1,394 results on '"MCARTHUR, GRANT A."'
Search Results
2. First-In-Human Phase I Study of the OX40 Agonist MOXR0916 in Patients with Advanced Solid Tumors.
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Kim, Tae, Burris, Howard, de Miguel Luken, Maria, Pishvaian, Michael, Bang, Yung-Jue, Gordon, Michael, Awada, Ahmad, Camidge, D, Hodi, F, McArthur, Grant, Miller, Wilson, Cervantes, Andres, Chow, Laura, Lesokhin, Alexander, Rutten, Annemie, Sznol, Mario, Rishipathak, Deepali, Chen, Shang-Chiung, Stefanich, Eric, Pourmohamad, Tony, Anderson, Maria, Kim, Jeong, Huseni, Mahrukh, Rhee, Ina, and Siu, Lillian
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Antibodies ,Monoclonal ,Humanized ,B7-H1 Antigen ,Carcinoma ,Transitional Cell ,Humans ,Lung Neoplasms ,Neoplasms ,Urinary Bladder Neoplasms - Abstract
PURPOSE: OX40, a receptor transiently expressed by T cells upon antigen recognition, is associated with costimulation of effector T cells and impairment of regulatory T-cell function. This first-in-human study evaluated MOXR0916, a humanized effector-competent agonist IgG1 monoclonal anti-OX40 antibody. PATIENTS AND METHODS: Eligible patients with locally advanced or metastatic refractory solid tumors were treated with MOXR0916 intravenously once every 3 weeks (Q3W). A 3+3 dose-escalation stage (0.2-1,200 mg; n = 34) was followed by expansion cohorts at 300 mg (n = 138) for patients with melanoma, renal cell carcinoma, non-small cell lung carcinoma, urothelial carcinoma, and triple-negative breast cancer. RESULTS: MOXR0916 was well tolerated with no dose-limiting toxicities observed. An MTD was not reached. Most patients (95%) experienced at least one adverse event (AE); 56% of AEs, mostly grade 1-2, were related to MOXR0916. Most common treatment-related AEs included fatigue (17%), diarrhea (8%), myalgia (7%), nausea (6%), decreased appetite (6%), and infusion-related reaction (5%). Pharmacokinetic (PK) parameters were dose proportional between 80 and 1,200 mg and supported Q3W administration. The recommended expansion dose based on PK and OX40 receptor saturation was 300 mg Q3W. Immune activation and upregulation of PD-L1 was observed in a subset of paired tumor biopsies. One renal cell carcinoma patient experienced a confirmed partial response. Overall, 33% of patients achieved stable disease. CONCLUSIONS: Although objective responses were rarely observed with MOXR0916 monotherapy, the favorable safety profile and evidence of tumor immune activation in a subset of patients support further investigation in combination with complementary agents such as PD-1/PD-L1 antagonists.
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- 2022
3. Statin use in resected, high-risk cutaneous melanoma: A multi-centre retrospective cohort study
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Wang, Charlie Yue, Shackleton, Mark, Mailer, Sonia, McArthur, Grant A., Zoungas, Sophia, Wolfe, Rory, and Mar, Victoria J.
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- 2024
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4. Designing a wholly online, multidisciplinary Master of Cancer Sciences degree
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Lai-Kwon, Julia, Dushyanthen, Sathana, Seignior, David, Barrett, Michelle, Buisman-Pijlman, Femke, Buntine, Andrew, Woodward-Kron, Robyn, McArthur, Grant, and Kok, David L
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- 2023
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5. The side effect registry immuno-oncology (SERIO) – A tool for systematic analysis of immunotherapy-induced side effects
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Ertl, Carolin, Ruf, Theresa, Mentzer, Dirk, Kong, Mingzi, Kramer, Rafaela, Bergwelt-Baildon, Michael von, Subklewe, Marion, Tomsitz, Dirk, Ascierto, Paolo A., Dummer, Reinhard, Gogas, Helen, Lebbé, Celeste, Long, Georgina V., McArthur, Grant, Neilan, Tomas G., Ribas, Antoni, Robert, Caroline, Schadendorf, Dirk, Zimmer, Lisa, Eigentler, Thomas, Grabbe, Stephan, Forschner, Andrea, Kähler, Katharina C., Milani, Valeria, Pföhler, Claudia, Hassel, Jessica, Gutzmer, Ralf, Loquai, Carmen, Routy, Bertrand, Furness, Andrew J.S., Blank, Christian, Wolchok, Jedd D., French, Lars E., Hauschild, Axel, and Heinzerling, Lucie
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- 2024
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6. 5-Year Outcomes with Cobimetinib plus Vemurafenib in BRAFV600 Mutation–Positive Advanced Melanoma: Extended Follow-up of the coBRIM Study5-Year Outcomes with Cobimetinib + Vemurafenib in Melanoma
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Ascierto, Paolo A, Dréno, Brigitte, Larkin, James, Ribas, Antoni, Liszkay, Gabriella, Maio, Michele, Mandalà, Mario, Demidov, Lev, Stroyakovskiy, Daniil, Thomas, Luc, de la Cruz-Merino, Luis, Atkinson, Victoria, Dutriaux, Caroline, Garbe, Claus, Hsu, Jessie, Jones, Surai, Li, Haocheng, McKenna, Edward, Voulgari, Athina, and McArthur, Grant A
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Clinical Research ,Clinical Trials and Supportive Activities ,Cancer ,Evaluation of treatments and therapeutic interventions ,6.1 Pharmaceuticals ,Antineoplastic Combined Chemotherapy Protocols ,Azetidines ,Follow-Up Studies ,Humans ,Melanoma ,Mutation ,Piperidines ,Proto-Oncogene Proteins B-raf ,Skin Neoplasms ,Vemurafenib ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
PurposeThe randomized phase III coBRIM study (NCT01689519) demonstrated improved progression-free survival (PFS) and overall survival (OS) with addition of cobimetinib to vemurafenib compared with vemurafenib in patients with previously untreated BRAFV600 mutation-positive advanced melanoma. We report long-term follow-up of coBRIM, with at least 5 years since the last patient was randomized.Patients and methodsEligible patients were randomized 1:1 to receive either oral cobimetinib (60 mg once daily on days 1-21 in each 28-day cycle) or placebo in combination with oral vemurafenib (960 mg twice daily).Results495 patients were randomized to cobimetinib plus vemurafenib (n = 247) or placebo plus vemurafenib (n = 248). Median follow-up was 21.2 months for cobimetinib plus vemurafenib and 16.6 months for placebo plus vemurafenib. Median OS was 22.5 months (95% CI, 20.3-28.8) with cobimetinib plus vemurafenib and 17.4 months (95% CI, 15.0-19.8) with placebo plus vemurafenib; 5-year OS rates were 31% and 26%, respectively. Median PFS was 12.6 months (95% CI, 9.5-14.8) with cobimetinib plus vemurafenib and 7.2 months (95% CI, 5.6-7.5) with placebo plus vemurafenib; 5-year PFS rates were 14% and 10%, respectively. OS and PFS were longest in patients with normal baseline lactate dehydrogenase levels and low tumor burden, and in those achieving complete response. The safety profile remained consistent with previously published reports.ConclusionsExtended follow-up of coBRIM confirms the long-term clinical benefit and safety profile of cobimetinib plus vemurafenib compared with vemurafenib monotherapy in patients with BRAFV600 mutation-positive advanced melanoma.
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- 2021
7. A tailored approach to horizon scanning for cancer medicines
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Soon, Jennifer A., To, Yat Hang, Alexander, Marliese, Trapani, Karen, Ascierto, Paolo A., Athan, Sophy, Brown, Michael P., Burge, Matthew, Haydon, Andrew, Hughes, Brett, Itchins, Malinda, John, Thomas, Kao, Steven, Koopman, Miriam, Li, Bob T., Long, Georgina V., Loree, Jonathan M., Markman, Ben, Meniawy, Tarek M., Menzies, Alexander M., Nott, Louise, Pavlakis, Nick, Petrella, Teresa M., Popat, Sanjay, Tie, Jeanne, Xu, Wen, Yip, Desmond, Zalcberg, John, Solomon, Benjamin J., Gibbs, Peter, McArthur, Grant A., Franchini, Fanny, and IJzerman, Maarten
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- 2023
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8. Impact of initial treatment and prognostic factors on postprogression survival in BRAF-mutated metastatic melanoma treated with dacarbazine or vemurafenib ± cobimetinib: a pooled analysis of four clinical trials
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Ascierto, Paolo A, Ribas, Antoni, Larkin, James, McArthur, Grant A, Lewis, Karl D, Hauschild, Axel, Flaherty, Keith T, McKenna, Edward, Zhu, Qian, Mun, Yong, and Dréno, Brigitte
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Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Immunology ,Cancer ,Clinical Trials and Supportive Activities ,Clinical Research ,Evaluation of treatments and therapeutic interventions ,6.1 Pharmaceuticals ,Antineoplastic Combined Chemotherapy Protocols ,Azetidines ,Dacarbazine ,Humans ,Melanoma ,Mutation ,Piperidines ,Prognosis ,Proto-Oncogene Proteins B-raf ,Skin Neoplasms ,Vemurafenib ,Cobimetinib ,Survival analysis ,Medical and Health Sciences ,Biomedical and clinical sciences ,Health sciences - Abstract
BackgroundWe sought to identify patient subgroups with distinct postprogression overall survival (ppOS) outcomes and investigate the impact of original treatment assignment and initial postprogression treatment (ppRx) on ppOS.MethodsRecursive partitioning analysis (RPA) was performed to model relationships between prespecified covariates and ppOS in patients with BRAFV600-mutated metastatic melanoma who had experienced progressive disease (PD) following treatment with cobimetinib plus vemurafenib, vemurafenib monotherapy, or dacarbazine in the BRIM-2, BRIM-3, BRIM-7, and coBRIM studies. Prognostic subgroups identified by RPA were then applied to pooled treatment cohorts. The primary endpoint was ppOS, defined as time from first PD to death from any cause.ResultsRPA identified baseline lactate dehydrogenase (LDH), baseline disease stage, Eastern Cooperative Oncology Group performance status at PD, and ppRx as significant prognostic factors for ppOS. Median ppOS was longest in patients with normal baseline LDH, stage M1c disease at baseline, and ppRx with immunotherapy or targeted therapy (12.2 months; 95% CI 10.3-16.1) and shortest in those with elevated baseline LDH > 2 × upper limit of normal (2.3 months; 95% CI 1.8-2.7). Original treatment assignment did not impact ppOS. Across treatment cohorts, patients treated with immunotherapy or targeted therapy after PD had better ppOS than those given other treatments.ConclusionA combination of factors at baseline (LDH, disease stage) and PD (performance status, ppRx) impact ppOS outcomes. ppRx with immunotherapy or targeted therapy is an independent prognostic factor for improved overall survival following progression regardless of original treatment. Trial registration The trials included in this analysis are registered with ClinicalTrials.gov: NCT00949702 (BRIM-2), NCT01006980 (BRIM-3), NCT01271803 (BRIM-7), and NCT01689519 (coBRIM).
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- 2020
9. Impact of depth of response on survival in patients treated with cobimetinib ± vemurafenib: pooled analysis of BRIM-2, BRIM-3, BRIM-7 and coBRIM
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Lewis, Karl D, Larkin, James, Ribas, Antoni, Flaherty, Keith T, McArthur, Grant A, Ascierto, Paolo A, Dréno, Brigitte, Yan, Yibing, Wongchenko, Matthew, McKenna, Edward, Zhu, Qian, Mun, Yong, and Hauschild, Axel
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Cancer ,Genetics ,Administration ,Oral ,Antineoplastic Agents ,Antineoplastic Combined Chemotherapy Protocols ,Azetidines ,Clinical Trials as Topic ,Gene Expression ,Humans ,Injections ,Intravenous ,Kaplan-Meier Estimate ,Melanoma ,Mitogen-Activated Protein Kinase Kinases ,Multicenter Studies as Topic ,Piperidines ,Placebos ,Progression-Free Survival ,Proto-Oncogene Proteins B-raf ,Randomized Controlled Trials as Topic ,Time Factors ,Treatment Outcome ,Tumor Burden ,Vemurafenib ,Public Health and Health Services ,Oncology & Carcinogenesis ,Oncology and carcinogenesis - Abstract
BackgroundThis pooled analysis investigated the prognostic value of depth of response in two cohorts of patients with BRAFV600-mutated metastatic melanoma treated with vemurafenib or cobimetinib plus vemurafenib.MethodsThe data were pooled from BRIM-2, BRIM-3, BRIM-7 and coBRIM. Association of depth of response with survival was estimated by Cox proportional hazards regression, adjusted for clinically relevant covariates. Depth of response was analysed in previously identified prognostic subgroups based on disease characteristics and gene signatures.ResultsGreater tumour reduction and longer time to maximal response were significantly associated with longer progression-free survival (PFS) and overall survival (OS) when evaluated as continuous variables. Patients with the deepest responses had long-lasting survival outcomes (median PFS: 14 months; OS: 32 months with vemurafenib; not estimable with cobimetinib plus vemurafenib). Cobimetinib plus vemurafenib improved depth of response versus vemurafenib monotherapy regardless of other prognostic factors, including gene signatures.ConclusionsGreater depth of response was associated with improved survival, supporting its utility as a measure of treatment efficacy in melanoma and further evaluation of its incorporation into existing prognostic models. Cobimetinib plus vemurafenib improved outcomes across quartiles of response regardless of prognostic factors or gene signatures and provided durable survival benefits in patients with deep responses.
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- 2019
10. Overall survival with first-line atezolizumab in combination with vemurafenib and cobimetinib in BRAFV600 mutation-positive advanced melanoma (IMspire150): second interim analysis of a multicentre, randomised, phase 3 study
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Ascierto, Paolo A, Stroyakovskiy, Daniil, Gogas, Helen, Robert, Caroline, Lewis, Karl, Protsenko, Svetlana, Pereira, Rodrigo P, Eigentler, Thomas, Rutkowski, Piotr, Demidov, Lev, Zhukova, Natalia, Schachter, Jacob, Yan, Yibing, Caro, Ivor, Hertig, Christian, Xue, Cloris, Kusters, Lieke, McArthur, Grant A, and Gutzmer, Ralf
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- 2023
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11. Triplet Therapy in Melanoma — Combined BRAF/MEK Inhibitors and Anti-PD-(L)1 Antibodies
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Dixon-Douglas, Julia R., Patel, Riyaben P., Somasundram, Pretashini M., and McArthur, Grant A.
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- 2022
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12. Clinical validation and implementation of droplet digital PCR for the detection of BRAF mutations from cell-free DNA
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Arnolda, Rainier, Howlett, Kerryn, Chan, Timmy, Raleigh, Jeanette, Hatzimihalis, Athena, Bell, Anthony, Fellowes, Andrew, Sandhu, Shahneen, McArthur, Grant A., Fox, Stephen B., Dawson, Sarah-Jane, Hewitt, Chelsee, Jones, Kate, and Wong, Stephen Q.
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- 2022
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13. Genomic Features of Exceptional Response in Vemurafenib ± Cobimetinib–treated Patients with BRAFV600-mutated Metastatic Melanoma
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Yan, Yibing, Wongchenko, Matthew J, Robert, Caroline, Larkin, James, Ascierto, Paolo A, Dréno, Brigitte, Maio, Michele, Garbe, Claus, Chapman, Paul B, Sosman, Jeffrey A, Shi, Zhen, Koeppen, Hartmut, Hsu, Jessie J, Chang, Ilsung, Caro, Ivor, Rooney, Isabelle, McArthur, Grant A, and Ribas, Antoni
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Immunology ,Human Genome ,Genetics ,Biotechnology ,Cancer ,Aetiology ,2.1 Biological and endogenous factors ,Alleles ,Antineoplastic Combined Chemotherapy Protocols ,Azetidines ,Biomarkers ,Tumor ,Clinical Trials ,Phase II as Topic ,Clinical Trials ,Phase III as Topic ,Gene Expression Profiling ,Genomics ,Humans ,Melanoma ,Mutation ,Piperidines ,Proto-Oncogene Proteins B-raf ,Randomized Controlled Trials as Topic ,Retrospective Studies ,Treatment Outcome ,Vemurafenib ,Exome Sequencing ,Oncology & Carcinogenesis ,Clinical sciences ,Oncology and carcinogenesis - Abstract
PurposePrevious investigations identified transcriptional signatures associated with innate resistance to anti-programmed cell death protein 1 therapy in melanoma. This analysis aimed to increase understanding of the role of baseline genetic features in the variability of response to BRAF and MEK inhibitor therapy for BRAF V600-mutated metastatic melanoma.Patients and methodsThis exploratory analysis compared genomic features, using whole-exome and RNA sequencing, of baseline tumors from patients who had complete response versus rapid progression (disease progression at first postbaseline assessment) on treatment with cobimetinib combined with vemurafenib or vemurafenib alone. Associations of gene expression with progression-free survival or overall survival were assessed by Cox proportional hazards modeling.ResultsWhole-exome sequencing showed that MITF and TP53 alterations were more frequent in tumors from patients with rapid progression, while NF1 alterations were more frequent in tumors from patients with complete response. However, the low frequency of alterations in any one gene precluded their characterization as drivers of response/resistance. Analysis of RNA profiles showed that expression of immune response-related genes was enriched in tumors from patients with complete response, while expression of keratinization-related genes was enriched in tumors from patients who experienced rapid progression.ConclusionsThese findings suggest that enriched immune infiltration might be a shared feature favoring response to both targeted and immune therapies, while features of innate resistance to targeted and immune therapies were distinct.
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- 2019
14. Checkpoint Inhibitors in the Treatment of Metastatic Melanoma : Mechanisms of Resistance to Checkpoint Immunotherapy
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Weppler, Alison, Lau, Peter, McArthur, Grant A., Balch, Charles M., editor, Atkins, Michael B., editor, Garbe, Claus, editor, Gershenwald, Jeffrey E., editor, Halpern, Allan C., editor, Kirkwood, John M., editor, McArthur, Grant A., editor, Thompson, John F., editor, and Sober, Arthur J., editor
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- 2020
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15. Molecularly Targeted Therapy for Patients with BRAF Wild-Type Melanoma
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Chandra, Sunandana, McArthur, Grant A., Sosman, Jeffrey, Balch, Charles M., editor, Atkins, Michael B., editor, Garbe, Claus, editor, Gershenwald, Jeffrey E., editor, Halpern, Allan C., editor, Kirkwood, John M., editor, McArthur, Grant A., editor, Thompson, John F., editor, and Sober, Arthur J., editor
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- 2020
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16. Harnessing the immunotherapeutic potential of CDK4/6 inhibitors in melanoma: is timing everything?
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Lelliott, Emily J., Sheppard, Karen E., and McArthur, Grant A.
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- 2022
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17. Adaptive translational reprogramming of metabolism limits the response to targeted therapy in BRAFV600 melanoma
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Smith, Lorey K., Parmenter, Tiffany, Kleinschmidt, Margarete, Kusnadi, Eric P., Kang, Jian, Martin, Claire A., Lau, Peter, Patel, Riyaben, Lorent, Julie, Papadopoli, David, Trigos, Anna, Ward, Teresa, Rao, Aparna D., Lelliott, Emily J., Sheppard, Karen E., Goode, David, Hicks, Rodney J., Tiganis, Tony, Simpson, Kaylene J., Larsson, Ola, Blythe, Benjamin, Cullinane, Carleen, Wickramasinghe, Vihandha O., Pearson, Richard B., and McArthur, Grant A.
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- 2022
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18. BRAF mutation testing for patients diagnosed with stage III or stage IV melanoma: practical guidance for the Australian setting
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Scolyer, Richard A., Atkinson, Victoria, Gyorki, David E., Lambie, Duncan, O'Toole, Sandra, Saw, Robyn P.M., Amanuel, Benhur, Angel, Christopher M., Button-Sloan, Alison E., Carlino, Matteo S., Ch'ng, Sydney, Colebatch, Andrew J., Daneshvar, Dariush, Pires da Silva, Inês, Dawson, Tamara, Ferguson, Peter M., Foster-Smith, Erwin, Fox, Stephen B., Gill, Anthony J., Gupta, Ruta, Henderson, Michael A., Hong, Angela M., Howle, Julie R., Jackett, Louise A., James, Craig, Lee, C. Soon, Lochhead, Alistair, Loh, Daphne, McArthur, Grant A., McLean, Catriona A., Menzies, Alexander M., Nieweg, Omgo E., O'Brien, Blake H., Pennington, Thomas E., Potter, Alison J., Prakash, Saurabh, Rawson, Robert V., Read, Rebecca L., Rtshiladze, Michael A., Shannon, Kerwin F., Smithers, B. Mark, Spillane, Andrew J., Stretch, Jonathan R., Thompson, John F., Tucker, Paul, Varey, Alexander H.R., Vilain, Ricardo E., Wood, Benjamin A., and Long, Georgina V.
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- 2022
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19. Patient Experience of Complex Genomic Sequencing Exploring Patient Preference, Barriers, and Enablers for Delivery.
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Smith, Kortnye, O'Haire, Sophie, Markman, Benjamin, Gan, Hui K., O'Byrne, Kenneth, Millward, Michael, Tran, Ben, Solomon, Benjamin J., Scott, Clare, Kee, Damien, McArthur, Grant, Fellowes, Andrew, Khoung-Quang, Dong Anh K., Ekert, Paul, James, Paul, Xu, Huiling, Martyn, Melissa, Lynch, Elly, Weerasuriya, Rona, and Gaff, Clara
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CANCER patients ,PATIENT experience ,PATIENTS' attitudes ,CANCER patient care ,PATIENT preferences - Abstract
PURPOSE: Despite increasing evidence of benefit supporting complex genomic sequencing (CGS) in personalizing cancer therapy, its widespread uptake remains limited. METHODS: This mixed-methods, prospective cross-institutional demonstration study was designed to evaluate implementation of CGS in the care of patients with advanced cancer. DNA sequencing was undertaken on formalin-fixed paraffin-embedded tumor and matched blood was completed with the Peter MacCallum Cancer Centre Comprehensive Cancer Panel; 391 genes via central laboratory. Oncologists performed consent and result delivery. Patients completed pre- and post-test surveys, including validated and study-specific questions and, if eligible, semistructured interviews. Qualitative interviews were undertaken with study clinicians to evaluate processes. RESULTS: One hundred ninety-nine (63%) had ≥1 finding with the potential to affect management, including 172 (55%) whose finding could affect their treatment options, 25 (8%) whose test led to the resolution of diagnostic ambiguity, and 49 (16%) with a pathogenic germline variant. In 6-month follow-up, 50 (16%) participants had their subsequent therapy changed on the basis of their CGS results. Two hundred ninety-three (88% of adult patients) completed surveys at three time points. At consent, patients cited multifaceted value in testing, showed good understanding of basic concepts, but most (69%) overestimated the likelihood of result-led change. Post-test patients remained consistently satisfied with accessing CGS. 21% struggled with understanding results but there were low levels of decisional regret after participation (89% had nil/mild regret). Clinicians cited collaboration and communication as critical to delivery. CONCLUSION: Patients undergoing CGS are generally satisfied and place value on its use beyond potential therapeutic benefit. Our results suggest that to improve test utility and delivery of CGS with value to patients and investing institutions, focus must be placed on addressing the additional barriers to its wider implications including efforts to improve process efficiencies, clinician genomic literacy, and decision-making support. [ABSTRACT FROM AUTHOR]
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- 2024
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20. CX-5461 Preferentially Induces Top2α-Dependent DNA Breaks at Ribosomal DNA Loci.
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Cameron, Donald P., Sornkom, Jirawas, Alsahafi, Sameerh, Drygin, Denis, Poortinga, Gretchen, McArthur, Grant A., Hein, Nadine, Hannan, Ross, and Panov, Konstantin I.
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DNA repair ,RIBOSOMAL DNA ,RNA polymerases ,DNA damage ,GENETIC transcription - Abstract
While genotoxic chemotherapeutic agents are among the most effective tools to combat cancer, they are often associated with severe adverse effects caused by indiscriminate DNA damage in non-tumor tissue as well as increased risk of secondary carcinogenesis. This study builds on our previous work demonstrating that the RNA Polymerase I (Pol I) transcription inhibitor CX-5461 elicits a non-canonical DNA damage response and our discovery of a critical role for Topoisomerase 2α (Top2α) in the initiation of Pol I-dependent transcription. Here, we identify Top2α as a mediator of CX-5461 response in the murine Eµ-Myc B lymphoma model whereby sensitivity to CX-5461 is dependent on cellular Top2α expression/activity. Most strikingly, and in contrast to canonical Top2α poisons, we found that the Top2α-dependent DNA damage induced by CX-5461 is preferentially localized at the ribosomal DNA (rDNA) promoter region, thereby highlighting CX-5461 as a loci-specific DNA damaging agent. This mechanism underpins the efficacy of CX-5461 against certain types of cancer and can be used to develop effective non-genotoxic anticancer drugs. [ABSTRACT FROM AUTHOR]
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- 2024
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21. Oncogenic Signaling Pathways in The Cancer Genome Atlas
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Sanchez-Vega, Francisco, Mina, Marco, Armenia, Joshua, Chatila, Walid K, Luna, Augustin, La, Konnor C, Dimitriadoy, Sofia, Liu, David L, Kantheti, Havish S, Saghafinia, Sadegh, Chakravarty, Debyani, Daian, Foysal, Gao, Qingsong, Bailey, Matthew H, Liang, Wen-Wei, Foltz, Steven M, Shmulevich, Ilya, Ding, Li, Heins, Zachary, Ochoa, Angelica, Gross, Benjamin, Gao, Jianjiong, Zhang, Hongxin, Kundra, Ritika, Kandoth, Cyriac, Bahceci, Istemi, Dervishi, Leonard, Dogrusoz, Ugur, Zhou, Wanding, Shen, Hui, Laird, Peter W, Way, Gregory P, Greene, Casey S, Liang, Han, Xiao, Yonghong, Wang, Chen, Iavarone, Antonio, Berger, Alice H, Bivona, Trever G, Lazar, Alexander J, Hammer, Gary D, Giordano, Thomas, Kwong, Lawrence N, McArthur, Grant, Huang, Chenfei, Tward, Aaron D, Frederick, Mitchell J, McCormick, Frank, Meyerson, Matthew, Network, The Cancer Genome Atlas Research, Caesar-Johnson, Samantha J, Demchok, John A, Felau, Ina, Kasapi, Melpomeni, Ferguson, Martin L, Hutter, Carolyn M, Sofia, Heidi J, Tarnuzzer, Roy, Wang, Zhining, Yang, Liming, Zenklusen, Jean C, Zhang, Jiashan, Chudamani, Sudha, Liu, Jia, Lolla, Laxmi, Naresh, Rashi, Pihl, Todd, Sun, Qiang, Wan, Yunhu, Wu, Ye, Cho, Juok, DeFreitas, Timothy, Frazer, Scott, Gehlenborg, Nils, Getz, Gad, Heiman, David I, Kim, Jaegil, Lawrence, Michael S, Lin, Pei, Meier, Sam, Noble, Michael S, Saksena, Gordon, Voet, Doug, Zhang, Hailei, Bernard, Brady, Chambwe, Nyasha, Dhankani, Varsha, Knijnenburg, Theo, Kramer, Roger, Leinonen, Kalle, Liu, Yuexin, Miller, Michael, Reynolds, Sheila, Thorsson, Vesteinn, Zhang, Wei, Akbani, Rehan, Broom, Bradley M, Hegde, Apurva M, and Ju, Zhenlin
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Biochemistry and Cell Biology ,Bioinformatics and Computational Biology ,Biological Sciences ,Biomedical and Clinical Sciences ,Genetics ,Oncology and Carcinogenesis ,Human Genome ,Cancer ,Cancer Genomics ,2.1 Biological and endogenous factors ,Good Health and Well Being ,Databases ,Genetic ,Genes ,Neoplasm ,Humans ,Neoplasms ,Phosphatidylinositol 3-Kinases ,Signal Transduction ,Transforming Growth Factor beta ,Tumor Suppressor Protein p53 ,Wnt Proteins ,Cancer Genome Atlas Research Network ,PanCanAtlas ,TCGA ,cancer genome atlas ,cancer genomics ,combination therapy ,pan-cancer ,precision oncology ,signaling pathways ,therapeutics ,whole exome sequencing ,Medical and Health Sciences ,Developmental Biology ,Biological sciences ,Biomedical and clinical sciences - Abstract
Genetic alterations in signaling pathways that control cell-cycle progression, apoptosis, and cell growth are common hallmarks of cancer, but the extent, mechanisms, and co-occurrence of alterations in these pathways differ between individual tumors and tumor types. Using mutations, copy-number changes, mRNA expression, gene fusions and DNA methylation in 9,125 tumors profiled by The Cancer Genome Atlas (TCGA), we analyzed the mechanisms and patterns of somatic alterations in ten canonical pathways: cell cycle, Hippo, Myc, Notch, Nrf2, PI-3-Kinase/Akt, RTK-RAS, TGFβ signaling, p53 and β-catenin/Wnt. We charted the detailed landscape of pathway alterations in 33 cancer types, stratified into 64 subtypes, and identified patterns of co-occurrence and mutual exclusivity. Eighty-nine percent of tumors had at least one driver alteration in these pathways, and 57% percent of tumors had at least one alteration potentially targetable by currently available drugs. Thirty percent of tumors had multiple targetable alterations, indicating opportunities for combination therapy.
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- 2018
22. Health-related quality of life impact of cobimetinib in combination with vemurafenib in patients with advanced or metastatic BRAFV600 mutation–positive melanoma
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Dréno, Brigitte, Ascierto, Paolo A, Atkinson, Victoria, Liszkay, Gabriella, Maio, Michele, Mandalà, Mario, Demidov, Lev, Stroyakovskiy, Daniil, Thomas, Luc, de la Cruz-Merino, Luis, Dutriaux, Caroline, Garbe, Claus, Bartley, Karen, Karagiannis, Thomas, Chang, Ilsung, Rooney, Isabelle, Koralek, Daniel O, Larkin, James, McArthur, Grant A, and Ribas, Antoni
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Clinical Research ,Cancer ,Antineoplastic Combined Chemotherapy Protocols ,Azetidines ,Double-Blind Method ,Female ,Humans ,Longitudinal Studies ,Male ,Melanoma ,Mutation ,Piperidines ,Placebos ,Proto-Oncogene Proteins B-raf ,Quality of Life ,Vemurafenib ,vemurafenib ,cobimetinib ,MEK inhibitor ,BRAF inhibitor ,HRQOL ,EORTC QLQ-C30 ,metastatic melanoma ,Public Health and Health Services ,Oncology & Carcinogenesis ,Oncology and carcinogenesis - Abstract
BackgroundIn the coBRIM study, cobimetinib plus vemurafenib (C+V) significantly improved survival outcomes vs placebo and vemurafenib (P+V) in patients with advanced/metastatic BRAFV600-mutated melanoma. An analysis of health-related quality of life (HRQOL) from coBRIM is reported.MethodsPatients completing the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (QLQ-C30) at baseline and ⩾1 time point thereafter constituted the analysis population. Change from baseline ⩾10 points was considered clinically meaningful.ResultsMean baseline scores for all QLQ-C30 domains were similar between arms. Most on-treatment scores for QLQ-C30 domains were also comparable between arms. A transient deterioration in role function in cycle 1 day 15 (C1D15; -14.7 points) in the P+V arm and improvement in insomnia in the C+V arm at C2D15 (-12.4 points) was observed. Among patients who experienced a ⩾10-point change from baseline (responders), between-group differences were greatest for insomnia (16%), social functioning (10%), fatigue (9%) and pain (7%), all favouring C+V. Diarrhoea, photosensitivity reaction, pyrexia, and rash did not meaningfully affect global health status (GHS). Serous retinopathy was associated with a transient decrease in GHS at C1D15 assessment.ConclusionsIn patients with advanced/metastatic BRAFV600-mutated melanoma, treatment with C+V maintained HRQOL compared with P+V, with superior efficacy.
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- 2018
23. Clinical features of serous retinopathy observed with cobimetinib in patients with BRAF-mutated melanoma treated in the randomized coBRIM study
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de la Cruz-Merino, Luis, Di Guardo, Lorenza, Grob, Jean-Jacques, Venosa, Alfredo, Larkin, James, McArthur, Grant A, Ribas, Antoni, Ascierto, Paolo A, Evans, Jeffrey TR, Gomez-Escobar, Antonio, Barteselli, Giulio, Eng, Susan, Hsu, Jessie J, Uyei, Anne, and Dréno, Brigitte
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Eye Disease and Disorders of Vision ,Clinical Research ,Clinical Trials and Supportive Activities ,Cancer ,Eye ,Adult ,Aged ,Azetidines ,Central Serous Chorioretinopathy ,Female ,Humans ,Indoles ,Male ,Melanoma ,Middle Aged ,Mutation ,Piperidines ,Proto-Oncogene Proteins B-raf ,Recurrence ,Skin Neoplasms ,Sulfonamides ,Time Factors ,Vemurafenib ,Cobimetinib ,MEK inhibition ,Serous retinopathy ,Visual disturbance ,Medical and Health Sciences ,Immunology - Abstract
BackgroundSerous chorioretinopathy has been associated with MEK inhibitors, including cobimetinib. We describe the clinical features of serous retinopathy observed with cobimetinib in patients with BRAF V600-mutated melanoma treated in the Phase III coBRIM study.MethodsIn the coBRIM study, 493 patients were treated in two randomly assigned treatment groups: cobimetinib and vemurafenib (n = 247) or vemurafenib (n = 246). All patients underwent prospective ophthalmic examinations at screening, at regular intervals during the study, and whenever ocular symptoms developed. Patients with serous retinopathy were identified in the study database using a group of relevant and synonymous adverse event terms.ResultsEighty-six serous retinopathy events were reported in 70 patients (79 events in 63 cobimetinib and vemurafenib-treated patients vs seven events in seven vemurafenib-treated patients). Most patients with serous retinopathy identified by ophthalmic examination had no symptoms or had mild symptoms, among them reduced visual acuity, blurred vision, dyschromatopsia, and photophobia. Serous retinopathy usually occurred early during cobimetinib and vemurafenib treatment; median time to onset was 1.0 month. Most events were managed by observation and continuation of cobimetinib without dose modification and resolved or were resolving by the data cutoff date (19 Sept 2014).ConclusionsCobimetinib treatment was associated with serous retinopathy in patients with BRAF V600-mutated melanoma. Retinopathy was generally asymptomatic or mild. Periodic ophthalmologic evaluations at regular intervals and at the manifestation of any visual disturbance are recommended to facilitate early detection and resolution of serous retinopathy while patients are taking cobimetinib. Trial Registration Clinicaltrials.gov (NCT01689519). First received: September 18, 2012.
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- 2017
24. POLARIS: A phase 2 trial of encorafenib plus binimetinib evaluating high-dose and standard-dose regimens in patients with BRAF V600-mutant melanoma with brain metastasis
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Menzies, Alexander M, primary, Long, Georgina V, additional, Kohn, Amiee, additional, Tawbi, Hussein, additional, Weber, Jeffrey, additional, Flaherty, Keith, additional, McArthur, Grant A, additional, Ascierto, Paolo A, additional, Pfluger, Yanina, additional, Lewis, Karl, additional, Tsai, Katy K, additional, Hamid, Omid, additional, Prenen, Hans, additional, Fein, Luis, additional, Wang, Erjian, additional, Guenzel, Carolin, additional, Zhang, Fan, additional, Kleha, Joseph F, additional, di Pietro, Alessandra, additional, and Davies, Michael A, additional
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- 2024
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25. Correction: Regulation of PRMT5–MDM4 axis is critical in the response to CDK4/6 inhibitors in melanoma
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AbuHammad, Shatha, Cullinane, Carleen, Martin, Claire, Bacolas, Zoe, Ward, Teresa, Chen, Huiqin, Slater, Alison, Ardley, Kerry, Kirby, Laura, Chan, Keefe T., Brajanovski, Natalie, Smith, Lorey K., Rao, Aparna D., Lelliott, Emily J., Kleinschmidt, Margarete, Vergara, Ismael A., Papenfuss, Anthony T., Lau, Peter, Ghosh, Prerana, Haupt, Sue, Haupt, Ygal, Sanij, Elaine, Poortinga, Gretchen, Pearson, Richard B., Falk, Hendrik, Curtis, David J., Stupple, Paul, Devlin, Mark, Street, Ian, Davies, Michael A., McArthur, Grant A., and Sheppard, Karen E.
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- 2020
26. Correlation of MRI signal characteristics of intracranial melanoma metastases with BRAF mutation status
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Lasocki, Arian and McArthur, Grant A.
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- 2022
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27. A Distinct Pretreatment Immune Gene Signature in Lentigo Maligna Is Associated with Imiquimod Response
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Halse, Heloise, Caramia, Franco, McLean, Catriona A., Wang, Minyu, Aw Yeang, Han Xian, Keam, Simon P., Behren, Andreas, Ly, Lena, Haskett, Martin, Cebon, Jonathan, McArthur, Grant A., Neeson, Paul J., and Mar, Victoria J.
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- 2020
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28. Vemurafenib in patients with BRAF(V600) mutation-positive meta-static melanoma: final overall survival results of the BRIM-3 study
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Chapman, Paul B, Robert, Caroline, Larkin, James, Haanen, John B, Ribas, Antoni, Hogg, David, Hamid, Omid, Ascierto, Paolo Antonio, Testori, Alessandro, Lorigan, Paul, Dummer, Reinhard, Sosman, Jeffrey A, Flaherty, Keith T, Yue, Huibin, Coleman, Shelley, Caro, Ivor, Hauschild, Axel, and McArthur, Grant A
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Immunology ,Medical and Health Sciences - Published
- 2016
29. Melanoma and immunotherapy bridge 2015
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Nanda, Vashisht GY, Peng, Weiyi, Hwu, Patrick, Davies, Michael A, Ciliberto, Gennaro, Fattore, Luigi, Malpicci, Debora, Aurisicchio, Luigi, Ascierto, Paolo Antonio, Croce, Carlo M, Mancini, Rita, Spranger, Stefani, Gajewski, Thomas F, Wang, Yangyang, Ferrone, Soldano, Vanpouille-Box, Claire, Wennerberg, Erik, Pilones, Karsten A, Formenti, Silvia C, Demaria, Sandra, Tang, Haidong, Wang, Yang, Fu, Yang-Xin, Dummer, Reinhard, Puzanov, Igor, Tarhini, Ahmad, Chauvin, Joe-Marc, Pagliano, Ornella, Fourcade, Julien, Sun, Zhaojun, Wang, Hong, Sanders, Cindy, Kirkwood, John M, Chen, Tseng-hui Timothy, Maurer, Mark, Korman, Alan J, Zarour, Hassane M, Stroncek, David F, Huber, Veronica, Rivoltini, Licia, Thurin, Magdalena, Rau, Tilman, Lugli, Alessandro, Pagès, Franck, Camarero, Jorge, Sancho, Arantxa, Jommi, Claudio, de Coaña, Yago Pico, Wolodarski, Maria, Yoshimoto, Yuya, Gentilcore, Giusy, Poschke, Isabel, Masucci, Giuseppe V, Hansson, Johan, Kiessling, Rolf, Scognamiglio, Giosuè, Sabbatino, Francesco, Marino, Federica Zito, Anniciello, Anna Maria, Cantile, Monica, Cerrone, Margherita, Scala, Stefania, D’alterio, Crescenzo, Ianaro, Angela, Cirin, Giuseppe, Liguori, Giuseppina, Bott, Gerardo, Chapman, Paul B, Robert, Caroline, Larkin, James, Haanen, John B, Ribas, Antoni, Hogg, David, Hamid, Omid, Testori, Alessandro, Lorigan, Paul, Sosman, Jeffrey A, Flaherty, Keith T, Yue, Huibin, Coleman, Shelley, Caro, Ivor, Hauschild, Axel, McArthur, Grant A, Sznol, Mario, Callahan, Margaret K, Kluger, Harriet, Postow, Michael A, Gordan, RuthAnn, Segal, Neil H, Rizvi, Naiyer A, Lesokhin, Alexander, Atkins, Michael B, Burke, Matthew M, Ralabate, Amanda, Rivera, Angel, Kronenberg, Stephanie A, Agunwamba, Blessing, Ruisi, Mary, Horak, Christine, and Jiang, Joel
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Immunology ,Clinical Research ,Cancer ,Good Health and Well Being ,Medical and Health Sciences ,Biomedical and clinical sciences ,Health sciences - Abstract
MELANOMA BRIDGE 2015 KEYNOTE SPEAKER PRESENTATIONS Molecular and immuno-advances K1 Immunologic and metabolic consequences of PI3K/AKT/mTOR activation in melanoma Vashisht G. Y. Nanda, Weiyi Peng, Patrick Hwu, Michael A. Davies K2 Non-mutational adaptive changes in melanoma cells exposed to BRAF and MEK inhibitors help the establishment of drug resistance Gennaro Ciliberto, Luigi Fattore, Debora Malpicci, Luigi Aurisicchio, Paolo Antonio Ascierto, Carlo M. Croce, Rita Mancini K3 Tumor-intrinsic beta-catenin signaling mediates tumor-immune avoidance Stefani Spranger, Thomas F. Gajewski K4 Intracellular tumor antigens as a source of targets of antibody-based immunotherapy of melanoma Yangyang Wang, Soldano Ferrone Combination therapies K5 Harnessing radiotherapy to improve responses to immunotherapy in cancer Claire Vanpouille-Box, Erik Wennerberg, Karsten A. Pilones, Silvia C. Formenti, Sandra Demaria K6 Creating a T cell-inflamed tumor microenvironment overcomes resistance to checkpoint blockade Haidong Tang, Yang Wang, Yang-Xin Fu K7 Biomarkers for treatment decisions? Reinhard Dummer K8 Combining oncolytic therapies in the era of checkpoint inhibitors Igor Puzanov K9 Immune checkpoint blockade for melanoma: should we combine or sequence ipilimumab and PD-1 antibody therapy? Michael A. Postow News in immunotherapy K10 An update on adjuvant and neoadjuvant therapy for melanom Ahmad Tarhini K11 Targeting multiple inhibitory receptors in melanoma Joe-Marc Chauvin, Ornella Pagliano, Julien Fourcade, Zhaojun Sun, Hong Wang, Cindy Sanders, John M. Kirkwood, Tseng-hui Timothy Chen, Mark Maurer, Alan J. Korman, Hassane M. Zarour K12 Improving adoptive immune therapy using genetically engineered T cells David F. Stroncek Tumor microenvironment and biomarkers K13 Myeloid cells and tumor exosomes: a crosstalk for assessing immunosuppression? Veronica Huber, Licia Rivoltini K14 Update on the SITC biomarker taskforce: progress and challenges Magdalena Thurin World-wide immunoscore task force: an update K15 The immunoscore in colorectal cancer highlights the importance of digital scoring systems in surgical pathology Tilman Rau, Alessandro Lugli K16 The immunoscore: toward an integrated immunomonitoring from the diagnosis to the follow up of cancer’s patients Franck Pagès Economic sustainability of melanoma treatments: regulatory, health technology assessment and market access issues K17 Nivolumab, the regulatory experience in immunotherapy Jorge Camarero, Arantxa Sancho K18 Evidence to optimize access for immunotherapies Claudio Jommi ORAL PRESENTATIONS Molecular and immuno-advances O1 Ipilimumab treatment results in CD4 T cell activation that is concomitant with a reduction in Tregs and MDSCs Yago Pico de Coaña, Maria Wolodarski, Yuya Yoshimoto, Giusy Gentilcore, Isabel Poschke, Giuseppe V. Masucci, Johan Hansson, Rolf Kiessling O2 Evaluation of prognostic and therapeutic potential of COX-2 and PD-L1 in primary and metastatic melanoma Giosuè Scognamiglio, Francesco Sabbatino, Federica Zito Marino, Anna Maria Anniciello, Monica Cantile, Margherita Cerrone, Stefania Scala, Crescenzo D’alterio, Angela Ianaro, Giuseppe Cirino, Paolo Antonio Ascierto, Giuseppina Liguori, Gerardo Botti O3 Vemurafenib in patients with BRAFV600 mutation–positive metastatic melanoma: final overall survival results of the BRIM-3 study Paul B. Chapman, Caroline Robert, James Larkin, John B. Haanen, Antoni Ribas, David Hogg, Omid Hamid, Paolo Antonio Ascierto, Alessandro Testori, Paul Lorigan, Reinhard Dummer, Jeffrey A. Sosman, Keith T. Flaherty, Huibin Yue, Shelley Coleman, Ivor Caro, Axel Hauschild, Grant A. McArthur O4 Updated survival, response and safety data in a phase 1 dose-finding study (CA209-004) of concurrent nivolumab (NIVO) and ipilimumab (IPI) in advanced melanoma Mario Sznol, Margaret K. Callahan, Harriet Kluger, Michael A. Postow, RuthAnn Gordan, Neil H. Segal, Naiyer A. Rizvi, Alexander Lesokhin, Michael B. Atkins, John M. Kirkwood, Matthew M. Burke, Amanda Ralabate, Angel Rivera, Stephanie A. Kronenberg, Blessing Agunwamba, Mary Ruisi, Christine Horak, Joel Jiang, Jedd Wolchok Combination therapies O5 Efficacy and correlative biomarker analysis of the coBRIM study comparing cobimetinib (COBI) + vemurafenib (VEM) vs placebo (PBO) + VEM in advanced BRAF-mutated melanoma patients (pts) Paolo A. Ascierto, Grant A. McArthur, James Larkin, Gabriella Liszkay, Michele Maio, Mario Mandalà, Lev Demidov, Daniil Stoyakovskiy, Luc Thomas, Luis de la Cruz-Merino, Victoria Atkinson, Caroline Dutriaux, Claus Garbe, Matthew Wongchenko, Ilsung Chang, Daniel O. Koralek, Isabelle Rooney, Yibing Yan, Antoni Ribas, Brigitte Dréno O6 Preliminary clinical safety, tolerability and activity results from a Phase Ib study of atezolizumab (anti-PDL1) combined with vemurafenib in BRAFV600-mutant metastatic melanoma Ryan Sullivan, Omid Hamid, Manish Patel, Stephen Hodi, Rodabe Amaria, Peter Boasberg, Jeffrey Wallin, Xian He, Edward Cha, Nicole Richie, Marcus Ballinger, Patrick Hwu O7 Preliminary safety and efficacy data from a phase 1/2 study of epacadostat (INCB024360) in combination with pembrolizumab in patients with advanced/metastatic melanoma Thomas F. Gajewski, Omid Hamid, David C. Smith, Todd M. Bauer, Jeffrey S. Wasser, Jason J. Luke, Ani S. Balmanoukian, David R. Kaufman, Yufan Zhao, Janet Maleski, Lance Leopold, Tara C. Gangadhar O8 Primary analysis of MASTERKEY-265 phase 1b study of talimogene laherparepvec (T-VEC) and pembrolizumab (pembro) for unresectable stage IIIB-IV melanoma Reinhard Dummer, Georgina V. Long, Antoni Ribas, Igor Puzanov, Olivier Michielin, Ari VanderWalde, Robert H.I. Andtbacka, Jonathan Cebon, Eugenio Fernandez, Josep Malvehy, Anthony J. Olszanski, Thomas F. Gajewski, John M. Kirkwood, Christine Gause, Lisa Chen, David R. Kaufman, Jeffrey Chou, F. Stephen Hodi News in immunotherapy O9 Two-year survival and safety update in patients (pts) with treatment-naïve advanced melanoma (MEL) receiving nivolumab (NIVO) or dacarbazine (DTIC) in CheckMate 066 Victoria Atkinson, Paolo A. Ascierto, Georgina V. Long, Benjamin Brady, Caroline Dutriaux, Michele Maio, Laurent Mortier, Jessica C. Hassel, Piotr Rutkowski, Catriona McNeil, Ewa Kalinka-Warzocha, Celeste Lebbé, Lars Ny, Matias Chacon, Paola Queirolo, Carmen Loquai, Parneet Cheema, Alfonso Berrocal, Karmele Mujika Eizmendi, Luis De La Cruz-Merino, Gil Bar-Sela, Christine Horak, Joel Jiang, Helene Hardy, Caroline Robert O10 Efficacy and safety of nivolumab (NIVO) in patients (pts) with advanced melanoma (MEL) who were treated beyond progression in CheckMate 066/067 Georgina V. Long, Jeffrey S. Weber, James Larkin, Victoria Atkinson, Jean-Jacques Grob, Reinhard Dummer, Caroline Robert, Ivan Marquez-Rodas, Catriona McNeil, Henrik Schmidt, Karen Briscoe, Jean-François Baurain, F. Stephen Hodi, Jedd D. Wolchok Tumor microenvironment and biomarkers O11 New biomarkers for response/resistance to BRAF inhibitor therapy in metastatic melanoma Rosamaria Pinto, Simona De Summa, Vito Michele Garrisi, Sabino Strippoli, Amalia Azzariti, Gabriella Guida, Michele Guida, Stefania Tommasi O12 Chemokine receptor patterns in lymphocytes mirror metastatic spreading in melanoma and response to ipilimumab Nicolas Jacquelot, David Enot, Caroline Flament, Jonathan M. Pitt, Nadège Vimond, Carolin Blattner, Takahiro Yamazaki, Maria-Paula Roberti, Marie Vetizou, Romain Daillere, Vichnou Poirier-Colame, Michaëla Semeraro, Anne Caignard, Craig L Slingluff Jr, Federica Sallusto, Sylvie Rusakiewicz, Benjamin Weide, Aurélien Marabelle, Holbrook Kohrt, Stéphane Dalle, Andréa Cavalcanti, Guido Kroemer, Anna Maria Di Giacomo, Michaele Maio, Phillip Wong, Jianda Yuan, Jedd Wolchok, Viktor Umansky, Alexander Eggermont, Laurence Zitvogel O13 Serum levels of PD1- and CD28-positive exosomes before Ipilimumab correlate with therapeutic response in metastatic melanoma patients Passarelli Anna, Tucci Marco, Stucci Stefania, Mannavola Francesco, Capone Mariaelena, Madonna Gabriele, Ascierto Paolo Antonio, Silvestris Franco O14 Immunological prognostic factors in stage III melanomas María Paula Roberti, Nicolas Jacquelot, David P Enot, Sylvie Rusakiewicz, Michaela Semeraro, Sarah Jégou, Camila Flores, Lieping Chen, Byoung S. Kwon, Ana Carrizossa Anderson, Caroline Robert, Christophe Borg, Benjamin Weide, François Aubin, Stéphane Dalle, Michele Maio, Jedd D. Wolchok, Holbrook Kohrt, Maha Ayyoub, Guido Kroemer, Aurélien Marabelle, Andréa Cavalcanti, Alexander Eggermont, Laurence Zitvogel POSTER PRESENTATIONS Molecular and immuno-advances P1 Human melanoma cells resistant to B-RAF and MEK inhibition exhibit mesenchymal-like features Anna Lisa De Presbiteris, Fabiola Gilda Cordaro, Rosa Camerlingo, Federica Fratangelo, Nicola Mozzillo, Giuseppe Pirozzi, Eduardo J. Patriarca, Paolo A. Ascierto, Emilia Caputo P2 Anti-proliferative and pro-apoptotic effect of ABT888 on melanoma cell lines and its potential role in the treatment of melanoma resistant to B-RAF inhibitors Federica Fratangelo, Rosa Camerlingo, Emilia Caputo, Maria Letizia Motti, Rosaria Falcone, Roberta Miceli, Mariaelena Capone, Gabriele Madonna, Domenico Mallardo, Maria Vincenza Carriero, Giuseppe Pirozzi and Paolo Antonio Ascierto P3 Involvement of the L-cysteine/CSE/H2S pathway in human melanoma progression Elisabetta Panza, Paola De Cicco, Chiara Armogida, Giuseppe Ercolano, Rosa Camerlingo, Giuseppe Pirozzi, Giosuè Scognamiglio, Gerardo Botti, Giuseppe Cirino, Angela Ianaro P4 Cancer stem cell antigen revealing pattern of antibody variable region genes were defined by immunoglobulin repertoire analysis in patients with malignant melanoma Beatrix Kotlan, Gabriella Liszkay, Miri Blank, Timea Balatoni, Judit Olasz, Emil Farkas, Andras Szollar, Akos Savolt, Maria Godeny, Orsolya Csuka, Szabolcs Horvath, Klara Eles, Yehuda Shoenfeld and Miklos Kasler P5 Upregulation of Neuregulin-1 expression is a hallmark of adaptive response to BRAF/MEK inhibitors in melanoma Debora Malpicci, Luigi Fattore, Susan Costantini, Francesca Capone, Paolo Antonio Ascierto, Rita Mancini, Gennaro Ciliberto P6 HuR positively regulates migration of HTB63 melanoma cells Farnaz Moradi, Pontus Berglund, Karin Leandersson, Rickard Linnskog, Tommy Andersson, Chandra Prakash Prasad P7 Prolyl 4- (C-P4H) hydroxylases have opposing effects in malignant melanoma: implication in prognosis and therapy Cristiana Lo Nigro, Laura Lattanzio, Hexiao Wang, Charlotte Proby, Nelofer Syed, Marcella Occelli, Carolina Cauchi, Marco Merlano, Catherine Harwood, Alastair Thompson, Tim Crook P8 Urokinase receptor antagonists: novel agents for the treatment of melanoma Maria Letizia Motti, Katia Bifulco, Vincenzo Ingangi, Michele Minopoli, Concetta Ragone, Federica Fratangelo, Antonello Pessi, Gennaro Ciliberto, Paolo Antonio Ascierto, Maria Vincenza Carriero P9 Exosomes released by melanoma cell lines enhance chemotaxis of primary tumor cells Francesco Mannavola, Stella D’Oronzo, Claudia Felici, Marco Tucci, Antonio Doronzo, Franco Silvestris P10 New insights in mitochondrial metabolic reprogramming in melanoma Anna Ferretta, Gabriella Guida, Stefania Guida, Imma Maida, Tiziana Cocco, Sabino Strippoli, Stefania Tommasi, Amalia Azzariti, Michele Guida P11 Lenalidomide restrains the proliferation in melanoma cells through a negative regulation of their cell cycle Stella D’Oronzo, Anna Passarelli, Claudia Felici, Marco Tucci, Davide Quaresmini, Franco Silvestris Combination therapies P12 Chemoimmunotherapy elicits polyfunctional anti-tumor CD8 + T cells depending on the activation of an AKT pathway sustained by ICOS Ornella Franzese, Belinda Palermo, Cosmo Di Donna, Isabella Sperduti, MariaLaura Foddai, Helena Stabile, Angela Gismondi, Angela Santoni, Paola Nisticò P13 Favourable toxicity profile of combined BRAF and MEK inhibitors in metastatic melanoma patients Andrea P. Sponghini, Francesca Platini, Elena Marra, David Rondonotti, Oscar Alabiso, Maria T. Fierro, Paola Savoia, Florian Stratica, Pietro Quaglino P14 Electrothermal bipolar vessel sealing system dissection reduces seroma output or time to drain removal following axillary and ilio-inguinal node dissection in melanoma patients: a pilot study Di Monta Gianluca, Caracò Corrado, Di Marzo Massimiliano, Marone Ugo, Di Cecilia Maria Luisa, Mozzillo Nicola News in immunotherapy P15 Clinical and immunological response to ipilimumab in a metastatic melanoma patient with HIV infection Francesco Sabbatino, Celeste Fusciello1, Antonio Marra, Rosario Guarrasi, Carlo Baldi, Rosa Russo, Di Giulio Giovanni, Vincenzo Faiola, Pio Zeppa, Stefano Pepe P16 Immunotherapy and hypophysitis: a case report Elisabetta Gambale, Consiglia Carella, Alessandra Di Paolo, Michele De Tursi Tumor microenvironment and biomarkers P17 New immuno- histochemical markers for the differential diagnosis of atypical melanocytic lesions with uncertain malignant potential Laura Marra, Giosuè Scognamiglio, Monica Cantile, Margherita Cerrone, Fara De Murtas, Valeria Sorrentino, Anna Maria Anniciello, Gerardo Botti P18 Utility of simultaneous measurement of three serum tumor markers in melanoma patients Angela Sandru, Silviu Voinea, Eugenia Panaitescu, Madalina Bolovan, Adina Stanciu, Sabin Cinca P19 The significance of various cut-off levels of melanoma inhibitory activity in evaluation of cutaneous melanoma patients Angela Sandru, Silviu Voinea, Eugenia Panaitescu, Madalina Bolovan, Adina Stanciu, Sabin Cinca P20 The long noncoding RNA HOTAIR is associated to metastatic progression of melanoma and it can be identified in the blood of patients with advanced disease Chiara Botti, Giosuè Scognamiglio, Laura Marra, Gabriella Aquino, Rosaria Falcone, Annamaria Anniciello, Paolo Antonio Ascierto, Gerardo Botti, Monica Cantile Other P21 The effect of Sentinel Lymph Node Biopsy in melanoma mortality: timing of dissection Cristina Fortes, Simona Mastroeni, Alessio Caggiati, Francesca Passarelli, Alba Zappalà, Maria Capuano, Riccardo Bono, Maurizio Nudo, Claudia Marino, Paola Michelozzi P22 Epidemiological survey on related psychopathology in melanoma Valeria De Biasio, Vincenzo C. Battarra IMMUNOTHERAPY BRIDGE KEYNOTE SPEAKER PRESENTATIONS Immunotherapy beyond melanoma K19 Predictor of response to radiation and immunotherapy Silvia Formenti K20 Response and resistance to PD-1 pathway blockade: clues from the tumor microenvironment Maria Libera Ascierto, Tracee L. McMiller, Alan E. Berger, Ludmila Danilova, Robert A. Anders, George J. Netto, Haiying Xu, Theresa S. Pritchard, Jinshui Fan, Chris Cheadle, Leslie Cope, Charles G. Drake, Drew M. Pardoll, Janis M. Taube and Suzanne L. Topalian K21 Combination immunotherapy with autologous stem cell transplantation, protein immunization, and PBMC reinfusion in myeloma patients Sacha Gnjatic, Sarah Nataraj, Naoko Imai, Adeeb Rahman, Achim A. Jungbluth, Linda Pan, Ralph Venhaus, Andrew Park, Frédéric F. Lehmann, Nikoletta Lendvai, Adam D. Cohen, and Hearn J. Cho K22 Anti-cancer immunity despite T cell “exhaustion” Speiser Daniel Immunotherapy in oncology (I-O): data from clinical trial K23 The Checkpoint Inhibitors for the Treatment of Metastatic Non-small Cell Lung Cancer (NSCLC) Vera Hirsh
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- 2016
30. The state of melanoma: challenges and opportunities.
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Merlino, Glenn, Herlyn, Meenhard, Fisher, David E, Bastian, Boris C, Flaherty, Keith T, Davies, Michael A, Wargo, Jennifer A, Curiel-Lewandrowski, Clara, Weber, Michael J, Leachman, Sancy A, Soengas, Maria S, McMahon, Martin, Harbour, J William, Swetter, Susan M, Aplin, Andrew E, Atkins, Michael B, Bosenberg, Marcus W, Dummer, Reinhard, Gershenwald, Jeffrey E, Halpern, Allan C, Herlyn, Dorothee, Karakousis, Giorgos C, Kirkwood, John M, Krauthammer, Michael, Lo, Roger S, Long, Georgina V, McArthur, Grant, Ribas, Antoni, Schuchter, Lynn, Sosman, Jeffrey A, Smalley, Keiran S, Steeg, Patricia, Thomas, Nancy E, Tsao, Hensin, Tueting, Thomas, Weeraratna, Ashani, Xu, George, Lomax, Randy, Martin, Alison, Silverstein, Steve, Turnham, Tim, and Ronai, Ze'ev A
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Humans ,Melanoma ,Signal Transduction ,Biomedical Research ,Societies ,Scientific ,dormancy ,early diagnosis ,melanoma ,metastasis ,prevention ,therapy ,Cancer ,Prevention ,Vaccine Related ,early diagnosis ,Biological Sciences ,Medical and Health Sciences ,Dermatology & Venereal Diseases - Abstract
The Melanoma Research Foundation (MRF) has charted a comprehensive assessment of the current state of melanoma research and care. Intensive discussions among members of the MRF Scientific Advisory Council and Breakthrough Consortium, a group that included clinicians and scientists, focused on four thematic areas - diagnosis/early detection, prevention, tumor cell dormancy (including metastasis), and therapy (response and resistance). These discussions extended over the course of 2015 and culminated at the Society of Melanoma Research 2015 International Congress in November. Each of the four groups has outlined their thoughts as per the current status, challenges, and opportunities in the four respective areas. The current state and immediate and long-term needs of the melanoma field, from basic research to clinical management, are presented in the following report.
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- 2016
31. Survival of patients with advanced metastatic melanoma: The impact of novel therapies
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Ugurel, Selma, Röhmel, Joachim, Ascierto, Paolo A, Flaherty, Keith T, Grob, Jean Jacques, Hauschild, Axel, Larkin, James, Long, Georgina V, Lorigan, Paul, McArthur, Grant A, Ribas, Antoni, Robert, Caroline, Schadendorf, Dirk, and Garbe, Claus
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Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Immunology ,Cancer ,Clinical Research ,Clinical Trials and Supportive Activities ,6.1 Pharmaceuticals ,Development of treatments and therapeutic interventions ,5.1 Pharmaceuticals ,Evaluation of treatments and therapeutic interventions ,Antibodies ,Monoclonal ,Antineoplastic Agents ,Clinical Trials as Topic ,Drug Therapy ,Combination ,Humans ,Ipilimumab ,Kaplan-Meier Estimate ,Melanoma ,Molecular Targeted Therapy ,Neoplasm Metastasis ,Protein Kinase Inhibitors ,Skin Neoplasms ,Therapies ,Investigational ,Therapy ,Kinase inhibitors ,Immune checkpoint blockers ,Survival ,Public Health and Health Services ,Oncology & Carcinogenesis ,Oncology and carcinogenesis - Abstract
The survival of advanced metastatic melanoma has been greatly improved within the past few years. New therapeutic strategies like kinase inhibitors for BRAF-mutant melanoma and immune checkpoint blockers proved to prolong survival times within clinical trials, and many of them have already entered routine clinical use. However, these different treatment modalities have not yet been tested against each other, which complicate therapy decisions. We performed an explorative analysis of survival data from recent clinical trials. Thirty-five Kaplan-Meier survival curves from 17 trials were digitised, re-grouped by matching inclusion criteria and treatment line, and averaged by therapy strategy. Notably, the survival curves grouped by therapy strategy revealed a very high concordance, even if different agents were used. The greatest survival improvement was observed with the combination of BRAF plus MEK inhibitors as well as with Programmed-death-1 (PD1) blockers with or without cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) blockers, respectively, with these two treatment strategies showing similar survival outcomes. For first-line therapy, averaged survival proportions of patients alive at 12 months were 74.5% with BRAF plus MEK inhibitor treatment versus 71.9% with PD-1 blockade. This explorative comparison shows the kinase inhibitors as similarly effective as immune checkpoint blockers with regard to survival. However, to confirm these first trends for implementation into an individualised treatment of melanoma patients, data from prospective clinical trials comparing the different treatment strategies head-to-head have to be awaited.
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- 2016
32. Validation of epidermal AMBRA1 and loricrin (AMBLor) as a prognostic biomarker for nonulcerated American Joint Committee on Cancer stage I/II cutaneous melanoma
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Ewen, Tom, primary, Husain, Akhtar, additional, Stefanos, Niki, additional, Barrett, Paul, additional, Jones, Claire, additional, Ness, Tom, additional, Long, Anna, additional, Horswell, Stuart, additional, Bosomworth, Helen, additional, Lowenstein, Joe, additional, Richardson, Grant, additional, Swan, David, additional, McConnell, Ashleigh, additional, Rose, Aidan, additional, Andrew, Tom, additional, Reynolds, Nick, additional, Malvehy, Josep, additional, Carrera, Christina, additional, Alos, Llucia, additional, Mailer, Sonia, additional, Helm, Thomas, additional, Ding, Liang, additional, Bogner, Paul, additional, Podlipnik, Sebastian, additional, Puig, Susana, additional, McArthur, Grant A, additional, Paragh, Gyorgy, additional, Labus, Marie, additional, Sloan, Philip, additional, Armstrong, Jane L, additional, and Lovat, Penny E, additional
- Published
- 2023
- Full Text
- View/download PDF
33. The role of systemic therapies in current and emerging opportunities for de-intensification in melanoma: a scoping review protocol
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Soon, Jennifer A, primary, Franchini, Fanny, additional, IJzerman, Maarten J, additional, and McArthur, Grant A, additional
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- 2023
- Full Text
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34. Regulation of PRMT5–MDM4 axis is critical in the response to CDK4/6 inhibitors in melanoma
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AbuHammad, Shatha, Cullinane, Carleen, Martin, Claire, Bacolas, Zoe, Ward, Teresa, Chen, Huiqin, Slater, Alison, Ardley, Kerry, Kirby, Laura, Chan, Keefe T., Brajanovski, Natalie, Smith, Lorey K., Rao, Aparna D., Lelliott, Emily J., Kleinschmidt, Margarete, Vergara, Ismael A., Papenfuss, Anthony T., Lau, Peter, Ghosh, Prerana, Haupt, Sue, Haupt, Ygal, Sanij, Elaine, Poortinga, Gretchen, Pearson, Richard B., Falk, Hendrik, Curtis, David J., Stupple, Paul, Devlin, Mark, Street, Ian, Davies, Michael A., McArthur, Grant A., and Sheppard, Karen E.
- Published
- 2019
35. Evolution of late-stage metastatic melanoma is dominated by aneuploidy and whole genome doubling
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Vergara, Ismael A., Mintoff, Christopher P., Sandhu, Shahneen, McIntosh, Lachlan, Young, Richard J., Wong, Stephen Q., Colebatch, Andrew, Cameron, Daniel L., Kwon, Julia Lai, Wolfe, Rory, Peng, Angela, Ellul, Jason, Dou, Xuelin, Fedele, Clare, Boyle, Samantha, Arnau, Gisela Mir, Raleigh, Jeanette, Hatzimihalis, Athena, Szeto, Pacman, Mooi, Jennifer, Widmer, Daniel S., Cheng, Phil F., Amann, Valerie, Dummer, Reinhard, Hayward, Nicholas, Wilmott, James, Scolyer, Richard A., Cho, Raymond J., Bowtell, David, Thorne, Heather, Alsop, Kathryn, Cordner, Stephen, Woodford, Noel, Leditschke, Jodie, O’Brien, Patricia, Dawson, Sarah-Jane, McArthur, Grant A., Mann, Graham J., Levesque, Mitchell P., Papenfuss, Anthony T., and Shackleton, Mark
- Published
- 2021
- Full Text
- View/download PDF
36. Long-term outcome in BRAF V600E melanoma patients treated with vemurafenib: Patterns of disease progression and clinical management of limited progression
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Puzanov, Igor, Amaravadi, Ravi K, McArthur, Grant A, Flaherty, Keith T, Chapman, Paul B, Sosman, Jeffrey A, Ribas, Antoni, Shackleton, Mark, Hwu, Patrick, Chmielowski, Bartosz, Nolop, Keith B, Lin, Paul S, and Kim, Kevin B
- Subjects
Cancer ,Brain Disorders ,Clinical Trials and Supportive Activities ,Clinical Research ,Adult ,Aged ,Aged ,80 and over ,Disease Progression ,Disease-Free Survival ,Dose-Response Relationship ,Drug ,Female ,Humans ,Indoles ,Male ,Melanoma ,Middle Aged ,Proto-Oncogene Proteins B-raf ,Skin Neoplasms ,Sulfonamides ,Survival Rate ,Vemurafenib ,Young Adult ,BRAF inhibitor ,Metastatic melanoma ,Oncology and Carcinogenesis ,Public Health and Health Services ,Oncology & Carcinogenesis - Abstract
IntroductionVemurafenib induces tumour regression in most patients with BRAF(V600E)-mutant melanoma; eventually, most experience progressive disease (PD). Long-term follow-up of patients with BRAF(V600E) melanoma treated in the phase 1 vemurafenib trial is reported.MethodsPatients received vemurafenib 240-1120 mg (dose escalation cohort) or 960 mg (extension cohort) orally twice daily. Clinical response was evaluated every 8 weeks by Response Evaluation Criteria In Solid Tumors (RECIST). Patients with PD amenable to local therapy (surgery or radiotherapy) were allowed to continue vemurafenib after progression. Overall survival (OS) from time of treatment initiation and from PD was estimated. Sites of PD were recorded.ResultsForty-eight patients (escalation cohort, n = 16; extension cohort, n = 32) received therapeutic doses of vemurafenib (⩾ 240 mg twice daily). Forty-four patients had PD by the time of this analysis and four remained progression free (follow-up time, 1.2-56.1 months). Median OS was 14 months (range, 1.2-56.1); 3- and 4-year melanoma-specific survival rate in the extension cohort was 26% and 19%, respectively. Median OS was 26.0 months (range, 7.7-56.1) among 20 patients who continued vemurafenib after local therapy. Median treatment duration beyond initial PD was 3.8 months (range, 1.1-26.6). In the extension cohort, six and five patients were alive after 3 and 4 years, respectively, on vemurafenib monotherapy.ConclusionsSome patients with melanoma achieved long-term survival with vemurafenib monotherapy. Continuation of vemurafenib after PD might be beneficial in some patients because remaining disease might continue to respond to BRAF inhibition.
- Published
- 2015
37. Molecular Genomic Profiling of Melanocytic Nevi
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Colebatch, Andrew J., Ferguson, Peter, Newell, Felicity, Kazakoff, Stephen H., Witkowski, Tom, Dobrovic, Alexander, Johansson, Peter A., Saw, Robyn P.M., Stretch, Jonathan R., McArthur, Grant A., Long, Georgina V., Thompson, John F., Pearson, John V., Mann, Graham J., Hayward, Nicholas K., Waddell, Nicola, Scolyer, Richard A., and Wilmott, James S.
- Published
- 2019
- Full Text
- View/download PDF
38. Neoadjuvant systemic therapy in melanoma: recommendations of the International Neoadjuvant Melanoma Consortium
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Andrews, Miles C, Berry, Donald A, Block, Matthew S, Boland, Genevieve M, Bollin, Kathryn B, Carlino, Matteo S, Carvajal, Richard D, Cohen, Jonathan, Davar, Diwakar, Delman, Keith A, Dummer, Reinhard, Farwell, Michael D, Fisher, David E, Fusi, Alberto, Glitza, Isabella C, de Gruijl, Tanja D, Gyorki, David E, Hauschild, Axel, Hieken, Tina J, Larkin, James, Lawson, David H, Lebbe, Celeste, Lee, Jeffrey E, Lowe, Michael C, Luke, Jason J, McArthur, Grant A, McDermott, David F, McQuade, Jennifer L, Mitchell, Tara C, Petrella, Teresa M, Prieto, Peter A, Puzanov, Igor, Robert, Caroline, Salama, April K, Sandhu, Shaneen, Schadendorf, Dirk, Shoushtari, Alexander N, Sosman, Jeffrey A, Swetter, Susan M, Tanabe, Ken K, Turajlic, Samra, Tyler, Douglas S, Woodman, Scott E, Wright, Frances C, Zager, Jonathan S, Amaria, Rodabe N, Menzies, Alexander M, Burton, Elizabeth M, Scolyer, Richard A, Tetzlaff, Michael T, Antdbacka, Robert, Ariyan, Charlotte, Bassett, Roland, Carter, Brett, Daud, Adil, Faries, Mark, Fecher, Leslie A, Flaherty, Keith T, Gershenwald, Jeffrey E, Hamid, Omid, Hong, Angela, Kirkwood, John M, Lo, Serigne, Margolin, Kim, Messina, Jane, Postow, Michael A, Rizos, Helen, Ross, Merrick I, Rozeman, Elisa A, Saw, Robyn P M, Sondak, Vernon, Sullivan, Ryan J, Taube, Janis M, Thompson, John F, van de Wiel, Bart A, Eggermont, Alexander M, Davies, Michael A, Ascierto, Paolo A, Spillane, Andrew J, van Akkooi, Alexander C J, Wargo, Jennifer A, Blank, Christian U, Tawbi, Hussein A, and Long, Georgina V
- Published
- 2019
- Full Text
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39. Response of BRAF-Mutant Melanoma to BRAF Inhibition Is Mediated by a Network of Transcriptional Regulators of Glycolysis
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Parmenter, Tiffany J, Kleinschmidt, Margarete, Kinross, Kathryn M, Bond, Simon T, Li, Jason, Kaadige, Mohan R, Rao, Aparna, Sheppard, Karen E, Hugo, Willy, Pupo, Gulietta M, Pearson, Richard B, McGee, Sean L, Long, Georgina V, Scolyer, Richard A, Rizos, Helen, Lo, Roger S, Cullinane, Carleen, Ayer, Donald E, Ribas, Antoni, Johnstone, Ricky W, Hicks, Rodney J, and McArthur, Grant A
- Subjects
Clinical Research ,Genetics ,Cancer ,Development of treatments and therapeutic interventions ,5.1 Pharmaceuticals ,Cell Line ,Tumor ,Drug Resistance ,Neoplasm ,Glycolysis ,HEK293 Cells ,Humans ,Indoles ,MAP Kinase Signaling System ,Melanoma ,Piperazines ,Protein Kinase Inhibitors ,Proto-Oncogene Proteins B-raf ,Pyridines ,Sulfonamides ,Transcription Factors ,Vemurafenib ,Oncology and Carcinogenesis - Abstract
UnlabelledDeregulated glucose metabolism fulfills the energetic and biosynthetic requirements for tumor growth driven by oncogenes. Because inhibition of oncogenic BRAF causes profound reductions in glucose uptake and a strong clinical benefit in BRAF-mutant melanoma, we examined the role of energy metabolism in responses to BRAF inhibition. We observed pronounced and consistent decreases in glycolytic activity in BRAF-mutant melanoma cells. Moreover, we identified a network of BRAF-regulated transcription factors that control glycolysis in melanoma cells. Remarkably, this network of transcription factors, including hypoxia-inducible factor-1α, MYC, and MONDOA (MLXIP), drives glycolysis downstream of BRAF(V600), is critical for responses to BRAF inhibition, and is modulated by BRAF inhibition in clinical melanoma specimens. Furthermore, we show that concurrent inhibition of BRAF and glycolysis induces cell death in BRAF inhibitor (BRAFi)-resistant melanoma cells. Thus, we provide a proof-of-principle for treatment of melanoma with combinations of BRAFis and glycolysis inhibitors.SignificanceBRAF is suppress glycolysis and provide strong clinical benefi t in BRAF V600 melanoma. We show that BRAF inhibition suppresses glycolysis via a network of transcription factors that are critical for complete BRAFi responses. Furthermore, we provide evidence for the clinical potential of therapies that combine BRAFis with glycolysis inhibitors.
- Published
- 2014
40. Safety and efficacy of vemurafenib in BRAF V600E and BRAF V600K mutation-positive melanoma (BRIM-3): extended follow-up of a phase 3, randomised, open-label study
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McArthur, Grant A, Chapman, Paul B, Robert, Caroline, Larkin, James, Haanen, John B, Dummer, Reinhard, Ribas, Antoni, Hogg, David, Hamid, Omid, Ascierto, Paolo A, Garbe, Claus, Testori, Alessandro, Maio, Michele, Lorigan, Paul, Lebbé, Celeste, Jouary, Thomas, Schadendorf, Dirk, O'Day, Stephen J, Kirkwood, John M, Eggermont, Alexander M, Dréno, Brigitte, Sosman, Jeffrey A, Flaherty, Keith T, Yin, Ming, Caro, Ivor, Cheng, Suzanne, Trunzer, Kerstin, and Hauschild, Axel
- Subjects
Genetics ,Cancer ,Clinical Trials and Supportive Activities ,Clinical Research ,Prevention ,Good Health and Well Being ,Adult ,Aged ,Dacarbazine ,Disease-Free Survival ,Female ,Follow-Up Studies ,Humans ,Indoles ,Male ,Melanoma ,Middle Aged ,Mutation ,Protein Kinase Inhibitors ,Proto-Oncogene Proteins B-raf ,Sulfonamides ,Vemurafenib ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
BackgroundIn the BRIM-3 trial, vemurafenib was associated with risk reduction versus dacarbazine of both death and progression in patients with advanced BRAF(V600) mutation-positive melanoma. We present an extended follow-up analysis of the total population and in the BRAF(V600E) and BRAF(V600K) mutation subgroups.MethodsPatients older than 18 years, with treatment-naive metastatic melanoma and whose tumour tissue was positive for BRAF(V600) mutations were eligible. Patients also had to have a life expectancy of at least 3 months, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and adequate haematological, hepatic, and renal function. Patients were randomly assigned by interactive voice recognition system to receive either vemurafenib (960 mg orally twice daily) or dacarbazine (1000 mg/m(2) of body surface area intravenously every 3 weeks). Coprimary endpoints were overall survival and progression-free survival, analysed in the intention-to-treat population (n=675), with data censored at crossover. A sensitivity analysis was done. This trial is registered with ClinicalTrials.gov, NCT01006980.Findings675 eligible patients were enrolled from 104 centres in 12 countries between Jan 4, 2010, and Dec 16, 2010. 337 patients were randomly assigned to receive vemurafenib and 338 to receive dacarbazine. Median follow-up was 12·5 months (IQR 7·7-16·0) on vemurafenib and 9·5 months (3·1-14·7) on dacarbazine. 83 (25%) of the 338 patients initially randomly assigned to dacarbazine crossed over from dacarbazine to vemurafenib. Median overall survival was significantly longer in the vemurafenib group than in the dacarbazine group (13·6 months [95% CI 12·0-15·2] vs 9·7 months [7·9-12·8]; hazard ratio [HR] 0·70 [95% CI 0·57-0·87]; p=0·0008), as was median progression-free survival (6·9 months [95% CI 6·1-7·0] vs 1·6 months [1·6-2·1]; HR 0·38 [95% CI 0·32-0·46]; p
- Published
- 2014
41. Management of Melanoma
- Author
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Lee, Belinda, McArthur, Grant A., Bomanji, Jamshed B., Series editor, Gnanasegaran, Gopinath, Series editor, Fanti, Stefano, Series editor, Macapinlac, Homer A., Series editor, Hofman, Michael S., editor, and Hicks, Rodney J., editor
- Published
- 2017
- Full Text
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42. Pathology of Melanoma
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Colebatch, Andrew J., McArthur, Grant A., Bomanji, Jamshed B., Series editor, Gnanasegaran, Gopinath, Series editor, Fanti, Stefano, Series editor, Macapinlac, Homer A., Series editor, Hofman, Michael S., editor, and Hicks, Rodney J., editor
- Published
- 2017
- Full Text
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43. Melanoma
- Author
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Spillane, John, Henderson, Michael, McArthur, Grant A., Bomanji, Jamshed B., Series editor, Gnanasegaran, Gopinath, Series editor, Fanti, Stefano, Series editor, Macapinlac, Homer A., Series editor, Hofman, Michael S., editor, and Hicks, Rodney J., editor
- Published
- 2017
- Full Text
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44. Rechallenge with BRAF-directed treatment in metastatic melanoma: A multi-institutional retrospective study
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Valpione, Sara, Carlino, Matteo S., Mangana, Johanna, Mooradian, Meghan J., McArthur, Grant, Schadendorf, Dirk, Hauschild, Axel, Menzies, Alexander M., Arance, Ana, Ascierto, Paolo A., Di Giacomo, AnnaMaria, de Rosa, Francesco, Larkin, James, Park, John J., Goldinger, Simone M., Sullivan, Ryan J., Xu, Wen, Livingstone, Elisabeth, Weichenthal, Michael, Rai, Rajat, Gaba, Lydia, Long, Georgina V., and Lorigan, Paul
- Published
- 2018
- Full Text
- View/download PDF
45. Future perspectives in melanoma research. Meeting report from the ¿Melanoma Bridge. Napoli, December 2nd-4th 2012¿
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Ascierto, Paolo A, Grimaldi, Antonio M, Acquavella, Nicolas, Borgognoni, Lorenzo, Calabrò, Luana, Cascinelli, Natale, Cesano, Alessandra, Del Vecchio, Michele, Eggermont, Alexander M, Faries, Mark, Ferrone, Soldano, Fox, Bernard A, Gajewski, Thomas F, Galon, Jérôme, Gnjatic, Sacha, Gogas, Helen, Kashani-Sabet, Mohammed, Kaufman, Howard L, Larkin, James, Lo, Roger S, Mantovani, Alberto, Margolin, Kim, Melief, Cornelis, McArthur, Grant, Palmieri, Giuseppe, Puzanov, Igor, Ribas, Antoni, Seliger, Barbara, Sosman, Jeff, Suenaert, Peter, Tarhini, Ahmad A, Trinchieri, Giorgio, Vidal-Vanaclocha, Fernando, Wang, Ena, Ciliberto, Gennaro, Mozzillo, Nicola, Marincola, Francesco M, and Thurin, Magdalena
- Abstract
Abstract Recent insights into the genetic and somatic aberrations have initiated a new era of rapidly evolving targeted and immune-based treatments for melanoma. After decades of unsuccessful attempts to finding a more effective cure in the treatment of melanoma now we have several drugs active in melanoma. The possibility to use these drugs in combination to improve responses to overcome the resistance, to potentiate the action of immune system with the new immunomodulating antibodies, and identification of biomarkers that can predict the response to a particular therapy represent new concepts and approaches in the clinical management of melanoma. The third “Melanoma Research: “A bridge from Naples to the World” meeting, shortened as “Bridge Melanoma Meeting” took place in Naples, December 2 to 4th, 2012. The four topics of discussion at this meeting were: advances in molecular profiling and novel biomarkers, combination therapies, novel concepts toward integrating biomarkers and therapies into contemporary clinical management of patients with melanoma across the entire spectrum of disease stage, and the knowledge gained from the biology of tumor microenvironment across different tumors as a bridge to impact on prognosis and response to therapy in melanoma. This international congress gathered more than 30 international faculty members who in an interactive atmosphere which stimulated discussion and exchange of their experience regarding the most recent advances in research and clinical management of melanoma patients.
- Published
- 2013
46. BRAF-targeted therapy and immune responses to melanoma
- Author
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Ngiow, Shin Foong, Knight, Deborah A, Ribas, Antoni, McArthur, Grant A, and Smyth, Mark J
- Subjects
Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Immunology ,Cancer ,Vaccine Related ,Immunization ,5.1 Pharmaceuticals ,Development of treatments and therapeutic interventions ,BRAF ,checkpoint ,immunity ,melanoma ,T cell ,Oncology and carcinogenesis - Abstract
Type I BRAF inhibitors and immunotherapy constitute two new exciting approaches for the treatment of advanced malignant melanoma. We have recently elucidated a role for host C-C chemokine receptor type 2 (CCR2) in the antineoplastic effects of type I BRAF inhibitors in mice, supporting the therapeutic potential of combining BRAF inhibitors with immunotherapy.
- Published
- 2013
47. Genome-wide RNAi screen for genes regulating glycolytic response to vemurafenib in BRAFV600 melanoma cells
- Author
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Smith, Lorey K., Parmenter, Tiffany, Gould, Cathryn M., Madhamshettiwar, Piyush B., Sheppard, Karen E., Simpson, Kaylene J., and McArthur, Grant A.
- Published
- 2020
- Full Text
- View/download PDF
48. Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma
- Author
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Bollag, Gideon, Hirth, Peter, Tsai, James, Zhang, Jiazhong, Ibrahim, Prabha N, Cho, Hanna, Spevak, Wayne, Zhang, Chao, Zhang, Ying, Habets, Gaston, Burton, Elizabeth A, Wong, Bernice, Tsang, Garson, West, Brian L, Powell, Ben, Shellooe, Rafe, Marimuthu, Adhirai, Nguyen, Hoa, Zhang, Kam YJ, Artis, Dean R, Schlessinger, Joseph, Su, Fei, Higgins, Brian, Iyer, Raman, D’Andrea, Kurt, Koehler, Astrid, Stumm, Michael, Lin, Paul S, Lee, Richard J, Grippo, Joseph, Puzanov, Igor, Kim, Kevin B, Ribas, Antoni, McArthur, Grant A, Sosman, Jeffrey A, Chapman, Paul B, Flaherty, Keith T, Xu, Xiaowei, Nathanson, Katherine L, and Nolop, Keith
- Subjects
Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Clinical Trials and Supportive Activities ,Clinical Research ,Cancer ,5.1 Pharmaceuticals ,Development of treatments and therapeutic interventions ,Alleles ,Animals ,Dogs ,Extracellular Signal-Regulated MAP Kinases ,Humans ,Indoles ,MAP Kinase Signaling System ,Macaca fascicularis ,Melanoma ,Models ,Molecular ,Mutant Proteins ,Mutation ,Neoplasm Metastasis ,Phosphorylation ,Positron-Emission Tomography ,Proto-Oncogene Proteins B-raf ,Rats ,Substrate Specificity ,Sulfonamides ,Vemurafenib ,Xenograft Model Antitumor Assays ,General Science & Technology - Abstract
B-RAF is the most frequently mutated protein kinase in human cancers. The finding that oncogenic mutations in BRAF are common in melanoma, followed by the demonstration that these tumours are dependent on the RAF/MEK/ERK pathway, offered hope that inhibition of B-RAF kinase activity could benefit melanoma patients. Herein, we describe the structure-guided discovery of PLX4032 (RG7204), a potent inhibitor of oncogenic B-RAF kinase activity. Preclinical experiments demonstrated that PLX4032 selectively blocked the RAF/MEK/ERK pathway in BRAF mutant cells and caused regression of BRAF mutant xenografts. Toxicology studies confirmed a wide safety margin consistent with the high degree of selectivity, enabling Phase 1 clinical trials using a crystalline formulation of PLX4032 (ref. 5). In a subset of melanoma patients, pathway inhibition was monitored in paired biopsy specimens collected before treatment initiation and following two weeks of treatment. This analysis revealed substantial inhibition of ERK phosphorylation, yet clinical evaluation did not show tumour regressions. At higher drug exposures afforded by a new amorphous drug formulation, greater than 80% inhibition of ERK phosphorylation in the tumours of patients correlated with clinical response. Indeed, the Phase 1 clinical data revealed a remarkably high 81% response rate in metastatic melanoma patients treated at an oral dose of 960 mg twice daily. These data demonstrate that BRAF-mutant melanomas are highly dependent on B-RAF kinase activity.
- Published
- 2010
49. Terminal Osteoblast Differentiation, Mediated by Runx2 and p27 KIP1 , Is Disrupted in Osteosarcoma
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Thomas, David M., Johnson, Sandra A., Sims, Natalie A., Trivett, Melanie K., Slavin, John L., Rubin, Brian P., Waring, Paul, McArthur, Grant A., Walkley, Carl R., Holloway, Andrew J., Diyagama, Dileepa, Grim, Jonathan E., Clurman, Bruce E., Lee, Jong-Seo, Gutierrez, Gabriel M., Piscopo, Denise M., Carty, Shannon A., and Hinds, Philip W.
- Published
- 2004
50. Recombinant NY-ESO-1 Protein with ISCOMATRIX Adjuvant Induces Broad Integrated Antibody and CD4+ and CD8+ T Cell Responses in Humans
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Davis, Ian D., Chen, Weisan, Jackson, Heather, Parente, Phillip, Shackleton, Mark, Hopkins, Wendie, Chen, Qiyuan, Dimopoulos, Nektaria, Luke, Tina, Murphy, Roger, Scott, Andrew M., Maraskovsky, Eugene, McArthur, Grant, MacGregor, Duncan, Sturrock, Sue, Tai, Tsin Yee, Green, Simon, Cuthbertson, Andrew, Maher, Darryl, Miloradovic, Lena, Mitchell, Susan V., Ritter, Gerd, Jungbluth, Achim A., Chen, Yao-Tseng, Gnjatic, Sacha, Hoffman, Eric W., Old, Lloyd J., and Cebon, Jonathan S.
- Published
- 2004
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