical trials to determine whether ACT provides benefit in stage IV melanoma. Here, we provide an overview of the current state-of-the art in T-cell-based therapies for melanoma focusing on ACT using expanded TIL and address some of the key unanswered biological and clinical questions in the field. Different phase II/III randomized clinical trial scenarios comparing the efficacy of TIL therapy to high-dose IL-2 alone are described. Finally, we provide a roadmap describing the critical steps required to test TIL therapy in a randomized multicenter setting. We suggest an approach using centralized cell expansion facilities that will receive specimens and ship expanded TIL infusion products to participating centers to ensure maximal yield and product consistency. If successful, this approach will definitively answer the question of whether ACT can enter mainstream treatment for cancer.

3 Review Immunotherapy for melanoma. 2011

Weber, Jeffrey. ·Moffitt Cancer Center, Tampa, FL, USA. jeffrey.weber@moffitt.org ·Curr Opin Oncol · Pubmed #21192262.

ABSTRACT: PURPOSE OF REVIEW: Melanoma therapy has recently seen significant progress, with several new drugs in phase II/III trials showing promising results. In this review, we discuss the most promising immunotherapies either already established or being developed, concentrating on agents for which there are high-level data to support or refute their role in treating this disease. This topic is timely, given the lengthy list of immune checkpoint inhibitors and vaccine formulations in development for melanoma. RECENT FINDINGS: The discovery of immune checkpoint proteins like CTLA-4, PD-1 and CD40 and the development of antibodies and small molecules that either inhibit or promote their activity has lent a huge impetus to the immunotherapy of melanoma. The development of vaccines that include agonists of various immune signaling like the MAGE-3 ASCI has also revived the field of cancer vaccines. Melanoma is the 'poster child' for immunotherapy of cancer, since a recent randomized phase III trial showed a survival benefit for immunotherapy. SUMMARY: The burgeoning field of immunotherapy for melanoma has important implications for clinicians, and for the novel paradigms of treatment and response assessment that immunotherapies will promote. The unique side-effect profile for immune checkpoint inhibitors will be a challenge but new skills for dealing with them in community based practice will be learned. The concept that physicians might see late regression, or progression followed by regression will cause a sea-change in the way patients are treated, since treating beyond progression may be suitable in some cases using immunotherapy.

4 Review Ipilimumab: controversies in its development, utility and autoimmune adverse events. 2009

Weber, Jeffrey. ·H. Lee Moffitt Cancer Center and Research Institute, Donald A. Adam Comprehensive Melanoma Research Center, Department of Oncologic Sciences, University of South Florida, 12902 Magnolia Drive, Tampa, FL 33612, USA. Jeffrey.Weber@moffitt.org ·Cancer Immunol Immunother · Pubmed #19198837.

ABSTRACT: A promising new class of anti-cancer drugs includes antibodies that mediate immune regulatory effects. It has become very clear over the last decade that different types of immune cells and different pathways serve to suppress anti-cancer immunity, particularly in the microenvironment of the tumor. The first examples of immune modulating antibodies are those directed against cytotoxic T lymphocyte antigen-4 (CTLA-4), a molecule present on activated T cells. Human antibodies that abrogate the function of CTLA-4 have been tested in the clinic and found to have clinical activity against melanoma. In this review, we discuss some of the controversies surrounding the potential clinical utility of one of those antibodies, ipilimumab, formerly MDX-010, from Medarex and Bristol Myers Squibb. The optimal dose and schedule of ipilimumab was derived in multiple clinical trials whose latest results are described below. Favorable survival in patients with stage IV melanoma were observed that appear to be associated with unique side effects of the drug called "immune-related adverse events". The management of these side effects is described, and the unusual kinetics of anti-tumor response with ipilimumab as well as a newly proposed schema for assessing anti-tumor responses in patients receiving biologic compounds like ipilimumab, which may supercede RECIST or WHO criteria, are addressed.

5 Clinical Trial Long-Term Outcomes in Patients With BRAF V600-Mutant Metastatic Melanoma Who Received Dabrafenib Combined With Trametinib. 2018

Long, Georgina V / Eroglu, Zeynep / Infante, Jeffrey / Patel, Sapna / Daud, Adil / Johnson, Douglas B / Gonzalez, Rene / Kefford, Richard / Hamid, Omid / Schuchter, Lynn / Cebon, Jonathan / Sharfman, William / McWilliams, Robert / Sznol, Mario / Redhu, Suman / Gasal, Eduard / Mookerjee, Bijoyesh / Weber, Jeffrey / Flaherty, Keith T. ·Georgina V. Long, University of Sydney, and Royal North Shore Hospital · Richard Kefford, Macquarie University, Sydney, and Westmead Hospital, Westmead, New South Wales · Jonathan Cebon, Ludwig Institute for Cancer Research, Melbourne, Victoria, Australia · Zeynep Eroglu, Moffitt Cancer Center, Tampa, FL · Jeffrey Infante, Tennessee Oncology · Douglas B. Johnson, Vanderbilt-Ingram Cancer Center, Nashville, TN · Sapna Patel, The University of Texas MD Anderson Cancer Center, Houston, TX · Adil Daud, University of California, San Francisco, San Francisco · Omid Hamid, The Angeles Clinic and Research Institute, Los Angeles, CA · Rene Gonzalez, University of Colorado, Denver, CO · Lynn Schuchter, University of Pennsylvania, Philadelphia, PA · William Sharfman, Sidney Kimmel Cancer Center, Baltimore, MD · Robert McWilliams, Mayo Clinic, Rochester, MN · Mario Sznol, Yale University, New Haven, CT · Suman Redhu, Eduard Gasal, and Bijoyesh Mookerjee, Novartis, East Hanover, NJ · Jeffrey Weber, New York University Langone Medical Center, New York, NY · and Keith T. Flaherty, Dana-Farber/Harvard Cancer Center, Boston, MA. ·J Clin Oncol · Pubmed #28991513.

ABSTRACT: Purpose To report 5-year landmark analysis efficacy and safety outcomes in patients with BRAF V600-mutant metastatic melanoma (MM) who received BRAF inhibitor dabrafenib (D) and MEK inhibitor trametinib (T) combination therapy versus D monotherapy in the randomized phase II BRF113220 study part C. Patients and Methods BRAF inhibitor-naive patients with BRAF V600-mutant MM were randomly assigned 1:1:1 to receive D 150 mg twice a day, D 150 mg twice a day plus T 1 mg once daily, or D 150 mg twice a day plus T 2 mg once daily (D + T 150/2). Patients who received D monotherapy could cross over to D + T 150/2 postprogression. Efficacy and safety were analyzed 4 and 5 years after initiation in patients with ≥ 5 years of follow-up. Results As of October 13, 2016, 18 patients who received D + T 150/2 remained in the study (13 [24%] of 54 enrolled at this dose plus five [11%] of 45 initially administered D who crossed over to D + T). With D + T 150/2, overall survival (OS; 4 years, 30%; 5 years, 28%) and progression-free survival (4 and 5 years, both 13%) appeared to stabilize with extended follow-up. Increased OS was observed in patients who received D + T with baseline normal lactate dehydrogenase (5 years, 45%) and normal lactate dehydrogenase with fewer than three organ sites with metastasis (5 years, 51%). With extended follow-up, one additional patient who received D + T 150/2 improved from a partial to a complete response. No new safety signals were observed. Conclusion This 5-year analysis represents the longest follow-up to date with BRAF + MEK inhibitor combination therapy in BRAF V600-mutant MM. Consistent with trends observed in landmark analyses with shorter follow-up, this therapy elicits durable plateaus of long-term OS and progression-free survival that last ≥ 5 years in some patients with MM.

6 Clinical Trial Overall Survival in Patients With Advanced Melanoma Who Received Nivolumab Versus Investigator's Choice Chemotherapy in CheckMate 037: A Randomized, Controlled, Open-Label Phase III Trial. 2018

Larkin, James / Minor, David / D'Angelo, Sandra / Neyns, Bart / Smylie, Michael / Miller, Wilson H / Gutzmer, Ralf / Linette, Gerald / Chmielowski, Bartosz / Lao, Christopher D / Lorigan, Paul / Grossmann, Kenneth / Hassel, Jessica C / Sznol, Mario / Daud, Adil / Sosman, Jeffrey / Khushalani, Nikhil / Schadendorf, Dirk / Hoeller, Christoph / Walker, Dana / Kong, George / Horak, Christine / Weber, Jeffrey. ·James Larkin, Royal Marsden NHS Foundation Trust, London · Paul Lorigan, The Christie National Health Service Foundation Trust, Manchester, United Kingdom · David Minor, California Pacific Medical Center Research Institute · Adil Daud, University of California San Francisco, San Francisco · Bartosz Chmielowski, University of California, Santa Monica, CA · Sandra D'Angelo, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College · Jeffrey Weber, Perlmutter Cancer Center at New York University-Langone Medical Center, New York · Nikhil Khushalani, Roswell Park Cancer Institute, Buffalo, NY · Gerald Linette, Washington University, St. Louis, MO · Christopher D. Lao, University of Michigan, Ann Arbor, MI · Kenneth Grossmann, Huntsman Cancer Institute, Salt Lake City, UT · Mario Sznol, Yale Comprehensive Cancer Center, New Haven, CT · Jeffrey Sosman, Northwestern University, Chicago, IL · Dana Walker, George Kong, and Christine Horak, Bristol-Myers Squibb, Princeton, NJ · Bart Neyns, University Hospital, Vrije Universiteit Brussel, Brussels, Belgium · Michael Smylie, Cross Cancer Institute, Edmonton, Alberta · Wilson H. Miller Jr, Jewish General Hospital and Segal Cancer Centre, McGill University, Montreal, Quebc, Canada · Ralf Gutzmer, Medizinische Hochschule Hannover, Hannover · Jessica C. Hassel, Nationale Centrum für Tumorerkrankungen Heidelberg, Heidelberg · Dirk Schadendorf, University Hospital Essen, Essen, Germany · and Christoph Hoeller, Medical University of Vienna, Wien, Austria. ·J Clin Oncol · Pubmed #28671856.

ABSTRACT: Purpose Until recently, limited options existed for patients with advanced melanoma who experienced disease progression while receiving treatment with ipilimumab. Here, we report the coprimary overall survival (OS) end point of CheckMate 037, which has previously shown that nivolumab resulted in more patients achieving an objective response compared with chemotherapy regimens in ipilimumab-refractory patients with advanced melanoma. Patients and Methods Patients were stratified by programmed death-ligand 1 expression, BRAF status, and best prior cytotoxic T-lymphocyte antigen-4 therapy response, then randomly assigned 2:1 to nivolumab 3 mg/kg intravenously every 2 weeks or investigator's choice chemotherapy (ICC; dacarbazine 1,000 mg/m

7 Clinical Trial Adjuvant Nivolumab versus Ipilimumab in Resected Stage III or IV Melanoma. 2017

Weber, Jeffrey / Mandala, Mario / Del Vecchio, Michele / Gogas, Helen J / Arance, Ana M / Cowey, C Lance / Dalle, Stéphane / Schenker, Michael / Chiarion-Sileni, Vanna / Marquez-Rodas, Ivan / Grob, Jean-Jacques / Butler, Marcus O / Middleton, Mark R / Maio, Michele / Atkinson, Victoria / Queirolo, Paola / Gonzalez, Rene / Kudchadkar, Ragini R / Smylie, Michael / Meyer, Nicolas / Mortier, Laurent / Atkins, Michael B / Long, Georgina V / Bhatia, Shailender / Lebbé, Celeste / Rutkowski, Piotr / Yokota, Kenji / Yamazaki, Naoya / Kim, Tae M / de Pril, Veerle / Sabater, Javier / Qureshi, Anila / Larkin, James / Ascierto, Paolo A / Anonymous7111184. ·From New York University Perlmutter Cancer Center, New York (J.W.) · Papa Giovanni XXIII Cancer Center Hospital, Bergamo (M. Mandala), Medical Oncology, National Cancer Institute, Milan (M.D.V.), Oncology Institute of Veneto Istituti di Ricovero e Cura a Carattere Scientifico, Padua (V.C.-S.), Center for Immuno-Oncology, University Hospital of Siena, Istituto Toscano Tumori, Siena (M. Maio), Ospedale Policlinico San Martino, Genoa (P.Q.), and Istituto Nazionale Tumori Fondazione Pascale, Naples (P.A.A.) - all in Italy · National and Kapodistrian University of Athens, Athens (H.J.G.) · Hospital Clinic de Barcelona, Barcelona (A.M.A.), and General University Hospital Gregorio Marañón, Madrid (I.M.-R.) - both in Spain · Texas Oncology-Baylor Cancer Center, Dallas (C.L.C.) · Hospices Civils de Lyon, Pierre Bénite (S.D.), Aix-Marseille University, Hospital de la Timone, Marseille (J.-J.G.), Institut Universitaire du Cancer de Toulouse and Centre Hospitalier Universitaire (CHU), Toulouse (N.M.), Université Lille, INSERM Unité 1189, CHU Lille, Lille (L.M.), and Assistance Publique-Hôpitaux de Paris, Dermatology and Centres d'Investigation Clinique, INSERM Unité 976, Hôpital Saint Louis, Université Paris Diderot, Paris (C.L.) - all in France · Oncology Center Sf. Nectarie, Craiova, Romania (M. Schenker) · Princess Margaret Cancer Centre, University of Toronto, Toronto (M.O.B.), and Cross Cancer Institute, Edmonton, AB (M. Smylie) - both in Canada · the Department of Oncology, University of Oxford, Oxford (M.R.M.), and Royal Marsden NHS Foundation Trust, London (J.L.) - both in the United Kingdom · Gallipoli Medical Research Foundation and University of Queensland, Queensland, VIC (V.A.), and Melanoma Institute Australia, University of Sydney, and Royal North Shore and Mater Hospitals, Sydney (G.V.L.) - all in Australia · University of Colorado, Denver (R.G.) · Winship Cancer Institute, Emory University School of Medicine, Atlanta (R.R.K.) · Georgetown-Lombardi Comprehensive Cancer Center, Washington DC (M.B.A.) · University of Washington, Seattle (S.B.) · Maria Sklodowska-Curie Institute-Oncology Center, Warsaw, Poland (P.R.) · Nagoya University Graduate School of Medicine, Nagoya (K.Y.), and the National Cancer Center Hospital, Tokyo (N.Y.) - both in Japan · Seoul National University Hospital, Seoul, South Korea (T.M.K.) · and Bristol-Myers Squibb, Princeton, NJ (V.P, J.S., A.Q.). ·N Engl J Med · Pubmed #28891423.

ABSTRACT: BACKGROUND: Nivolumab and ipilimumab are immune checkpoint inhibitors that have been approved for the treatment of advanced melanoma. In the United States, ipilimumab has also been approved as adjuvant therapy for melanoma on the basis of recurrence-free and overall survival rates that were higher than those with placebo in a phase 3 trial. We wanted to determine the efficacy of nivolumab versus ipilimumab for adjuvant therapy in patients with resected advanced melanoma. METHODS: In this randomized, double-blind, phase 3 trial, we randomly assigned 906 patients (≥15 years of age) who were undergoing complete resection of stage IIIB, IIIC, or IV melanoma to receive an intravenous infusion of either nivolumab at a dose of 3 mg per kilogram of body weight every 2 weeks (453 patients) or ipilimumab at a dose of 10 mg per kilogram every 3 weeks for four doses and then every 12 weeks (453 patients). The patients were treated for a period of up to 1 year or until disease recurrence, a report of unacceptable toxic effects, or withdrawal of consent. The primary end point was recurrence-free survival in the intention-to-treat population. RESULTS: At a minimum follow-up of 18 months, the 12-month rate of recurrence-free survival was 70.5% (95% confidence interval [CI], 66.1 to 74.5) in the nivolumab group and 60.8% (95% CI, 56.0 to 65.2) in the ipilimumab group (hazard ratio for disease recurrence or death, 0.65; 97.56% CI, 0.51 to 0.83; P<0.001). Treatment-related grade 3 or 4 adverse events were reported in 14.4% of the patients in the nivolumab group and in 45.9% of those in the ipilimumab group; treatment was discontinued because of any adverse event in 9.7% and 42.6% of the patients, respectively. Two deaths (0.4%) related to toxic effects were reported in the ipilimumab group more than 100 days after treatment. CONCLUSIONS: Among patients undergoing resection of stage IIIB, IIIC, or IV melanoma, adjuvant therapy with nivolumab resulted in significantly longer recurrence-free survival and a lower rate of grade 3 or 4 adverse events than adjuvant therapy with ipilimumab. (Funded by Bristol-Myers Squibb and Ono Pharmaceutical; CheckMate 238 ClinicalTrials.gov number, NCT02388906 ; Eudra-CT number, 2014-002351-26 .).

8 Clinical Trial Phase I/II Study of Metastatic Melanoma Patients Treated with Nivolumab Who Had Progressed after Ipilimumab. 2016

Weber, Jeffrey / Gibney, Geoffrey / Kudchadkar, Ragini / Yu, Bin / Cheng, Pingyan / Martinez, Alberto J / Kroeger, Jodie / Richards, Allison / McCormick, Lori / Moberg, Valerie / Cronin, Heather / Zhao, Xiuhua / Schell, Michael / Chen, Yian Ann. ·Comprehensive Melanoma Research Center and Department of Cutaneous Oncology, Moffitt Cancer Center, Tampa, Florida. Jeffrey.weber2@nyumc.org. · Comprehensive Melanoma Research Center and Department of Cutaneous Oncology, Moffitt Cancer Center, Tampa, Florida. · Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, Florida. ·Cancer Immunol Res · Pubmed #26873574.

ABSTRACT: The checkpoint inhibitor nivolumab is active in patients with metastatic melanoma who have failed ipilimumab. In this phase I/II study, we assessed nivolumab's safety in 92 ipilimumab-refractory patients with unresectable stage III or IV melanoma, including those who experienced grade 3-4 drug-related toxicity to ipilimumab. We report long-term survival, response duration, and biomarkers in these patients after nivolumab treatment (3 mg/kg) every 2 weeks for 24 weeks, then every 12 weeks for up to 2 years, with or without a multipeptide vaccine. The response rate for ipilimumab-refractory patients was 30% (95% CI, 21%-41%). The median duration of response was 14.6 months, median progression-free survival was 5.3 months, and median overall survival was 20.6 months, when patients were followed up for a median of 16 months. One- and 2-year survival rates were 68.4% and 31.2%, respectively. Ipilimumab-naïve and ipilimumab-refractory patients showed no significant difference in survival. The 21 patients with prior grade 3-4 toxicity to ipilimumab that was managed with steroids tolerated nivolumab well, with 62% (95% CI, 38%-82%) having complete or partial responses or stabilized disease at 24 weeks. High numbers of myeloid-derived suppressor cells (MDSC) were associated with poor survival. Thus, survival and long-term safety were excellent in ipilimumab-refractory patients treated with nivolumab. Prior grade 3-4 immune-related adverse effects from ipilimumab were not indicative of nivolumab toxicities, and patients had a high overall rate of remission or stability at 24 weeks. Prospectively evaluating MDSC numbers before treatment could help assess the expected benefit of nivolumab.

9 Clinical Trial A phase 2, multicenter, open-label study of sepantronium bromide (YM155) plus docetaxel in patients with stage III (unresectable) or stage IV melanoma. 2015

Kudchadkar, Ragini / Ernst, Scott / Chmielowski, Bartosz / Redman, Bruce G / Steinberg, Joyce / Keating, Anne / Jie, Fei / Chen, Caroline / Gonzalez, Rene / Weber, Jeffrey. ·Winship Cancer Institute, Emory University, Atlanta, Georgia. · London Regional Cancer Centre, London, Ontario, Canada. · University of California-Los Angeles, Ronald Reagan UCLA Medical Center, Los Angeles, California. · University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan. · Astellas Pharmaceuticals Global Development, Northbrook, Illinois. · University of Colorado Denver, Comprehensive Cancer Center, Denver, Colorado. · H. Lee Moffitt Cancer Center, Tampa, Florida. ·Cancer Med · Pubmed #25533314.

ABSTRACT: Survivin is a microtubule-associated protein believed to be involved in preserving cell viability and regulating tumor cell mitosis, and it is overexpressed in many primary tumor types, including melanoma. YM155 is a first-in-class survivin suppressant. The purpose of this Phase 2 study was to evaluate the 6-month progression-free survival (PFS) rate in patients with unresectable Stage III or IV melanoma receiving a combination of YM155 plus docetaxel. The study had two parts: Part 1 established the dose of docetaxel that was tolerable in combination with YM155, and Part 2 evaluated the tolerable docetaxel dose (75 mg/m(2) ) in combination with YM155 (5 mg/m(2) per day continuous infusion over 168 h every 3 weeks). The primary endpoint was 6-month PFS rate. Secondary endpoints were objective response rate (ORR), 1-year overall survival (OS) rate, time from first response to progression, clinical benefit rate (CBR), and safety. Sixty-four patients with metastatic melanoma were treated with docetaxel and YM155. Eight patients received an initial docetaxel dose of 100 mg/m(2) and 56 patients received 75 mg/m(2) of docetaxel. Six-month PFS rate per Independent Review Committee (IRC) was 34.8% (n = 64; 95% CI, 21.3-48.6%), and per Investigator was 31.3% (n = 64; 95% CI, 19.5-43.9%). The best ORR (complete response [CR] + partial response [PR]) per IRC was 12.5% (8/64). The stable disease (SD) rate was 51.6% (33/64), leading to a CBR (CR + PR + SD) of 64.1% (41/64). Estimated probability of 1-year survival was 56.3%. YM155 is a novel agent showing modest activity when combined with docetaxel for treating patients with melanoma. YM155 was generally well tolerated, but the predetermined primary efficacy endpoint (i.e., 6-month PFS rate ≥20%) was not achieved.

10 Clinical Trial Metabolic response by FDG-PET to imatinib correlates with exon 11 KIT mutation and predicts outcome in patients with mucosal melanoma. 2014

Zukotynski, Katherine / Yap, Jeffrey T / Giobbie-Hurder, Anita / Weber, Jeffrey / Gonzalez, Rene / Gajewski, Thomas F / O'Day, Steven / Kim, Kevin / Hodi, F Stephen / Van den Abbeele, Annick D. · ·Cancer Imaging · Pubmed #25609545.

ABSTRACT: BACKGROUND: In patients with metastatic melanoma and KIT amplifications and/or mutations, therapy with imatinib mesylate may prolong survival. 18F-labeled 2-fluoro-2-deoxy-D-glucose (18F-FDG) PET/CT may be used to assess metabolic response. We investigated associations of metabolic response, mutational status, progression-free survival and overall survival in this population. METHODS: Baseline and 4-week follow-up 18F-FDG-PET/CT were evaluated in 17 patients with metastatic melanoma and KIT amplifications and/or mutations treated with imatinib in a multicenter phase II clinical trial. The maximum standardized uptake values (SUVmax) were measured in up to 10 lesions on each scan. Metabolic response was classified using modified EORTC criteria. Each patient had a diagnostic CT or MR at baseline, after 6 weeks of therapy and then at intervals of 2 months and anatomic response was classified using RECIST 1.0. Median follow-up was 9.8 months. RESULTS: Partial metabolic response (PMR), stable metabolic disease (SMD) and progressive metabolic disease (PMD) was seen in 5 (29%), 5 (29%), and 7 (41%) patients respectively. Five patients (29%) had a KIT mutation in exon 11, four of whom (80%) had PMR while 1 (20%) had SMD. Twelve patients (71%) did not have a KIT mutation in exon 11, and only 1 (8%) had PMR, 4 (33%) had SMD and 7 (58%) had PMD. There was agreement of metabolic and anatomic classification in 12 of 17 patients (71%). Four of 17 patients (24%) had PR on both metabolic and anatomic imaging and all had a KIT mutation in exon 11. Survival of patients with PMD was lower than with SMD or PMR. CONCLUSIONS: Metabolic response by 18F-FDG-PET/CT is associated with mutational status in metastatic melanoma patients treated with imatinib. 18F-FDG-PET/CT may be a predictor of outcome, although a larger study is needed to verify this. CLINICAL TRIAL REGISTRATION: NCT00424515.

11 Clinical Trial Randomized phase I pharmacokinetic study of ipilimumab with or without one of two different chemotherapy regimens in patients with untreated advanced melanoma. 2013

Weber, Jeffrey / Hamid, Omid / Amin, Asim / O'Day, Steven / Masson, Eric / Goldberg, Stacie M / Williams, Daphne / Parker, Susan M / Chasalow, Scott D / Alaparthy, Suresh / Wolchok, Jedd D. ·Moffitt Cancer Center, Tampa, FL 33612, USA. jeffrey.weber@moffitt.org ·Cancer Immun · Pubmed #23833564.

ABSTRACT: We describe a randomized three-arm phase I study of ipilimumab administered alone (I group) or in combination with dacarbazine (D group) or carboplatin/paclitaxel (CP group) in patients with previously untreated advanced melanoma. The primary objective was to estimate the effect of ipilimumab on the pharmacokinetics (PK) of dacarbazine and paclitaxel and, conversely, to estimate the effects of dacarbazine and carboplatin/paclitaxel on the PK of ipilimumab. Secondary objectives included evaluation of the safety and anti-tumor activity of ipilimumab when administered alone or with either dacarbazine or carboplatin/paclitaxel, and assessment of pharmacodynamic (PD) effects of ipilimumab on the immune system when administered alone or with either of the two chemotherapies. Ipilimumab was administered at a dose of 10 mg/kg intravenously (IV) every 3 weeks for up to 4 doses. Patients in the D group received dacarbazine 850 mg/m(2) IV every 3 weeks. Patients in the CP group received paclitaxel 175 mg/m(2) IV and carboplatin [AUC=6] IV every 3 weeks. Starting at week 24, patients without dose-limiting toxicities were eligible to receive maintenance ipilimumab at 10 mg/kg every 12 weeks until disease progressed or toxicity required discontinuation. Of 59 randomized patients, 18 (30.5%) discontinued treatment due to adverse events. Response rates by modified WHO criteria were 29.4% (I group), 27.8% (D group), and 11.1% (CP group). No major PK or PD interactions were observed when ipilimumab was administered with dacarbazine or with the carboplatin/paclitaxel combination. This study demonstrated that ipilimumab can be combined safely with two chemotherapy regimens commonly used in advanced melanoma.

12 Clinical Trial Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. 2012

Flaherty, Keith T / Infante, Jeffery R / Daud, Adil / Gonzalez, Rene / Kefford, Richard F / Sosman, Jeffrey / Hamid, Omid / Schuchter, Lynn / Cebon, Jonathan / Ibrahim, Nageatte / Kudchadkar, Ragini / Burris, Howard A / Falchook, Gerald / Algazi, Alain / Lewis, Karl / Long, Georgina V / Puzanov, Igor / Lebowitz, Peter / Singh, Ajay / Little, Shonda / Sun, Peng / Allred, Alicia / Ouellet, Daniele / Kim, Kevin B / Patel, Kiran / Weber, Jeffrey. ·Massachusetts General Hospital Cancer Center, Boston, USA. ·N Engl J Med · Pubmed #23020132.

ABSTRACT: BACKGROUND: Resistance to therapy with BRAF kinase inhibitors is associated with reactivation of the mitogen-activated protein kinase (MAPK) pathway. To address this problem, we conducted a phase 1 and 2 trial of combined treatment with dabrafenib, a selective BRAF inhibitor, and trametinib, a selective MAPK kinase (MEK) inhibitor. METHODS: In this open-label study involving 247 patients with metastatic melanoma and BRAF V600 mutations, we evaluated the pharmacokinetic activity and safety of oral dabrafenib (75 or 150 mg twice daily) and trametinib (1, 1.5, or 2 mg daily) in 85 patients and then randomly assigned 162 patients to receive combination therapy with dabrafenib (150 mg) plus trametinib (1 or 2 mg) or dabrafenib monotherapy. The primary end points were the incidence of cutaneous squamous-cell carcinoma, survival free of melanoma progression, and response. Secondary end points were overall survival and pharmacokinetic activity. RESULTS: Dose-limiting toxic effects were infrequently observed in patients receiving combination therapy with 150 mg of dabrafenib and 2 mg of trametinib (combination 150/2). Cutaneous squamous-cell carcinoma was seen in 7% of patients receiving combination 150/2 and in 19% receiving monotherapy (P=0.09), whereas pyrexia was more common in the combination 150/2 group than in the monotherapy group (71% vs. 26%). Median progression-free survival in the combination 150/2 group was 9.4 months, as compared with 5.8 months in the monotherapy group (hazard ratio for progression or death, 0.39; 95% confidence interval, 0.25 to 0.62; P<0.001). The rate of complete or partial response with combination 150/2 therapy was 76%, as compared with 54% with monotherapy (P=0.03). CONCLUSIONS: Dabrafenib and trametinib were safely combined at full monotherapy doses. The rate of pyrexia was increased with combination therapy, whereas the rate of proliferative skin lesions was nonsignificantly reduced. Progression-free survival was significantly improved. (Funded by GlaxoSmithKline; ClinicalTrials.gov number, NCT01072175.).

13 Clinical Trial Efficacy of adoptive cell transfer of tumor-infiltrating lymphocytes after lymphopenia induction for metastatic melanoma. 2012

Pilon-Thomas, Shari / Kuhn, Lisa / Ellwanger, Sabine / Janssen, William / Royster, Erica / Marzban, Suroosh / Kudchadkar, Ragini / Zager, Jonathan / Gibney, Geoffrey / Sondak, Vernon K / Weber, Jeffrey / Mulé, James J / Sarnaik, Amod A. ·Donald A. Adam Comprehensive Melanoma Research Center, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA. ·J Immunother · Pubmed #22996367.

ABSTRACT: A single-institution pilot clinical trial was performed combining nonmyeloablative chemotherapy and the adoptive transfer of tumor-infiltrating lymphocytes with interleukin-2 in patients with metastatic melanoma. Nineteen patients were enrolled with 13 patients (68%) successfully completing treatment. An overall response rate (partial and complete responses) of 26% by intention to treat was achieved with a median follow-up time of 10 months. Of the 13 treated patients, there were 2 complete responses and 3 partial responses (38% response rate among treated patients), along with 4 patients with stable disease ranging from 2+ to 24+months. Three of the 4 patients with stable disease have had disease control without additional therapy, including one at 24+ months. Adoptive therapy with infiltrating lymphocytes is labor intensive but feasible and has a high response rate in treated patients.

14 Clinical Trial Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. 2011

Robert, Caroline / Thomas, Luc / Bondarenko, Igor / O'Day, Steven / Weber, Jeffrey / Garbe, Claus / Lebbe, Celeste / Baurain, Jean-François / Testori, Alessandro / Grob, Jean-Jacques / Davidson, Neville / Richards, Jon / Maio, Michele / Hauschild, Axel / Miller, Wilson H / Gascon, Pere / Lotem, Michal / Harmankaya, Kaan / Ibrahim, Ramy / Francis, Stephen / Chen, Tai-Tsang / Humphrey, Rachel / Hoos, Axel / Wolchok, Jedd D. ·Institute Gustave, Roussy, Villejuif, France. ·N Engl J Med · Pubmed #21639810.

ABSTRACT: BACKGROUND: Ipilimumab monotherapy (at a dose of 3 mg per kilogram of body weight), as compared with glycoprotein 100, improved overall survival in a phase 3 study involving patients with previously treated metastatic melanoma. We conducted a phase 3 study of ipilimumab (10 mg per kilogram) plus dacarbazine in patients with previously untreated metastatic melanoma. METHODS: We randomly assigned 502 patients with previously untreated metastatic melanoma, in a 1:1 ratio, to ipilimumab (10 mg per kilogram) plus dacarbazine (850 mg per square meter of body-surface area) or dacarbazine (850 mg per square meter) plus placebo, given at weeks 1, 4, 7, and 10, followed by dacarbazine alone every 3 weeks through week 22. Patients with stable disease or an objective response and no dose-limiting toxic effects received ipilimumab or placebo every 12 weeks thereafter as maintenance therapy. The primary end point was overall survival. RESULTS: Overall survival was significantly longer in the group receiving ipilimumab plus dacarbazine than in the group receiving dacarbazine plus placebo (11.2 months vs. 9.1 months, with higher survival rates in the ipilimumab-dacarbazine group at 1 year (47.3% vs. 36.3%), 2 years (28.5% vs. 17.9%), and 3 years (20.8% vs. 12.2%) (hazard ratio for death, 0.72; P<0.001). Grade 3 or 4 adverse events occurred in 56.3% of patients treated with ipilimumab plus dacarbazine, as compared with 27.5% treated with dacarbazine and placebo (P<0.001). No drug-related deaths or gastrointestinal perforations occurred in the ipilimumab-dacarbazine group. CONCLUSIONS: Ipilimumab (at a dose of 10 mg per kilogram) in combination with dacarbazine, as compared with dacarbazine plus placebo, improved overall survival in patients with previously untreated metastatic melanoma. The types of adverse events were consistent with those seen in prior studies of ipilimumab; however, the rates of elevated liver-function values were higher and the rates of gastrointestinal events were lower than expected on the basis of prior studies. (Funded by Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00324155.).

15 Clinical Trial Blockade of cytotoxic T-lymphocyte antigen-4 by ipilimumab results in dysregulation of gastrointestinal immunity in patients with advanced melanoma. 2010

Berman, David / Parker, Susan M / Siegel, Jonathan / Chasalow, Scott D / Weber, Jeffrey / Galbraith, Susan / Targan, Stephan R / Wang, Hanlin L. ·Bristol-Myers Squibb Company, Princeton, New Jersey, USA. david.berman@bms.com ·Cancer Immun · Pubmed #21090563.

ABSTRACT: Blockade of cytotoxic T-lymphocyte antigen-4 (CTLA-4) by ipilimumab leads to immune-mediated tumor regression and immune-related adverse events (irAEs), including diarrhea and colitis. The current analyses were undertaken to promote an understanding of the underlying mechanism of action and to identify potential biomarkers that could help in the prediction and management of ipilimumab-induced gastrointestinal irAEs. Treatment-naïve or previously treated patients with unresectable stage III/IV melanoma (n = 115) received open-label ipilimumab (10 mg/kg every 3 weeks for four doses) and were randomized to receive concomitant blinded prophylactic oral budesonide (9 mg/d with gradual taper through week 16) or placebo. Outcome measures included histologic assessment of bowel biopsies and assessment of serologic markers of inflammatory bowel disease (IBD), fecal calprotectin levels, and polymorphisms in immune-related genes. Ipilimumab resulted in dysregulation of gastrointestinal mucosal immunity as evidenced by altered antibody levels to enteric flora, inflammatory cell infiltration into gastrointestinal mucosa, and increased fecal calprotectin associated with diarrhea and clinical evidence of colitis. The pattern of ipilimumab-induced antibody titers to microbial flora and the histologic features and location of the inflammation were distinct from classic IBD. Prophylactic budesonide did not prevent ipilimumab-induced bowel inflammation. Despite an observed association between colonic inflammation and grade 2 or higher diarrhea, no baseline biomarkers could reliably predict development of gastrointestinal toxicity. Although classic IBD and ipilimumab-related gastrointestinal toxicity are both immune mediated, the observed pattern of biomarkers suggests ipilimumab-related gastrointestinal toxicity may be a distinct clinicopathologic entity.

16 Clinical Trial A randomized, double-blind, placebo-controlled, phase II study comparing the tolerability and efficacy of ipilimumab administered with or without prophylactic budesonide in patients with unresectable stage III or IV melanoma. 2009

Weber, Jeffrey / Thompson, John A / Hamid, Omid / Minor, David / Amin, Asim / Ron, Ilan / Ridolfi, Ruggero / Assi, Hazem / Maraveyas, Anthony / Berman, David / Siegel, Jonathan / O'Day, Steven J. ·Moffitt Cancer Center, Tampa, Florida 33612, USA. Jeffrey.Weber@moffitt.org ·Clin Cancer Res · Pubmed #19671877.

ABSTRACT: PURPOSE: Diarrhea (with or without colitis) is an immune-related adverse event (irAE) associated with ipilimumab. A randomized, double-blind, placebo-controlled, multicenter, multinational phase II trial was conducted to determine whether prophylactic budesonide (Entocort EC), a nonabsorbed oral steroid, reduced the rate of grade >or=2 diarrhea in ipilimumab-treated patients with advanced melanoma. EXPERIMENTAL DESIGN: Previously treated and treatment-naïve patients (N = 115) with unresectable stage III or IV melanoma received open-label ipilimumab (10 mg/kg every 3 weeks for four doses) with daily blinded budesonide (group A) or placebo (group B) through week 16. The first scheduled tumor evaluation was at week 12; eligible patients received maintenance treatment starting at week 24. Diarrhea was assessed using Common Terminology Criteria for Adverse Events (CTCAE) 3.0. Patients kept a diary describing their bowel habits. RESULTS: Budesonide did not affect the rate of grade >or=2 diarrhea, which occurred in 32.7% and 35.0% of patients in groups A and B, respectively. There were no bowel perforations or treatment-related deaths. Best overall response rates were 12.1% in group A and 15.8% in group B, with a median overall survival of 17.7 and 19.3 months, respectively. Within each group, the disease control rate was higher in patients with grade 3 to 4 irAEs than in patients with grade 0 to 2 irAEs, although many patients with grade 1 to 2 irAEs experienced clinical benefit. Novel patterns of response to ipilimumab were observed. CONCLUSIONS: Ipilimumab shows activity in advanced melanoma, with encouraging survival and manageable adverse events. Budesonide should not be used prophylactically for grade >or=2 diarrhea associated with ipilimumab therapy.

17 Article Autoimmune genetic risk variants as germline biomarkers of response to melanoma immune-checkpoint inhibition. 2019

Chat, Vylyny / Ferguson, Robert / Simpson, Danny / Kazlow, Esther / Lax, Rebecca / Moran, Una / Pavlick, Anna / Frederick, Dennie / Boland, Genevieve / Sullivan, Ryan / Ribas, Antoni / Flaherty, Keith / Osman, Iman / Weber, Jeffrey / Kirchhoff, Tomas. ·Laura and Issac Perlmutter Cancer Center, New York University School of Medicine, 522 First Avenue, New York, NY, 10016, USA. · Departments of Population Health and Environmental Medicine, New York University School of Medicine, New York, NY, USA. · The Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, NY, USA. · Department of Medicine, New York University School of Medicine, New York, NY, USA. · Ronald O. Perelman, Department of Dermatology, New York University, New York, NY, USA. · Center for Melanoma, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA. · Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA. · Laura and Issac Perlmutter Cancer Center, New York University School of Medicine, 522 First Avenue, New York, NY, 10016, USA. tomas.kirchhoff@nyumc.org. · Departments of Population Health and Environmental Medicine, New York University School of Medicine, New York, NY, USA. tomas.kirchhoff@nyumc.org. · The Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, NY, USA. tomas.kirchhoff@nyumc.org. ·Cancer Immunol Immunother · Pubmed #30863922.

ABSTRACT: Immune-checkpoint inhibition (ICI) treatments improve outcomes for metastatic melanoma; however, > 60% of treated patients do not respond to ICI. Current biomarkers do not reliably explain ICI resistance. Given the link between ICI and autoimmunity, we investigated if genetic susceptibility to autoimmunity modulates ICI efficacy. In 436 patients with metastatic melanoma receiving single line ICI or combination treatment, we tested 25 SNPs, associated with > 2 autoimmune diseases in recent genome-wide association studies, for modulation of ICI efficacy. We found that rs17388568-a risk variant for allergy, colitis and type 1 diabetes-was associated with increased anti-PD-1 response, with significance surpassing multiple testing adjustments (OR 0.26; 95% CI 0.12-0.53; p = 0.0002). This variant maps to a locus of established immune-related genes: IL2 and IL21. Our study provides first evidence that autoimmune genetic susceptibility may modulate ICI efficacy, suggesting that systematic testing of autoimmune risk loci could reveal personalized biomarkers of ICI response.

18 Article Neurologic Serious Adverse Events Associated with Nivolumab Plus Ipilimumab or Nivolumab Alone in Advanced Melanoma, Including a Case Series of Encephalitis. 2017

Larkin, James / Chmielowski, Bartosz / Lao, Christopher D / Hodi, F Stephen / Sharfman, William / Weber, Jeffrey / Suijkerbuijk, Karijn P M / Azevedo, Sergio / Li, Hewei / Reshef, Daniel / Avila, Alexandre / Reardon, David A. ·The Royal Marsden, London, United Kingdom James.larkin@rmh.nhs.uk. · University of California Los Angeles Medical Center, Santa Monica, California, USA. · University of Michigan, Ann Arbor, Michigan, USA. · Dana-Farber Cancer Institute, Boston, Massachusetts, USA. · Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins, Baltimore, Maryland, USA. · New York University Langone Medical Center, New York, New York, USA. · University Medical Center Utrecht Cancer Center, Utrecht, Netherlands. · Hospital Mae de Deus, Porto Alegre, Brazil. · Bristol-Myers Squibb, Princeton, New Jersey, USA. ·Oncologist · Pubmed #28495807.

ABSTRACT: BACKGROUND: Despite unprecedented efficacy across multiple tumor types, immune checkpoint inhibitor therapy is associated with a unique and wide spectrum of immune-related adverse events (irAEs), including neurologic events ranging from mild headache to potentially life-threatening encephalitis. Here, we summarize neurologic irAEs associated with nivolumab and ipilimumab melanoma treatment, present cases of treatment-related encephalitis, and provide practical guidance on diagnosis and management. METHODS: We searched a Global Pharmacovigilance and Epidemiology database for neurologic irAEs reported over an 8-year period in patients with advanced melanoma receiving nivolumab with or without ipilimumab from 12 studies sponsored by Bristol-Myers Squibb. Serious neurologic irAEs were reviewed, and relationship to nivolumab or ipilimumab was assigned. RESULTS: In our search of 3,763 patients, 35 patients (0.93%) presented with 43 serious neurologic irAEs, including neuropathy ( CONCLUSION: Both oncologists and neurologists need to be aware of signs and symptoms of serious but uncommon neurologic irAEs associated with checkpoint inhibitors. Prompt diagnosis and management using an established algorithm are critical to minimize serious complications from these neurologic irAEs. IMPLICATIONS FOR PRACTICE: With increasing use of checkpoint inhibitors in cancer, practicing oncologists need to be aware of the potential risk of neurologic immune-related adverse events and be able to provide prompt treatment of this uncommon, but potentially serious, class of adverse events. We summarize neurologic adverse events related to nivolumab alone or in combination with ipilimumab in patients with advanced melanoma from 12 studies and examine in depth 6 cases of encephalitis. We also provide input and guidance on the existing neurologic adverse events management algorithm for nivolumab and ipilimumab.

19 Article HDAC Inhibition Upregulates PD-1 Ligands in Melanoma and Augments Immunotherapy with PD-1 Blockade. 2015

Woods, David M / Sodré, Andressa L / Villagra, Alejandro / Sarnaik, Amod / Sotomayor, Eduardo M / Weber, Jeffrey. ·H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida. jeffrey.weber@moffitt.org esotomayor@mfa.gwu.edu. · H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida. ·Cancer Immunol Res · Pubmed #26297712.

ABSTRACT: Expression of PD-1 ligands by tumors and interaction with PD-1-expressing T cells in the tumor microenvironment can result in tolerance. Therapies targeting this coinhibitory axis have proven clinically successful in the treatment of metastatic melanoma, non-small cell lung cancer, and other malignancies. Therapeutic agents targeting the epigenetic regulatory family of histone deacetylases (HDAC) have shown clinical success in the treatment of some hematologic malignancies. Beyond direct tumor cell cytotoxicity, HDAC inhibitors have also been shown to alter the immunogenicity and enhance antitumor immune responses. Here, we show that class I HDAC inhibitors upregulated the expression of PD-L1 and, to a lesser degree, PD-L2 in melanomas. Evaluation of human and murine cell lines and patient tumors treated with a variety of HDAC inhibitors in vitro displayed upregulation of these ligands. This upregulation was robust and durable, with enhanced expression lasting past 96 hours. These results were validated in vivo in a B16F10 syngeneic murine model. Mechanistically, HDAC inhibitor treatment resulted in rapid upregulation of histone acetylation of the PD-L1 gene leading to enhanced and durable gene expression. The efficacy of combining HDAC inhibition with PD-1 blockade for treatment of melanoma was also explored in a murine B16F10 model. Mice receiving combination therapy had a slower tumor progression and increased survival compared with control and single-agent treatments. These results highlight the ability of epigenetic modifiers to augment immunotherapies, providing a rationale for combining HDAC inhibitors with PD-1 blockade.

20 Article Manipulating the tumor microenvironment ex vivo for enhanced expansion of tumor-infiltrating lymphocytes for adoptive cell therapy. 2015

Chacon, Jessica Ann / Sarnaik, Amod A / Chen, Jie Qing / Creasy, Caitlin / Kale, Charuta / Robinson, John / Weber, Jeffrey / Hwu, Patrick / Pilon-Thomas, Shari / Radvanyi, Laszlo. ·Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. The Immunology Program of the University of Texas Health Science Center, Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, Texas. jchacon@mail.med.upenn.edu laszlo.radvanyi@lionbio.com. · Donald A. Adam Comprehensive Melanoma Research Center, H. Lee Moffitt Cancer Center, Tampa, Florida. · Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Lion Biotechnologies, Woodland Hills, Los Angeles, California. · Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. The Immunology Program of the University of Texas Health Science Center, Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. The Immunology Program of the University of Texas Health Science Center, Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, Florida. Lion Biotechnologies, Woodland Hills, Los Angeles, California. jchacon@mail.med.upenn.edu laszlo.radvanyi@lionbio.com. ·Clin Cancer Res · Pubmed #25472998.

ABSTRACT: PURPOSE: Cultured tumor fragments from melanoma metastases have been used for years as a source of tumor-infiltrating lymphocytes (TIL) for adoptive cell therapy (ACT). The expansion of tumor-reactive CD8(+) T cells with interleukin-2 (IL2) in these early cultures is critical in generating clinically active TIL infusion products, with a population of activated 4-1BB CD8(+) T cells recently found to constitute the majority of tumor-specific T cells. EXPERIMENTAL DESIGN: We used an agonistic anti-4-1BB antibody added during the initial tumor fragment cultures to provide in situ 4-1BB costimulation. RESULTS: We found that addition of an agonistic anti-4-1BB antibody could activate 4-1BB signaling within early cultured tumor fragments and accelerated the rate of memory CD8(+) TIL outgrowth that were highly enriched for melanoma antigen specificity. This was associated with NFκB activation and the induction of T-cell survival and memory genes, as well as enhanced IL2 responsiveness, in the CD8(+) T cells in the fragments and emerging from the fragments. Early provision of 4-1BB costimulation also affected the dendritic cells (DC) by activating NFκB in DC and promoting their maturation inside the tumor fragments. Blocking HLA class I prevented the enhanced outgrowth of CD8(+) T cells with anti-4-1BB, suggesting that an ongoing HLA class I-mediated antigen presentation in early tumor fragment cultures plays a role in mediating tumor-specific CD8(+) TIL outgrowth. CONCLUSIONS: Our results highlight a previously unrecognized concept in TIL ACT that the tumor microenvironment can be dynamically regulated in the initial tumor fragment cultures to regulate the types of T cells expanded and their functional characteristics.

21 Article The antimelanoma activity of the histone deacetylase inhibitor panobinostat (LBH589) is mediated by direct tumor cytotoxicity and increased tumor immunogenicity. 2013

Woods, David M / Woan, Karrune / Cheng, Fengdong / Wang, Hongwei / Perez-Villarroel, Patricio / Lee, Calvin / Lienlaf, Maritza / Atadja, Peter / Seto, Edward / Weber, Jeffrey / Sotomayor, Eduardo M / Villagra, Alejandro. ·Department of Immunology, H Lee Moffitt Cancer and Research Institute, Tampa, Florida 33612, USA. ·Melanoma Res · Pubmed #23963286.

ABSTRACT: Melanoma is the deadliest skin cancer, and its incidence has been increasing faster than any other cancer. Although immunogenic, melanoma is not effectively cleared by host immunity. In this study, we investigate the therapeutic, antimelanoma potential of the histone deacetylase inhibitor (HDACi) panobinostat (LBH589) by assessing both its cytotoxic effects on melanoma cells as well as enhancement of immune recognition of melanoma. Utilizing murine and human melanoma cell lines, we analyzed the effects of LBH589 on proliferation and survival. In addition, we analyzed the expression of several immunologically relevant surface markers and melanoma differentiation antigens, and the ability of LBH589-treated melanoma to activate antigen-specific T cells. Finally, we assessed the in-vivo effects of LBH589 in a mouse melanoma model. Low nanomolar concentrations of LBH589 inhibit the growth of all melanoma cell lines tested, but not normal melanocytes. This inhibition is characterized by increased apoptosis as well as a G1 cell cycle arrest. In addition, LBH589 augments the expression of major histocompatibility complex and costimulatory molecules on melanoma cells leading to an increased ability to activate antigen-specific T cells. Treatment also increases expression of melanoma differentiation antigens. In vivo, LBH589 treatment of melanoma-bearing mice results in a significant increase in survival. However, in immunodeficient mice, the therapeutic effect of LBH589 is lost. Taken together, LBH589 exerts a dual effect upon melanoma cells by affecting not only growth/survival but also by increasing melanoma immunogenicity. These effects provide the framework for future evaluation of this HDAC inhibitor in melanoma treatment.

22 Article Co-stimulation through 4-1BB/CD137 improves the expansion and function of CD8(+) melanoma tumor-infiltrating lymphocytes for adoptive T-cell therapy. 2013

Chacon, Jessica Ann / Wu, Richard C / Sukhumalchandra, Pariya / Molldrem, Jeffrey J / Sarnaik, Amod / Pilon-Thomas, Shari / Weber, Jeffrey / Hwu, Patrick / Radvanyi, Laszlo. ·Department of Melanoma Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA. ·PLoS One · Pubmed #23560068.

ABSTRACT: Adoptive T-cell therapy (ACT) using tumor-infiltrating lymphocytes (TIL) can induce tumor regression in up to 50% or more of patients with unresectable metastatic melanoma. However, current methods to expand melanoma TIL, especially the "rapid expansion protocol" (REP) were not designed to enhance the generation of optimal effector-memory CD8(+) T cells for infusion. One approach to this problem is to manipulate specific co-stimulatory signaling pathways to enhance CD8(+) effector-memory T-cell expansion. In this study, we determined the effects of activating the TNF-R family member 4-1BB/CD137, specifically induced in activated CD8(+) T cells, on the yield, phenotype, and functional activity of expanded CD8(+) T cells during the REP. We found that CD8(+) TIL up-regulate 4-1BB expression early during the REP after initial TCR stimulation, but neither the PBMC feeder cells in the REP or the activated TIL expressed 4-1BB ligand. However, addition of an exogenous agonistic anti-4-1BB IgG4 (BMS 663513) to the REP significantly enhanced the frequency and total yield of CD8(+) T cells as well as their maintenance of CD28 and increased their anti-tumor CTL activity. Gene expression analysis found an increase in bcl-2 and survivin expression induced by 4-1BB that was associated with an enhanced survival capability of CD8(+) post-REP TIL when re-cultured in the absence or presence of cytokines. Our findings suggest that adding an agonistic anti-4-1BB antibody during the time of TIL REP initiation produces a CD8(+) T cell population capable of improved effector function and survival. This may greatly improve TIL persistence and anti-tumor activity in vivo after adoptive transfer into patients.

23 Article PD1 blockade reverses the suppression of melanoma antigen-specific CTL by CD4+ CD25(Hi) regulatory T cells. 2009

Wang, Wenshi / Lau, Roy / Yu, Daohai / Zhu, Weiwei / Korman, Alan / Weber, Jeffrey. ·Donald A Adam Comprehensive Melanoma Research Center, Department of Immunology and Immunotherapy, Moffitt Cancer Center, 12902 Magnolia Drive, SRB-24324, Tampa, FL 33612, USA. wenshi.wang@moffitt.org ·Int Immunol · Pubmed #19651643.

ABSTRACT: Regulatory CD4(+)CD25(Hi) T cells (Treg) and programmed death-1 (PD-1) molecule have emerged as pivotal players in immune regulation. However, the underlying mechanisms by which they impact antigen-specific CD8(+) immune responses in cancer patients and how they interact with each other under physiologic conditions remain unclear. Herein, we examined the relationship of PD-1 and its abrogation to the function of Treg in patients with melanoma using short-term in vitro assays to generate melanoma-specific T cells. We identified Treg in the circulation of vaccinated melanoma patients and detected PD-1 expression on vaccine-induced melanoma antigen-specific CTLs, as well as on and within Treg from patients' peripheral blood. Programmed death ligand (PD-L) 1 expression was also detected on patients' Treg. PD-1 blockade promoted the generation of melanoma antigen-specific CTLs and masked their inhibition by Treg. The mechanisms by which PD-1 blockade mediated immune enhancement included direct augmentation of melanoma antigen-specific CTL proliferation, heightening their resistance to inhibition by Treg and direct limitation of the inhibitory ability of Treg. PD-1 blockade reversed the increased expression of PD-1 and PD-L1 on melanoma antigen-specific CTL by Treg, rescued INF-gamma and IL-2 or INF-gamma and tumor necrosis factor-alpha co-expression and expression of IL-7 receptor by melanoma antigen-specific CTL which were diminished by Treg. PD-1 blockade also resulted in down-regulation of intracellular FoxP3 expression by Treg. These data suggest that PD-1 is importantly implicated in the regulation of Treg function in melanoma patients.

24 Minor Adjuvant Therapy in Resected Melanoma. 2018

Weber, Jeffrey / Qureshi, Anila / Ascierto, Paolo A. ·New York University Perlmutter Cancer Center, New York, NY jeffrey.weber2@nyumc.org · Bristol-Myers Squibb, Princeton, NJ · Istituto Nazionale Tumori Fondazione Pascale, Naples, Italy ·N Engl J Med · Pubmed #29446288.

ABSTRACT: -- No abstract --

25 Minor Eighth American Joint Committee on Cancer (AJCC) melanoma classification: Let us reconsider stage III. 2018

Grob, Jean Jacques / Schadendorf, Dirk / Lorigan, Paul / Ascierto, Paolo / Larkin, James / Nathan, Paul / Robert, Caroline / Hauschild, Axel / Weber, Jeffrey / Daud, Adil / Hamid, Omid / Dummer, Reinhard / Hansson, Johan / Hoeller, Christoph / Schachter, Jacob / Van Akkooi, Alexander C J / Garbe, Claus. ·Aix Marseille University and APHM University-Hospital Marseille France, France. Electronic address: jean-jacques.grob@ap-hm.fr. · University of Essen and German Cancer Consortium, Heidelberg, Germany. · University of Manchester, Christie National Foundation Trust Manchester, UK. · Istituto Nazionale Tumori - Fondazione "G. Pascale", Napoli, Italy. · Royal Marsden Hospital, London, UK. · Mount Vernon Cancer Centre, UK. · Gustave Roussy and Paris-Sud University, Paris, France. · Universitätsklinikum Schleswig-Holstein, Kiel, Germany. · Laura and Isaac Perlmutter Cancer Center Professor of Medicine NYU, New-York, USA. · University of California, San Francisco, San Francisco, CA, USA. · The Angeles Clinic and Research Institute, Los Angeles, CA, USA. · University of Zurich, Zurich, Switzerland. · Karolinska University Hospital Solna, Stockholm Sweden. · Medical University of Vienna, Austria. · The Ella Lemelbaum Institute for Immuno-Oncology Division of Oncology Sheba Medical Center Tel Hashomer, Israel. · Netherlands Cancer Institute, The Netherlands. · University Hospital Tuebingen, Germany. ·Eur J Cancer · Pubmed #29224903.

ABSTRACT: -- No abstract --