0000000000006556
AUTHOR
Helga Bernhard
showing 28 related works from this author
Chemotherapy in advanced pancreatic cancer
1997
Patients with advanced adenocarcinomas of the pancreas have an exceptionally poor prognosis. Modest activity has been demonstrated with single agents (response rates of 25% at best with 5-fluorouracil [5-FU] and mitomycin). Better results have not been obtained by combination chemotherapy. Improvements in the palliation have been achieved by treatment with 5-FU, folinic acid (FA), and interferon-alpha-2A (IFN-alpha) weekly in the context of a phase II trial. Of 57 evaluable patients, eight (14%) had a partial response (PR), eight (14%) a minor response (MR), and 28 (49%) had no change of disease (NC). The median survival time was 10 mo for patients with progressive disease. Twenty-two out o…
Treatment of advanced pancreatic cancer with 5-fluorouracil, folinic acid and interferon alpha-2A: results of a phase II trial.
1995
Interferon alpha-2a (IFN-alpha) and folinic acid (FA) have been shown to modulate the cytotoxic effects of 5-fluorouracil (5-FU) in the treatment of cancer. A phase II study was initiated to evaluate the effect of a combination of 5-FU/FA/IFN-alpha in patients with advanced pancreatic cancer. Sixty previously untreated patients with advanced adenocarcinoma of the pancreas were treated with 500 mg m-2 FU via an intravenous bolus 1 h after the initiation of a 2 h infusion of 500 mg m-2 FA. Before starting the FA infusion, 6 million units (MU) of IFN-alpha was administered subcutaneously. The treatment was repeated once a week. Of 57 evaluable patients, eight (14%) had a partial response (PR),…
Generation of tumor-reactive CTL against the tumor-associated antigen HER2 using retrovirally transduced dendritic cells derived from CD34+ hemopoiet…
2000
Abstract Ag-specific CD8+ CTL are crucial for effective tumor rejection. Attempts to treat human malignancies by adoptive transfer of tumor-reactive CTL have been limited due to the difficulty of generating and expanding autologous CTL with defined Ag specificity. The current study examined whether human CTL can be generated against the tumor-associated Ag HER2 using autologous dendritic cells (DC) that had been genetically engineered to express HER2. DC progenitors were expanded by culturing CD34+ hemopoietic progenitor cells in the presence of the designer cytokine HyperIL-6. Proliferating precursor cells were infected by a retroviral vector encoding the HER2 Ag and further differentiated…
Final results of the AIO 0307 study: A controlled, randomized, double-blind phase II study of FOLFOX6 or FOLFIRI combined with sorafenib (S) versus p…
2013
3586 Background: The oral multikinase inhibitor Sorafenib (S) inhibits angiogenesis and tumor growth in preclinical models of CRC. This study investigated the addition of S to standard 2nd line chemotherapy (CTX). Methods: Patients (pts) with mCRC and progression after first-line therapy with an oxaliplatin- or irinotecan based fluoropyrimidine containing regimen ± Bevacizumab (Bev), were randomized to receive chemotherapy (CTX) (FOLFOX6 or FOLFIRI) + S (400 mg bid) or CTX + placebo (P). 240 pts were planned to be enrolled to ensure a power of 80% if median progression-free survival (PFS) with S is increased by 2 months compared to P. Results: Between 04/09 and 10/11, 101 pts were enrolled…
Adjuvant MUC vaccination with tecemotide after resection of colorectal liver metastases: a randomized, double-blind, placebo-controlled, multicenter …
2020
ABSTRACT Resection of colorectal liver metastases (CRLM) is a potential curative treatment for patients with metastatic colorectal cancer (mCRC) with liver-limited disease (LLD). Although long-term survival improved considerably within the last decades, high recurrence rates of 50-75% after resection remain a major challenge.Tecemotide (L-BLP25) is an antigen-specific cancer vaccine inducing immunity against mucin-1 (MUC1). The LICC trial aimed to improve survival in patients with mCRC after R0/R1 resection of CRLM. LICC was a binational, randomized, double-blind, placebo-controlled, multicenter phase 2 study including patients with R0/R1 resected CRLM without evidence of metastatic disease…
Gen-Immuntherapie zur Gen-Immuntherapie zur Behandlung von Malignomen Behandlung von Malignomen
2001
Entartete Zellen unterliegen, so eine derzeitige Hypothese, der auseren Kontrolle durch das Immunsystem. Dies ist in der Lage, von Tumorzellen prozessierte und uber Haupthistokompatibilitatskomplexe (MHC) prasentierte Peptide via T-Zellen zu erkennen. Da Tumorzellen sich bei der Prasentation von Peptiden in den MHC-Komplexen durch Peptid-Quantitat und/oder Peptid-Qualitat (so genannte Tumorantigene) von den normalen Zellen unterscheiden, kann dies zu ihrer Erkennung und Zerstorung fuhren. Kommt es zur Manifestation eines Malignoms, so hat offensichtlich diese immunologische Kontrolle versagt. Die Grunde hierfur sind vielfaltig: Verlust der Fahigkeit zur Prasentation von Tumorantigenen, redu…
Melanoma-Reactive Class I-Restricted Cytotoxic T Cell Clones Are Stimulated by Dendritic Cells Loaded with Synthetic Peptides, but Fail to Respond to…
2003
Abstract Immunization with heat shock proteins (hsp) isolated from cancer cells has been shown to induce a protective antitumor response. The mechanism of hsp-dependent cellular immunity has been attributed to a variety of immunological activities mediated by hsp. Hsp have been shown to bind antigenic peptides, trim the bound peptides by intrinsic enzymatic activity, improve endocytosis of the chaperoned peptides by APCs, and enhance the ability of APCs to stimulate peptide-specific T cells. We have investigated the potential capacity of hsp70 and gp96 to function as a mediator for Ag-specific CTL stimulation in an in vitro model for human melanoma. Repetitive stimulation of PBLs by autolog…
A randomized, double-blinded, placebo-controlled multicenter phase II trial of adjuvant immunotherapy with tecemotide (L-BLP25) after R0/R1 hepatic c…
2019
480 Background: Hepatic metastasectomy is the only potential curative treatment option for stage IV colorectal cancer (CRC) limited to liver metastases (LM). After R0 resection of LM the high recurrence rate remains a major challenge. L-BLP25 is an antigen-specific cancer vaccine targeting mucin 1 (MUC1). The LICC trial aimed to improve survival outcome in mCRC patients (pts) after R0/R1 LM resection. Methods: This LICC trial, a binational, multicenter, double-blinded, placebo controlled phase II trial, included pts with stage IV LM limited CRC after resection of primary tumor and LM (R0/R1) within the last 8 weeks, ECOG 0/1 and adequate organ function. Pts were 2:1 randomized to receive L…
Induction of tumor-cell lysis by bi-specific antibody recognizing ganglioside GD2 and T-cell antigen CD3
1993
Human tumor cells expressing ganglioside GD2 were lysed by various effector populations targeted with an anti-CD3-anti-GD2 bi-specific antibody (BAb CD3 x GD2). This antibody-heteroconjugate was prepared by chemically cross-linking the OKT-3 monoclonal antibody (MAb) reactive with CD3 antigen on T lymphocytes with the ganglioside MAb ME 361, which binds preferentially to the tumor-associated ganglioside GD2. The specificity of target-cell lysis by the cytotoxic T cells (CTL) was mediated by the specificity of the targeting antibody: GD2-negative cells were not lysed in the presence of the CD3 x GD2 BAb. A dose-dependent response was observed in a range of 10 to 10,000 ng/ml. In contrast, 2 …
Generation of cytotoxic T-cell responses with synthetic melanoma-associated peptidesin vivo: Implications for tumor vaccines with melanoma-associated…
1996
Peptide epitopes derived from differentiation antigens of the melanocyte lineage have been identified in human melanomas and normal cultured melanocytes as targets for MHC-restricted cytotoxic T lymphocytes (CTL). Characterization of multiple CTL-defined antigenic determinants and the presence of corresponding precursor CTL open perspectives for the development of antigen-based vaccines. In the present study, we determined the CTL reactivity against melanoma-associated peptides derived from Melan A/MART-1, tyrosinase and gp100/Pmel17 in 10 HLA-A2+ melanoma patients and 10 healthy individuals. Then, we examined the immunological effects and toxicity of intradermal inoculation of synthetic me…
Azacitidine-Containing Induction Regimens Followed by Azacitidine Maintenance Therapy in High Risk Acute Myeloid Leukemia: First Results of the Rando…
2012
Abstract Abstract 412 Background: A large proportion of patients are currently not eligible for genotype-adapted strategies in acute myeloid leukemia (AML), in particular those lacking specific genetic aberrations such as PML-RARA, CBFB-MYH11, RUNX1-RUNX1T1, NPM1 or activating FLT3 mutations. This subgroup of patients accounts for about one-third of all AML patients and mainly includes the large group of AML with myelodysplasia-related changes, AML with recurrent cytogenetic abnormalities [inv(3) or t(3;3), t(9;11), t(v;11q23)] and cytogenetically normal AML (CN-AML) with wild-type NPM1 and FLT3. Prognosis in this subgroup of patients is generally poor. Azacitidine has been shown to be acti…
Survival after secondary liver resection in metastatic colorectal cancer: Comparing data of three prospective randomized European trials ( LICC , CEL…
2021
Metastatic colorectal cancer (mCRC) patients with liver-limited disease (LLD) have a chance of long-term survival and potential cure after hepatic metastasectomy. However, the appropriate postoperative treatment strategy is still controversial. The CELIM and FIRE-3 studies demonstrated that secondary hepatic resection significantly improved overall survival. The objective of this analysis was to compare these favorable outcome data with recent results from the LICC trial investigating the antigen-specific cancer vaccine tecemotide (L-BLP-25) as adjuvant therapy in mCRC patients with LLD after R0/R1 resection. Data from mCRC patients with LLD and secondary hepatic resection from each study w…
Allorestricted T lymphocytes with a high avidity T-cell receptor towards NY-ESO-1 have potent anti-tumor activity.
2009
The cancer-testis antigen NY-ESO-1 has been targeted as a tumor-associated antigen by immunotherapeutical strategies, such as cancer vaccines. The prerequisite for a T-cell-based therapy is the induction of T cells capable of recognizing the NY-ESO-1-expressing tumor cells. In this study, we generated human T lymphocytes directed against the immunodominant NY-ESO-1(157-165) epitope known to be naturally presented with HLA-A*0201. We succeeded to isolate autorestricted and allorestricted T lymphocytes with low, intermediate or high avidity TCRs against the NY-ESO-1 peptide. The avidity of the established CTL populations correlated with their capacity of lysing HLA-A2-positive, NY-ESO-1-expre…
Chronifizierte paranoid-halluzinatorische Psychose als Erstmanifestation einer HIV-Infektion?
2008
In a 36-year-old patient an acute onset of psychosis occurred, probably due to HIV infection. For one year HIV-infection with reduced T4/T8 ratio had been known without clinical manifestation (stage IV B of the CDC-classification). He developed chronic delusional hallucinations, which persisted for more than one year in spite of adequate psychoactive drug therapy. So far AIDS-related dementia has not become evident. Focal lesions caused by opportunistic infections or tumour were excluded by computed tomography and magnetic resonance imaging. The latter revealed several small lesions and the brain scan showed a nonhomogeneous pattern of cerebral blood flow. CSF-examination disclosed a mild l…
Dendritic Cells Lose Ability to Present Protein Antigen after Stimulating Antigen-Specific T Cell Responses, despite Upregulation of MHC Class II Exp…
2000
Abstract Immature dendritic cells (DC) take up, process and present protein antigens; mature DC are specialized for stimulating primary T cell responses with increased expression of MHC class II and co-stimulatory molecules, but are incapable of processing and presenting soluble protein. The current study examined whether maturation of DC is triggered by T cell recognition of antigens presented by immature DC. Human DC derived from CD34+ progenitor cells by culture with granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-6 (IL-6) in serum-free medium could prime naive CD4+ T cells to keyhole limpet hemocyanin (KLH) and ovalbumin (OVA). The cultured DC retained the abil…
Ganglioside GD3 shedding by human malignant melanoma cells
1989
Gangliosides appear to be important target molecules for immunological effector mechanisms on neuro-ectodermal tumors. Therefore in vitro studies were performed to examine whether ganglioside GD3, which is highly expressed on the cell surface of cultured human melanoma cells, is being shed into the culture medium. Measurable quantities of gangliosides GM3 and in particular GD3 were shed by the melanoma cells we have tested as detected on thin-layer chromatograms (TLC) stained with orcinol. Ganglioside GD3 was also evidenced by immunostaining with anti-GD3 MAb and by ELISA. The concentration of GD3 in the supernatant of human melanoma cells depended on the ganglioside pattern of the cell lin…
Paclitaxel and carboplatin vs gemcitabine and vinorelbine in patients with adeno- or undifferentiated carcinoma of unknown primary: a randomised pros…
2008
Platinum/taxane combinations are widely used in patients with carcinoma of unknown primary (CUP), yielding response rates of 30% and median overall survival of 9-11 months in selected patients. Yet these combinations have not been subject to a randomised trial to overcome selection bias, a major problem in CUP. We randomised 92 patients to either paclitaxel/carboplatin (arm A) or the non-platinum non-taxane regimen gemcitabine/vinorelbine (arm B). The primary endpoint was rate of practicability as defined: application of >or=2 cycles of therapy (1) with a maximal delay of 1 week (2) and survival of >or=8 months (3). Practicability was shown in 52.4% (95% CI 36-68%) in arm A and in 42.2% (95…
In Vitro Priming to Tumor-Associated Proteins
1997
Cancer can be cured in mice by adoptive transfer of T cells specific for the malignant cells or by vaccination to tumor-specific antigens. The application of immunotherapy to the treatment of human cancer hinges on the identification of human tumor antigens to which specific immunity can be elicited.
Cellular immune response to human renal-cell carcinomas: Definition of a common antigen recognized by HLA-A2-restricted cytotoxic T-Lymphocyte (CTL) …
1994
Cytotoxic T lymphocyte (CTL) clones directed against autologous renal-cell carcinoma (RCC) cell lines were generated by mixed lymphocyte/tumor-cell culture (MLTC) using peripheral blood lymphocytes (PBL). A CD8+, CD4- CTL clone MZ1257-CTL 5/30 with high cytolytic activity for the autologous tumor cell line MZ1257-RCC was established. No lysis of the autologous EBV-transformed B lymphocytes (EBV-B) or K562 cells was observed. A panel of HLA-A2-matched allogeneic RCC lines was recognized by CTL 5/30. Further specificity analysis showed a cross-reactivity with HLA-A2-matched allogeneic tumor cells of various origins, especially melanoma. CTL 5/30 was also cross-reactive with several HLA-A2-pos…
The gp130-stimulating designer cytokine hyper-IL-6 promotes the expansion of human hematopoietic progenitor cells capable to differentiate into funct…
2000
Abstract Objective . Hyper-IL-6, a fusion protein of interleukin-6 and its specific receptor, together with stem cell factor leads to the proliferation of primitive hematopoietic progenitor cells. Based on these findings, the current study examined whether hyper-IL-6 promotes the growth of precursor cells that can be further differentiated into dendritic cells in the presence of additional cytokines. Methods . Dendritic cell cultures were generated from CD34 + hematopoietic progenitor cells derived either from bone marrow or from peripheral blood. CD34 + cells were cultured in the presence of cytokines for 2 weeks and then used for phenotyping and T-cell stimulation assays. Results . Hyper-…
Recognition of human renal cell carcinoma and melanoma by HLA-A2-restricted cytotoxic T lymphocytes is mediated by shared peptide epitopes and up-reg…
1996
Cytotoxic T lymphocytes (CTL) have previously been isolated from peripheral blood of patients with renal cell carcinoma (RCC). The CD8-positive CTL line MZ1257-CTL-5 (CTL-5) has been shown to lyse autologous cultured RCC cells in an HLA-A2 restricted fashion. Allogeneic, HLA-A2-matched RCC and melanoma cell lines were also lysed by CTL-5, suggesting that melanoma and renal cancer share antigenic determinants. The aim of the study was to determine whether RCC and melanoma share peptide epitopes that are recognized by CTL-5 in the context of HLA-A2 molecules. Peptides were acideulated from various cell lines, separated by reversed phase high performance liquid chromatography (RP-HPLC), and as…
Survival after secondary liver resection in metastatic colorectal cancer: A comparative analysis of the LICC trial with historical controls (CELIM, F…
2019
e15025 Background: Metastatic colorectal cancer (mCRC) patients (pts) with liver-limited disease (LLD) have a chance of long-term overall survival (OS) and potential cure after complete hepatic metastasectomy. The appropriate postoperative treatment strategy is still controversial. L-BLP25 as antigen-specific cancer vaccine targeting mucin 1 (MUC1) was recently evaluated as adjuvant therapy in mCRC pts after R0/R1 LLD resection (LICC trial, NCT01462513). Here we compared the LICC surveillance program and efficacy results for secondarily resected LLD pts versus historical controls, i.e. the CELIM trial (Folprecht et al, Ann Oncol 2014) of potentially resectable LLD mCRC pts and a FIRE-3-LLD…
Immunorecognition of different ganglioside epitopes on human normal and melanoma tissues.
1992
There is increasing evidence that cell-surface gangliosides play a role in tumor growth, progression and metastases. In order to determine the frequency of ganglioside GD3 in patients with metastatic malignant melanoma for further therapeutic trials, GD3 ganglioside expression was determined in 119 tissue samples. Of these melanomas, 93% (111/119) were R-24-positive, which indicates the value of this diagnostic marker for melanoma. To study the structural epitopes of gangliosides, 10 ganglioside antibodies with defined specificities and affinities were tested on over 100 fresh-frozen tissue specimens of human normal and melanoma tissues. All the antibodies tested recognize the ganglioside G…
Survival after primary liver resection in metastatic colorectal cancer: A comparative analysis of the LICC trial with historical controls (FFCD ACHBT…
2019
e15019 Background: Metastatic colorectal cancer (mCRC) patients (pts) with liver-limited disease (LLD) have a chance of long-term survival and cure after hepatic metastasectomy. The optimal treatment after primary liver resection remains controversial. Here we compare results from the LICC trial with historical controls, the FFCD ACHBTH AURC 9002 trial (FFCD; Portier et al., 2006) and the EORTC Intergroup trial 40983 (EORTC; Nordlinger et al., 2008, 2013). The three trials investigated pts with mCRC LLD who underwent primary hepatic resection. Methods: LICC, FFCD and EORTC were compared regarding pts characteristics, treatment, surveillance and efficacy outcomes. LICC pts received the adju…
Reduced virus specific T helper cell induction by autologous dendritic cells in patients with chronic hepatitis B-restoration by exogenous interleuki…
2002
SUMMARYInsufficient stimulatory capacities of autologous dendritic cells (DC) may contribute in part to impaired T cell stimulation and therefore viral persistence in patients with chronic hepatitis B virus (HBV) infection. In order to characterize the antigen presenting functions of DC from chronic HBV carriers and controls antigen specific T cell responses were analysed. CD34+ peripheral blood progenitor cells were differentiated to immature DC in the presence of GM-CSF, IL-6/IL-6R fusion protein and stem cell factor. Proliferative CD4+ T cell responses and specific cytokine release were analysed in co-cultures of DC pulsed with HBV surface and core antigens or tetanus toxoid and autologo…
Antibodies to cell surface ganglioside GD3 perturb inductive epithelial-mesenchymal interactions
1988
Abstract Most epithelial sheets emerge during embryogenesis by a branching and growth of the epithelium. The surrounding mesenchyme is crucial for this process. We report that branching morphogenesis and the formation of a new epithelium from the mesenchyme in the embryonic kidney can be blocked by a monoclonal antibody reacting with a surface glycolipid, disialoganglioside G D3 . In contrast, a more than 10-fold excess of antibodies to adhesive glycoproteins (N-CAM, L -CAM, fibronectin) fails to inhibit morphogenesis. Although the anti-G D3 antibody affected epithelial development, the disialoganglioside G D3 was expressed not in the epithelium, but in the mesenchyme surrounding the develo…
Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epiru…
2019
Background Docetaxel-based chemotherapy is effective in metastatic gastric and gastro-oesophageal junction adenocarcinoma. This study reports on the safety and efficacy of the docetaxel-based triplet FLOT (fluorouracil plus leucovorin, oxaliplatin and docetaxel) as a perioperative therapy for patients with locally advanced, resectable tumours. Methods In this controlled, open-label, phase 2/3 trial, we randomly assigned 716 patients with histologically-confirmed advanced clinical stage cT2 or higher or nodal positive stage (cN+), or both, resectable tumours, with no evidence of distant metastases, via central interactive web-based-response system, to receive either three pre-operative and t…
Tumor associated antigens in human renal cell carcinoma: MHC restricted recognition by cytotoxic T lymphocytes.
1996
Based on previous studies in human melanoma leading to the molecular cloning of genes encoding peptide antigens recognized by MHC-restricted cytotoxic T lymphocytes (CTL) we extended our efforts to renal cancer systems established in tissue culture. In two patients we obtained stable CD8+ CTL clones with high cytolytic activity for the corresponding autologous tumor cell line in vitro. Neither autologous EBV-transformed B lymphocytes or PHA-activated PBL nor natural killer targets K562 were lysed by these CTL clones. MZ1257-RCC CTL5-30 lysed autologous tumor cells as well as normal kidney cell cultures in an HLA-A2 restricted fashion. Further specificity analysis showed cross reactivity wit…