Ralf Gutzmer

Hannover Medical School, Hanover, Lower Saxony, Germany

Are you Ralf Gutzmer?

Claim your profile

Publications (194)754.6 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Histamine is a developmentally highly conserved autacoid found in most vertebrate tissues. Its physiological functions are mediated by four 7-transmembrane G protein-coupled receptors (H1R, H2R, H3R, H4R) that are all targets of pharmacological intervention. The receptors display molecular heterogeneity and constitutive activity. H1R antagonists are long known antiallergic and sedating drugs, whereas the H2R was identified in the 1970s and led to the development of H2R-antagonists that revolutionized stomach ulcer treatment. The crystal structure of ligand-bound H1R has rendered it possible to design new ligands with novel properties. The H3R is an autoreceptor and heteroreceptor providing negative feedback on histaminergic and inhibition on other neurons. A block of these actions promotes waking. The H4R occurs on immuncompetent cells and the development of anti-inflammatory drugs is anticipated. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.
    Pharmacological reviews 07/2015; 67(3):601-55. DOI:10.1124/pr.114.010249 · 18.55 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Treatment with BRAF inhibitors (BRAFi) leads to complete remissions (CR) in 3-6% of patients with BRAF mutant metastatic melanoma. In cases of CR, it is unclear whether BRAFi therapy should be continued. We retrospectively analyzed the clinical course of patients with metastatic melanoma who discontinued BRAFi therapy after achieving a CR. In 12 patients, CR of metastatic melanoma was diagnosed after a median BRAFi treatment duration of 13 (range 0.3-32) months. Reasons for discontinuation were side effects in seven patients and patient demand in five patients. Six patients are still in CR after a median of 17 (range 2-26) months after discontinuation of BRAF inhibition. Six patients developed a melanoma recurrence after a median of 3 (range 2-17) months of discontinuation of BRAFi therapy. Subsequently, these patients were again treated with a BRAFi, which resulted in three CR, one stable disease, and one progressive disease; one patient could not be assessed. Melanoma patients achieving CR during BRAFi therapy represent a heterogeneous group. Discontinuation of BRAFi therapy after a CR has to be balanced carefully with the potential risk of nonresponding to BRAFi retreatment in the case of relapse.
    Melanoma research 06/2015; DOI:10.1097/CMR.0000000000000169 · 2.10 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Patients with advanced basal cell carcinoma have limited treatment options. Hedgehog pathway signalling is aberrantly activated in around 95% of tumours. We assessed the antitumour activity of sonidegib, a Hedgehog signalling inhibitor, in patients with advanced basal cell carcinoma. BOLT is an ongoing multicentre, randomised, double-blind, phase 2 trial. Eligible patients had locally advanced basal cell carcinoma not amenable to curative surgery or radiation or metastatic basal cell carcinoma. Patients were randomised via an automated system in a 1:2 ratio to receive 200 mg or 800 mg oral sonidegib daily, stratified by disease, histological subtype, and geographical region. The primary endpoint was the proportion of patients who achieved an objective response, assessed in the primary efficacy analysis population (patients with fully assessable locally advanced disease and all those with metastatic disease) with data collected up to 6 months after randomisation of the last patient. This trial is registered with ClinicalTrials.gov, number NCT01327053. Between July 20, 2011, and Jan 10, 2013, we enrolled 230 patients, 79 in the 200 mg sonidegib group, and 151 in the 800 mg sonidegib group. Median follow-up was 13·9 months (IQR 10·1-17·3). In the primary efficacy analysis population, 20 (36%, 95% CI 24-50) of 55 patients receiving 200 mg sonidegib and 39 (34%, 25-43) of 116 receiving 800 mg sonidegib achieved an objective response. In the 200 mg sonidegib group, 18 (43%, 95% CI 28-59) patients who achieved an objective response, as assessed by central review, were noted among the 42 with locally advanced basal cell carcinoma and two (15%, 2-45) among the 13 with metastatic disease. In the 800 mg group, 35 (38%, 95% CI 28-48) of 93 patients with locally advanced disease had an objective response, as assessed by central review, as did four (17%, 5-39) of 23 with metastatic disease. Fewer adverse events leading to dose interruptions or reductions (25 [32%] of 79 patients vs 90 [60%] of 150) or treatment discontinuation (17 [22%] vs 54 [36%]) occurred in patients in the 200 mg group than in the 800 mg group. The most common grade 3-4 adverse events were raised creatine kinase (five [6%] in the 200 mg group vs 19 [13%] in the 800 mg group) and lipase concentration (four [5%] vs eight [5%]). Serious adverse events occurred in 11 (14%) of 79 patients in the 200 mg group and 45 (30%) of 150 patients in the 800 mg group. The benefit-to-risk profile of 200 mg sonidegib might offer a new treatment option for patients with advanced basal cell carcinoma, a population that is difficult to treat. Novartis Pharmaceuticals Corporation. Copyright © 2015 Elsevier Ltd. All rights reserved.
    The Lancet Oncology 05/2015; 16(6). DOI:10.1016/S1470-2045(15)70100-2 · 24.73 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Monocyte-derived conventional dendritic cells (cDC) loaded with melanoma antigens showed modest responses in clinical trials. Efficacy studies were hampered by difficulties in cDC manufacturing and low potency. Overcoming these issues, we demonstrated higher potency of lentiviral vector (LV)-programmed DCs. Monocytes were directly induced to self-differentiate into DCs (SmartDC-TRP2) upon transduction with a tricistronic LV encoding for cytokines (GM-CSF and IL-4) and a melanoma antigen (TRP2). Here, SmartDC-TRP2 generated with monocytes from five advanced melanoma patients were tested in autologous DC:T cell stimulation assays, validating the activation of functional TRP2-specific cytotoxic T lymphocytes (CTLs) for all patients. We described methods compliant to good manufacturing practices (GMP) to produce LV and SmartDC-TRP2. Feasibility of monocyte transduction in a bag system and cryopreservation following a 24-hour standard operating procedure were achieved. After thawing, 50% of the initial monocyte input was recovered and SmartDC-TRP2 self-differentiated in vitro, showing uniform expression of DC markers, detectable LV copies and a polyclonal LV integration pattern not biased to oncogenic loci. GMP-grade SmartDC-TRP2 expanded TRP2-specific autologous CTLs in vitro. These results demonstrated a simpler GMP-compliant method of manufacturing an effective individualized DC vaccine. Such DC vaccine, when in combination with checkpoint inhibition therapies, might provide higher specificity against melanoma.Gene Therapy accepted article preview online, 12 May 2015. doi:10.1038/gt.2015.43.
    Gene therapy 05/2015; DOI:10.1038/gt.2015.43 · 4.20 Impact Factor
  • Ralf Gutzmer
    Journal der Deutschen Dermatologischen Gesellschaft 05/2015; 13(5). DOI:10.1111/ddg.12692 · 1.40 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Natural killer (NK) cells have been detected in the lesional skin of patients with inflammatory skin diseases, where high levels of histamine are also present. Therefore, we investigated the effect of histamine, in particular via the histamine H4 receptor (H4R), on gene expression levels in human NK cells. Comprehensive microarray-based mRNA expression profiling was performed to assess the gene expression levels in human NK cells in response to H4R stimulation in an unbiased approach. The expression of selected cytokines and chemokines was quantified by real-time PCR and enzyme-linked immunosorbent assay. The microarray analysis identified only few genes which were differentially regulated upon H4R stimulation. In follow-up studies, a significant upregulation of CCL3 and CCL4 at the mRNA level and in addition for CCL3 also at the protein level via the H4R was observed. The elevated expression levels of chemokines in response to H4R stimulation might foster the inflammation in allergic skin diseases and characterize the H4R as a promising therapeutic target. © 2015 S. Karger AG, Basel.
    International Archives of Allergy and Immunology 04/2015; 166(3):225-230. DOI:10.1159/000381340 · 2.43 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, can result in durable responses in patients with melanoma who have progressed after ipilimumab and BRAF inhibitors. We assessed the efficacy and safety of nivolumab compared with investigator's choice of chemotherapy (ICC) as a second-line or later-line treatment in patients with advanced melanoma. In this randomised, controlled, open-label, phase 3 trial, we recruited patients at 90 sites in 14 countries. Eligible patients were 18 years or older, had unresectable or metastatic melanoma, and progressed after ipilimumab, or ipilimumab and a BRAF inhibitor if they were BRAF(V 600) mutation-positive. Participating investigators randomly assigned (with an interactive voice response system) patients 2:1 to receive an intravenous infusion of nivolumab 3 mg/kg every 2 weeks or ICC (dacarbazine 1000 mg/m(2) every 3 weeks or paclitaxel 175 mg/m(2) combined with carboplatin area under the curve 6 every 3 weeks) until progression or unacceptable toxic effects. We stratified randomisation by BRAF mutation status, tumour expression of PD-L1, and previous best overall response to ipilimumab. We used permuted blocks (block size of six) within each stratum. Primary endpoints were the proportion of patients who had an objective response and overall survival. Treatment was given open-label, but those doing tumour assessments were masked to treatment assignment. We assessed objective responses per-protocol after 120 patients had been treated with nivolumab and had a minimum follow-up of 24 weeks, and safety in all patients who had had at least one dose of treatment. The trial is closed and this is the first interim analysis, reporting the objective response primary endpoint. This study is registered with ClinicalTrials.gov, number NCT01721746. Between Dec 21, 2012, and Jan 10, 2014, we screened 631 patients, randomly allocating 272 patients to nivolumab and 133 to ICC. Confirmed objective responses were reported in 38 (31·7%, 95% CI 23·5-40·8) of the first 120 patients in the nivolumab group versus five (10·6%, 3·5-23·1) of 47 patients in the ICC group. Grade 3-4 adverse events related to nivolumab included increased lipase (three [1%] of 268 patients), increased alanine aminotransferase, anaemia, and fatigue (two [1%] each); for ICC, these included neutropenia (14 [14%] of 102), thrombocytopenia (six [6%]), and anaemia (five [5%]). We noted grade 3-4 drug-related serious adverse events in 12 (5%) nivolumab-treated patients and nine (9%) patients in the ICC group. No treatment-related deaths occurred. Nivolumab led to a greater proportion of patients achieving an objective response and fewer toxic effects than with alternative available chemotherapy regimens for patients with advanced melanoma that has progressed after ipilimumab or ipilimumab and a BRAF inhibitor. Nivolumab represents a new treatment option with clinically meaningful durable objective responses in a population of high unmet need. Bristol-Myers Squibb. Copyright © 2015 Elsevier Ltd. All rights reserved.
    The Lancet Oncology 03/2015; 16(4). DOI:10.1016/S1470-2045(15)70076-8 · 24.73 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Recent evidence suggests that ionizing radiation may be associated with unexpected side effects in melanoma patients treated with concomitant BRAF inhibitors. A large multi-center analysis was performed to generate reliable safety data and elucidate the mechanism. A total of 161 melanoma patients from eleven European skin cancer centers were evaluated for acute and late toxicity, of whom 70 consecutive patients received 86 series of radiotherapy with concomitant BRAF inhibitor therapy. To further characterize and quantify a possible radiosensitization by BRAF inhibitors, blood samples of 35 melanoma patients were used for individual radiosensitivity testing by fluorescence-in-situ-hybridization of chromosomal breaks after ex vivo irradiation. With radiotherapy and concomitant BRAF inhibitor therapy the rate of acute radiodermatitis ≥2° was 36% and follicular cystic proliferation was seen in 13% of all radiotherapies. Non-skin toxicities included hearing disorders (4%) and dysphagia (2%). Following whole brain radiotherapy, rates of radiodermatitis ≥2° were 44% and 8% (p<0.001) for patients with and without BRAF inhibitor therapy, respectively. Concomitant treatment with vemurafenib induced acute radiodermatitis ≥2° more frequently than treatment with dabrafenib (40% versus 26%, p=0.07). In line with these findings, analysis of chromosomal breaks ex vivo indicated significantly increased radiosensitivity for patients under vemurafenib (p=0.004) and for patients switched from vemurafenib to dabrafenib (p=0.002), but not for patients on dabrafenib only. No toxicities were reported after stereotactic treatment. Radiotherapy with concomitant BRAF inhibitor therapy is feasible with an acceptable increase in toxicity. Vemurafenib is a more potent radiosensitizer than dabrafenib. © The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.
    Annals of Oncology 03/2015; 26(6). DOI:10.1093/annonc/mdv139 · 6.58 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: ImportanceBRAF inhibitors have been licensed for the therapy of BRAF-mutated melanoma. Recently, inflammatory skin lesions clinically resembling erythema nodosum have been reported as therapy side-effects that may lead to treatment discontinuation.Objective To identify and characterize cases with BRAF inhibitor-associated erythema nodosum-like inflammatory skin lesions and development of an algorithm for their management.Design and SettingRetrospective chart review of melanoma patients treated with BRAF inhibitors in 14 departments of Dermatology in Germany and Austria and PubMed search for cases in the literature.ResultsSixteen patients were identified who developed erythema nodosum-like lesions under BRAF inhibitor therapy; 14 had received vemurafenib and two dabrafenib plus trametinib. The most frequently involved body sites were the legs. Histopathology was performed in five cases and revealed panniculitis in three and vasculitis in two patients respectively. Arthralgia and fever were associated symptoms in 44% and 31% of patients respectively. Inflammatory symptoms led to discontinuation of treatment in three patients, while in the majority of cases symptomatic management was sufficient. Skin lesions finally resolved despite continued BRAF inhibitor therapy in seven patients. In the literature, 19 additional patients with similar cutaneous appearance under BRAF inhibitors could be identified. An algorithm for the management of such lesions is proposed.Conclusion Erythema nodosum-like skin lesions histologically correspond to panniculitis and/or vasculitis. Symptomatic treatment may be sufficient. However, additional work-up and interruption of BRAF inhibitor therapy may be necessary in severe cases which are commonly associated with systemic symptoms.
    Journal of the European Academy of Dermatology and Venereology 03/2015; DOI:10.1111/jdv.13039 · 3.11 Impact Factor
  • Source
  • Source
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Kinase inhibitors targeting the BRAF V600 mutation have become standard in the treatment of metastatic melanoma. Albeit in wide clinical use, the patterns associated with therapy outcome are not fully elucidated. The present study was aimed to identify predictive factors of therapy response and survival under the BRAF inhibitor vemurafenib. This multicenter retrospective study analyzed patient, tumor, and pretreatment characteristics collected in BRAF V600 mutated stage IV melanoma patients prior to single agent therapy with the BRAF inhibitor vemurafenib. 300 patients from 14 centers were included into this study with a median follow-up time of 13.0 months. Median progression-free survival (PFS) was 5.1 months; median overall survival (OS) was 7.6 months. Best response under vemurafenib was associated with serum LDH (≤ versus >UNL; p=0.0000001), ECOG overall performance status (OPS) (0 versus ≥1; p=0.00089), and BRAF mutation subtype (V600E versus V600K; p=0.016). Multivariate analysis identified ECOG OPS ≥1 (HR=1.88; p=0.00005), immunotherapy pretreatment (HR=0.53; p=0.0067), elevated serum LDH (HR=1.45; p=0.012), age >55 years (HR=0.72; p=0.019), and chemotherapy pretreatment (HR=1.39; p=0.036) as independent predictors of PFS. For OS, elevated serum LDH (HR=1.99; p=0.00012), ECOG OPS ≥1 (HR=1.90; p=0.00063), age >55 years (HR=0.65; p=0.011), kinase inhibitor pretreatment (HR=1.86; p=0.014), immunotherapy pretreatment (HR=0.57; p=0.025), chemotherapy pretreatment (HR=2.17; p=0.039), and male gender (HR=0.70; 95%CI=0.50-0.98; p=0.039) were found as predictors. Our data demonstrate that the type of pretreatment strongly influences the outcome of vemurafenib therapy, with a precedent immunotherapy showing a positive, and a prior chemotherapy and kinase inhibitors showing a negative impact on survival, respectively. Moreover, we show that the patient's overall performance status, serum LDH, age and gend3er independently impact vemurafenib therapy outcome. These findings should be taken into account for the future design of therapy sequencing in BRAF V600 mutation-positive melanoma patients. © The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.
    Annals of Oncology 12/2014; 26(3). DOI:10.1093/annonc/mdu573 · 6.58 Impact Factor
  • Journal der Deutschen Dermatologischen Gesellschaft 10/2014; 12(10). DOI:10.1111/ddg.12342_suppl · 1.40 Impact Factor
  • 15th World Congress on Cancers of the Skin; 09/2014
  • 39th ESMO Congress (ESMO); 09/2014
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background: Aviscumine, a recombinant plant protein, is an immune modulator that induces ribotoxic stress at the 28S ribosomal RNA subunit. In this way cytokine release and T-cell responses are enhanced. This phase II trial was conducted to test the efficacy and safety of aviscumine in patients with systemically pre-treated metastatic melanoma stage IV. Methods: A total of 32 patients with progressive stage IV melanoma after failure of standard therapy were enrolled onto a single-arm, multi-centre, open-label, phase II trial. All patients had an ECOG performance status of 0 or 1. Patients received 350 ng aviscumine twice weekly by subcutaneous injection until progression. The primary end points were progression-free survival (PFS) and overall survival (OS). Safety was assessed as adverse events (AEs). Tumor response was assessed every eight weeks and survival of patients was followed up to one year after the end of therapy. Thirty one patients (intent-to-treat population (ITT)) were assessed for efficacy; safety was assessed in the whole population. Results: One patient achieved a partial response (PR) and 10 patients showed stable disease/no change (SD). The median progression-free survival (mPFS) was 63 days (95% CI 57–85) and median overall survival (mOS) was 335 days (95% CI 210–604). In total 210 treatment-emergent adverse events were recorded. Grade 1 or 2 AEs occurred in 72% of patients and were mostly application-site effects such as pruritus Grade 3–4 treatment-emergent drug-related adverse events occurred in 9% of patients. Conclusion: These results suggest that aviscumine may have a clinical impact in patients with previously treated metastatic melanoma and provide rationale for further clinical evaluation of this agent. In the light of effective new immune checkpoint blockers it might be a candidate for combinations with these agents. Trial registration: ClinicalTrials.gov: NCT00658437
    08/2014; 2. DOI:10.1186/s40425-014-0027-z
  • [Show abstract] [Hide abstract]
    ABSTRACT: Ipilimumab is an approved anti-cytotoxic T-lymphocyte-associated antigen-4 monoclonal antibody introducing immune responses in melanoma patients. Treatment experiences from named-patient programs support the evaluation of the efficacy and tolerability of new medicines under usual circumstances of health care practice. Here, the largest ever reported cohort treated with ipilimumab 3 mg/kg alone is described.
    Journal of immunotherapy (Hagerstown, Md.: 1997) 07/2014; DOI:10.1097/CJI.0000000000000046 · 3.35 Impact Factor
  • C Ulrich, U Hillen, R Gutzmer
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background Surgical treatment of acral lentiginous melanomas with wide excisional margins as recommended often requires amputation of distal extremities. The current study analyzes whether smaller excisions in combination with a complete histological evaluation of the excisional margins (3D histology) have a negative impact on the prognosis. Patients and methods304 patients were retrospectively evaluated. 192 patients with reduced excisional margins followed by 3D histology (group A) were compared with 112 patients treated with conventional wide margins (group B). The outcome of both groups was compared. ResultsThe median tumor thickness was higher in group A (p = 0.022) and ulcerations occured more frequently (p = 0.017). The median excisional margin was 8 mm in group A and 20 mm in group B (p < 0.0001). 10.9 % (4.2 % invasive) of group A und 8.9 % (4.5 % invasive) of group B (p = 0.577) developed a local recurrence in a median of 40 months. The melanoma specific 10-year survival was 66.8 % in group A und 63.4 % in group B (p = 0.531). There was no difference in survival of patients with or without local recurrence (p = 0.643). Conclusions Excision with small margins followed by 3D histology is not inferior to conventional surgery with wide margins in terms of the rate of local and has no negative impact on prognosis or the further course of the disease. Local recurrences are rare and do not influence patient survival.
    Journal der Deutschen Dermatologischen Gesellschaft 07/2014; 12(10). DOI:10.1111/ddg.12342 · 1.40 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The incidence of non-melanoma skin cancer (NMSC) is increasing. Squamous cell carcinoma of the skin (SCC) is a tumor of the elderly. Due to the increasing life expectancy, SCC will become more and more frequent in the future. Generally SCC has a favorable prognosis. Standard therapy is microscopically- controlled excision. Therapy of advanced and metastatic SCC is still challenging. Patients with regional lymph node metastasis have ten-year survival rates less than 20 %; patients with distant metastases less than 10 %. Immunosuppression has been shown to be one of the key prognostic factors for metastasis. The article reviews SCC and focusses on patients being at risk for an unfavorable course.
    Der Hautarzt 06/2014; 65(7). DOI:10.1007/s00105-013-2734-7 · 0.54 Impact Factor

Publication Stats

3k Citations
754.60 Total Impact Points

Institutions

  • 1997–2015
    • Hannover Medical School
      • • Department for Dermatology and Allergy
      • • Clinic for Dermatology, Allergology and Venerology
      Hanover, Lower Saxony, Germany
  • 2014
    • Medical University of Graz
      Gratz, Styria, Austria
  • 2013
    • University of Veterinary Medicine Hannover
      Hanover, Lower Saxony, Germany
    • Klinikum Ludwigshafen
      Ludwigshafen, Rheinland-Pfalz, Germany
  • 2008
    • University of Tuebingen
      • Department of Dermatology
      Tübingen, Baden-Wuerttemberg, Germany
  • 2004
    • Hochschule Hannover
      Hanover, Lower Saxony, Germany
    • Georg-August-Universität Göttingen
      Göttingen, Lower Saxony, Germany