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

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• 作者：Alfons JM van den Eertwegh ; MD^a ; ^&Dagger ; ; Jurjen Versluis ; MD^a ; ^&Dagger ; ; H Pieter van den Berg ; MD^a ; Saskia JAM Santegoets ; PhD^a ; Prof R Jeroen A van Moorselaar ; MD^c ; Tim M van der Sluis ; MD^c ; Helen E Gall ; MNAP^a ; Thomas C Harding ; MD^d ; Karin Jooss ; PhD^d ; Israel Lowy ; MD^e ; Prof Herbert M Pinedo ; MD^a ; Prof Rik J Scheper ; PhD^b ; Anita GM Stam ; BSc^b ; B Mary E von Blomberg ; PhD^b ; Tanja D de Gruijl ; PhD^a ; Kristen Hege ; MD^d ; Natalie Sacks ; MD^d ; Prof Winald R Gerritsen ; MD^a ; ^{winald.gerritsen@vumc.nl}
• 刊名：Lancet Oncology
• 出版年：2012
• 出版时间：May, 2012
• 年：2012
• 卷：13
• 期：5
• 页码：509-517
• 全文大小：305 K

文摘

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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¡Á10⁸ cell priming dose of GVAX intradermally on day 1 with subsequent intradermal injections of 3¡Á10⁸ 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 , number .

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¡ªall 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.