Journal ArticleDOI
Combined immunotherapy with granulocyte-macrophage colony-stimulating factor-transduced allogeneic prostate cancer cells and ipilimumab in patients with metastatic castration-resistant prostate cancer: a phase 1 dose-escalation trial
Alfons J.M. van den Eertwegh,Jurjen Versluis,H Pieter van den Berg,Saskia J. A. M. Santegoets,R. Jeroen A. van Moorselaar,Tim M. van der Sluis,H.E. Gall,Thomas Harding,Karin Jooss,Israel Lowy,Herbert M. Pinedo,Rik J. Scheper,Anita G.M. Stam,B. Mary E. von Blomberg,Tanja D. de Gruijl,Kristen Hege,Natalie Sacks,Winald R. Gerritsen +17 more
TLDR
GVAX combined with 3·0 mg/kg ipilimumab is tolerable and safe for patients with mCRPC, and the most common adverse events noted in all 28 patients were injection-site reactions, fatigue, and pyrexia.Abstract:
Summary Background The granulocyte-macrophage colony-stimulating factor-transduced allogeneic prostate cancer cells vaccine (GVAX) has antitumour activity against prostate cancer; preclinical studies have shown potent synergy when combined with ipilimumab, an antibody that blocks cytotoxic T-lymphocyte antigen 4. We aimed to assess the safety of combined treatment with GVAX and ipilimumab in patients with metastatic castration-resistant prostate cancer (mCRPC). Methods We did an open-labelled, single-centre, dose-escalation study of ipilimumab concurrent with a fixed dose of GVAX, with a subsequent expansion phase, both at the VU University Medical Centre (Amsterdam, Netherlands). Eligible patients had documented mCRPC and had not been previously treated with chemotherapy. All patients received a 5×10 8 cell priming dose of GVAX intradermally on day 1 with subsequent intradermal injections of 3×10 8 cells every 2 weeks for 24 weeks. The vaccinations were combined with intravenous ipilimumab every 4 weeks. We enrolled patients in cohorts of three; each cohort received an escalating dose of ipilimumab at 0·3, 1·0, 3·0, or 5·0 mg/kg. Our primary endpoint was safety. This study is registered with ClinicalTrials.gov, number NCT01510288. Findings We enrolled 12 patients into our dose-escalation cohort. We did not record any severe immune-related adverse events at the first two dose levels. At the 3·0 mg/kg dose level, one patient had grade 2 and two patients grade 3 hypophysitis; at the 5·0 mg/kg dose level, two patients had grade 3 hypophysitis and one patient developed grade 4 sarcoid alveolitis (a dose-limiting toxic effect). Due to observed clinical activity and toxic events, we decided to expand the 3·0 mg/kg dose level, rather than enrol a further three patients at the 5·0 mg/kg level. 16 patients were enrolled in the expansion cohort, two of whom developed grade 2 hypophysitis, three colitis (one grade 1 and two grade 2), and one grade 3 hepatitis—all immune-related adverse events. The most common adverse events noted in all 28 patients were injection-site reactions (grade 1–2 events seen in all patients), fatigue (grade 1–2 in 20 patients, grade 3 in two), and pyrexia (grade 1–2 in 15 patients, grade 3 in one). 50% or greater declines in prostate-specific antigen from baseline was recorded in seven patients (25%); all had received 3·0 mg/kg or 5·0 mg/kg ipilimumab. Interpretation GVAX combined with 3·0 mg/kg ipilimumab is tolerable and safe for patients with mCRPC. Further research on the combined treatment of patients with mCRPC with vaccination and ipilimumab is warranted. Funding Cell Genesys Inc, Prostate Cancer Foundation, Dutch Cancer Society (KWF-VU 2006-3697), and Foundation Stichting VUmc Cancer Center Amsterdam.read more
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The future of immune checkpoint therapy
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Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial
Eugene D. Kwon,Charles G. Drake,Howard I. Scher,Karim Fizazi,Alberto Bossi,Alfons J.M. van den Eertwegh,Michael Krainer,Nadine Houede,Ricardo Santos,Hakim Mahammedi,Siobhan Ng,Michele Maio,Fabio Franke,Santhanam Sundar,Neeraj Agarwal,Andries M. Bergman,Tudor Ciuleanu,Ernesto Korbenfeld,Lisa Sengeløv,Steinbjørn Hansen,Christopher J. Logothetis,Tomasz M. Beer,M. Brent McHenry,Paul Gagnier,David R. Liu,Winald R. Gerritsen +25 more
TL;DR: There was no significant difference between the ipilimumab group and the placebo group in terms of overall survival in the primary analysis, but there were signs of activity with the drug that warrant further investigation.
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Dendritic-cell-based therapeutic cancer vaccines.
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Coinhibitory Pathways in Immunotherapy for Cancer.
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Improved Survival with Ipilimumab in Patients with Metastatic Melanoma.
F. Stephen Hodi,Steven J. O'Day,David F. McDermott,R. W. Weber,Jeffrey A. Sosman,John B. A. G. Haanen,Rene Gonzalez,Caroline Robert,Dirk Schadendorf,Jessica C. Hassel,Wallace Akerley,Alfons J.M. van den Eertwegh,Jose Lutzky,Paul Lorigan,Julia Vaubel,Gerald P. Linette,David W. Hogg,Christian H. Ottensmeier,Céleste Lebbé,Christian Peschel,Ian Quirt,Joseph I. Clark,Jedd D. Wolchok,Jeffrey S. Weber,Jason Tian,Michael Yellin,Geoffrey M. Nichol,Axel Hoos,Walter J. Urba +28 more
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Docetaxel plus Prednisone or Mitoxantrone plus Prednisone for Advanced Prostate Cancer
Ian F. Tannock,Ronald de Wit,William R. Berry,Jozsef Horti,Anna Pluzanska,Kim N. Chi,Stéphane Oudard,Christine Theodore,Nicholas D. James,Ingela Turesson,Mark Rosenthal,Mario A. Eisenberger +11 more
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Philip W. Kantoff,Celestia S. Higano,N. Shore,E. Roy Berger,Eric J. Small,David F. Penson,Charles H. Redfern,Anna C. Ferrari,Robert Dreicer,Robert B. Sims,Yi Xu,Mark W. Frohlich,Paul F. Schellhammer +12 more
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Ipilimumab plus Dacarbazine for Previously Untreated Metastatic Melanoma
Caroline Robert,Luc Thomas,Igor Bondarenko,Steven J. O'Day,Jeffrey S. Weber,Claus Garbe,Céleste Lebbé,Jean Francois Baurain,Alessandro Testori,Jean-Jacques Grob,Neville Davidson,Jon M. Richards,Michele Maio,Axel Hauschild,Wilson H. Miller,Pere Gascón,Michal Lotem,Kaan Harmankaya,Ramy Ibrahim,Stephen Francis,Tai-Tsang Chen,R. Humphrey,Axel Hoos,Jedd D. Wolchok +23 more
TL;DR: 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.
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