Stephanie Brandlein - Academia.edu (original) (raw)
Papers by Stephanie Brandlein
Molecular Imaging and Biology, Apr 11, 2019
PurposeThe use of [18F]fluoroethyl)-l-tyrosine ([18F]FET) positron emission tomography/computed t... more PurposeThe use of [18F]fluoroethyl)-l-tyrosine ([18F]FET) positron emission tomography/computed tomography (PET/CT) has proven valuable in brain tumor management. This study aimed to investigate the prognostic value of radiotracer uptake in newly diagnosed grade II or III gliomas according to the current 2016 World Health Organization (WHO) classification.ProceduresA total of 35 treatment-naive patients (mean age, 48 ± 17 years) with histologically proven WHO grade II or III gliomas as defined by the current 2016 WHO classification were included. Static PET/CT imaging was performed 20 min after intravenous [18F]FET injection. Images were assessed visually and semi-quantitatively using regions of interest for both tumor (SUVmax, SUVmean) and background (BKGmean) to calculate tumor-to-background (TBR) ratios. The association among histological results, molecular markers (including isocitrate dehydrogenase enzyme and methylguanine-DNA methyltransferase status), clinical features (age), and PET findings was tested and compared with outcome (progression-free [PFS] and overall survival [OS]).ResultsFourteen patients presented with grade II (diffuse astrocytoma n = 10, oligodendroglioma n = 4) and 21 patients with grade III glioma (anaplastic astrocytoma n = 15, anaplastic oligodendroglioma n = 6). Twenty-seven out of the 35 patients were PET-positive (grade II n = 8/14, grade III n = 19/21), with grade III tumors exhibiting significantly higher amino acid uptake (TBRmean and TBRmax; p = 0.03 and p = 0.02, respectively). PET-negative lesions demonstrated significantly prolonged PFS (p = 0.003) as compared to PET-positive gliomas. PET-positive disease had a complementary value in prognostication in addition to patient age, glioma grade, and molecular markers.ConclusionsAmino acid uptake as assessed by [18F]FET-PET/CT imaging is useful as non-invasive read-out for tumor biology and prognosis in newly diagnosed, treatment-naive gliomas according to the 2016 WHO classification.
Purpose: Glucose-regulated protein (GRP) 78 is overexpressed in multiple myeloma, and both its su... more Purpose: Glucose-regulated protein (GRP) 78 is overexpressed in multiple myeloma, and both its surface expression and its biologic significance as key sensor of the unfolded protein response make GRP78 an ideal candidate for immunotherapeutic intervention. The monoclonal antibody PAT-SM6 targets surface GRP78 and leads to disease stabilization when used as single agent in a clinical trial. In this article, we evaluated expression of GRP78 in relapsed-refractory disease and explored PAT-SM6 therapy in combination regimens. Experimental Design: GRP78 expression was immunohistochemically analyzed during disease progression and development of drug resistance throughout different stages of multiple myeloma. Activity of PAT-SM6 was evaluated in combination with anti-multiple myeloma agents lenalidomide, bortezomib, and dexamethasone in vitro. Finally, we report on a multiple myeloma patient with relapsed-refractory disease treated with PAT-SM6 in combination with bortezomib and lenalidomide. Results: Although sGRP78 expression was present at all stages, it increased with disease progression and was even strongly elevated in patients with drug-resistant and extramedullary disease. Pretreatment with dexamethasone as well as dual combination of PAT-SM6/lenalidomide further increased sGRP78 expression and consecutively showed synergistic anti-multiple myeloma effects with PAT-SM6 in proliferation assays. As proof of concept, a 62-year-old male with triple resistant multiple myeloma treated with PAT-SM6, bortezomib, and lenalidomide experienced partial remission of both intra-and extramedullary lesions. Conclusions: PAT-SM6 therapy in combination regimens showed efficacy in relapsed-refractory multiple myeloma. Clin Cancer Res; 22(17); 4341-9. Ó2016 AACR.
Molecular Cancer Therapeutics, Nov 1, 2007
B208 Heat-shock proteins (HSPs) are critical components of a cell9s defense mechanism against inj... more B208 Heat-shock proteins (HSPs) are critical components of a cell9s defense mechanism against injury associated with adverse stresses. Although HSPs are very beneficial to the normal cell, cancer cells often over-express HSPs on the membrane and use them in response to stresses associated with various therapies (hyperthermia, chemotherapy, radiation), diminishing the treatment effects. The fully human monoclonal antibody SAM-6 is a germ-line coded IgM, isolated from a gastric cancer patient by TRIOMA technology. SAM-6 induces an excess of intracellular lipids by overfeeding malignant cells with oxidized LDL. The treated cells over-accumulate depots of cholesterol-esters and triglycerides and undergo apoptosis. Here we show that the SAM-6 antibody binds to a tumor-specific O-linked carbohydrate moiety expressed on a membrane-bound variant of GRP78, which is a member of the HSP70 family. These data show that cancer-specific modifications of cell surface protection molecules are ideal targets for immuno-therapeutical approaches.
Cancer Research, May 1, 2008
AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA 2128 Natural or innate immunity is the first... more AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA 2128 Natural or innate immunity is the first line defence against cancer. Antibodies play a major role in these processes and the majority of these germ-line coded antibodies are pentameric IgMs. Several of these natural antibodies have already been successfully used in clinical trials and for definition of new cancer targets. Natural immunity is also the bridge to immunological memory, resulting in affinity maturated IgG antibodies. We used the human hybridoma technology to screen cancer patients in a huge study on the humoral immune response for tumor-specific IgGs. Interestingly, we were able to isolate not only many cancer specific IgM antibodies, but also several tumor-reacting IgGs. We show in this study that these monomeric immunoglobulins show specific binding to carcinoma and melanoma cells, inhibit proliferation and induce apoptosis, similar to the already characterized natural IgMs. However, when sequenced, all found IgGs are not affinity-maturated. Biochemical studies on the antigens are underway. Natural IgG antibodies have been detected in sera, in quantities less than 1%, but so far, no one has been isolated, established and characterized in detail. This is the first report on natural monoclonal IgG antibodies with anti-cancer activity.
Springer eBooks, Oct 20, 2007
Introduction: The human monoclonal Ig-M antibody LM-1 was isolated by using the human hybridoma t... more Introduction: The human monoclonal Ig-M antibody LM-1 was isolated by using the human hybridoma technique with lymphocytes of lymph nodes, spleens and tumor tissue from patients with different gastrointestinal cancers. Immunohistochemical studies and apoptosis assays in colon cancer cell lines showed both the tumor specific binding of LM-1 and the induction of apoptosis in vitro. The aim of this study is the analysis of the tumoricide in vivo effects of LM-1 in a colon cancer nude mouse model. Material and methods: After intraportal injection of 5 × 106 HT-29 colon cancer cells in balb c nu/nu mice (n = 10) on day 0, the intraperitoneal injection of LM-1 was performed on days 7, 9, 11, 13, and 15 with 260 µg LM-1 in 300 µl medium. All animals were sacrificed after 8 weeks or in case of cachexy. The liver, lung, spleen and bone marrow of each animal was stored fixed in formalin of as fresh tissue. Histological and immunohistochemical analysis and TUNEL-assays were performed for the detection of liver metastases and the rate of apoptotic cells respectively. For the detection of tumor cells in the bone marrow, a ck-20 pcr-analysis was performed. Nude mice with intraportal injection of HT-29 colon cancer cells without further therapy (n = 10) and with injection of an unspecific human Ig-M antibody (n = 10) served as control group 1 and 2 respectively. Results: The nude mice without LM-1 injection showed a significant higher loss of weight with multiple liver metastases in 80 % (control group 1) and 70 % (control group 2) of all mice. In mice treated with LM-1 antibody only 20 % of the animals showed metastases in the liver with an increased rate of apoptotic tumor cells seen in the TUNEL-assay. In the bone marrow of the mice treated with LM-1, CK-20 positive cells were detectable in 30 % of all mice compared to 90 % in both control groups. Conclusion: In this in vivo study in a colon cancer liver metastases nude mouse model, the tumoricide effects of LM-1, a human, monoclonal antibody, could be demonstrated. The decrease in the number of hepatic metastases and the reduction of CK-20 positive cells (tumor cells) in the bone marrow of LM-1 treated animals are objective parameters of the anti-tumor capacity of LM-1 in vivo.
PubMed, Jul 1, 2005
Precancerous epithelial lesions are sites of uncontrolled cellular proliferation generated by irr... more Precancerous epithelial lesions are sites of uncontrolled cellular proliferation generated by irreversible genetic alterations. Not all of those lesions progress to invasive cancer, some may even regress, but the early detection of abnormal cells can be crucial for patient survival. Immune surveillance mechanisms are responsible for the removal of transformed cells and antibodies play an important role in these immune processes. In the past, analysis of the immunoglobuline repertoire has focused mainly on xenoimmunizations or the investigation of cancer patient immunity. The human hybridoma technology (Trioma technique) offers the unique possibility to study the humoral immunity of healthy people. Using this technique a series of tumor-binding antibodies could be isolated which all have several features in common: they are germ-line coded IgM antibodies, they predominantly bind to carbohydrates on post-transcriptionally modified antigens, they induce apoptosis and, most importantly, they detect not only malignant cells but also precursor stages. These data demonstrate that the body has a comprehensive defense system against malignant cells based on the production of natural antibodies.
Journal of Clinical Oncology, Jun 20, 2007
21173 Background: Pancreatic malignancies belong to the top-five killers among all cancers worldw... more 21173 Background: Pancreatic malignancies belong to the top-five killers among all cancers worldwide. The 5-year survival rate with conventional therapy is below 5%. This shows that there is a big need for new therapeutical approaches. The fully human monoclonal antibody SAM-6 is a germ-line coded IgM, isolated from a cancer patient by TRIOMA technology. SAM-6 antibody binds to a modified O-linked carbohydrate moiety expressed on a membrane-bound variant of GRP78, which is a member of the HSP70 family. Heat-shock proteins (HSPs) are critical components of a cell's defense mechanism against injury associated with adverse stresses. They can protect cells against subsequent, otherwise lethal, outcome. Although HSPs are very beneficial to the normal cell, cancer cells often over-express HSPs on the membrane. They use them in response to stresses associated with various therapies, diminishing the treatment effects. Methods: In vitro and in vivo assays were used to investigate the apoptotic effects of antibody SAM-6 on pancreas cancer cells. Results: Binding of SAM-6 antibody to GRP78 induces an overfeeding of malignant cells with oxidized LDL. The cancer cells over-accumulate depots of cholesterol and triglyceride esters and finally undergo apoptosis. The deadly effect of SAM-6 could be demonstrated in vitro and in vivo in experimental animal models. Conclusions: These data show that cancer-specific modifications of cell surface protection molecules are ideal targets for immuno-therapeutical approaches. No significant financial relationships to disclose.
International Journal of Molecular Sciences, Dec 13, 2022
Protein-Based Oncopanel as Addition to Target Sequencing in Head and Neck Squamous Cell Carcinoma... more Protein-Based Oncopanel as Addition to Target Sequencing in Head and Neck Squamous Cell Carcinoma to Individualize Treatment Decisions.
medRxiv (Cold Spring Harbor Laboratory), May 16, 2022
Background: Molecular Tumor Boards (MTBs) are crucial instruments for discussing and allocating t... more Background: Molecular Tumor Boards (MTBs) are crucial instruments for discussing and allocating targeted therapies to suitable cancer patients based on genetic findings. Currently, limited evidence is available regarding the regional impact and the outreach component of MTBs. Methods: We analyzed MTB patient data from four neighboring Bavarian tertiary care oncology centers in Würzburg, Erlangen, Regensburg, and Augsburg, together constituting the WERA Alliance. Absolute patient numbers and regional distribution across the WERA-wide catchment area were weighted with local population densities. Results: Highest MTB patient numbers were found close to the four cancer centers. However, peaks in absolute patient numbers were also detected in more distant and rural areas. Moreover, weighting absolute numbers with local population density allowed us to identify regions within our catchment area relatively underrepresented in WERA MTBs. Conclusion: Investigating patient data from four neighboring cancer centers, we comprehensively assessed the regional impact of our MTBs. The results confirmed the success of existing collaborative structures with our regional partners. Additionally, our results help identifying potential white spots in precision oncology and establishing a joint WERA-wide outreach strategy. .
Cancers, Oct 14, 2022
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
Journal of Investigative Dermatology, Oct 1, 2020
This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Journal of Molecular Biology, Jul 1, 2019
Precision medicine requires in vitro models which will both faithfully recapitulate the features ... more Precision medicine requires in vitro models which will both faithfully recapitulate the features of an individual's disease and enable drug testing on a wide variety of samples covering the greatest range of phenotypes possible for a particular disease. Organoid technology has immense potential to fulfill this demand, but it will be necessary to develop robust protocols that enable the generation of organoids in a dependable manner from nearly every patient. Here we provide a user's guide, including detailed step-by-step protocols, to the establishment, isolation and verification of gastric cancer organoids. Selection strategies include omission of growth factors, addition of drugs, isolation of distinct phenotypes and generation of monoclonal lines. For confirmation of cancer identity, we use sequencing, drug selection, karyotyping and histology. While we specify these protocols for human gastric cancer organoids here, the methods described are applicable to organoids derived from other tissues as well.
Journal of Clinical Oncology, Jun 1, 2005
7347 Background: Lung cancer is a major cause of mortality worldwide and the overall survival rat... more 7347 Background: Lung cancer is a major cause of mortality worldwide and the overall survival rate has not improved significantly in the past 20 years. Of the more than 150,000 new cases of lung cancer diagnosed in Europe every year, less than 10% of patients can be cured and enjoy long-term survival. Methods: Antibody-based targeted therapy offers a new alternative to conventional radiation and chemotherapy. The human monoclonal IgM antibody LM-1 was isolated from a lung cancer patient by using the conventional human hybridoma technology (trioma technique). Results: Sequencing of the antibodies variable regions revealed that the antibody hasn’t undergone affinity maturation and is therefore a component of the innate immunity to cancer. It binds to a N-linked carbohydrate residue on a membrane molecule of about 70 kDa that is specifically expressed on malignant cells. LM-1 reacts with a series of different tumors but shows no binding to normal tissue. Furthermore the antibody LM-1 induces apoptosis in vit...
Onkologe, May 1, 2005
ABSTRACT
Journal of Clinical Oncology, Jul 15, 2004
4070 Background: The human IgM antibody SC-1 binds to CD55SC-1, which is exclusively expressed on... more 4070 Background: The human IgM antibody SC-1 binds to CD55SC-1, which is exclusively expressed on the surface of GC cells. After binding to CD55SC-1, SC-1 induces tumor specific apoptosis of GC cel...
Human antibodies, Sep 20, 2001
Advanced Drug Delivery Reviews, Aug 1, 2006
Natural IgM antibodies are typical victims of prejudices which originated in the mid 80 s. Over t... more Natural IgM antibodies are typical victims of prejudices which originated in the mid 80 s. Over the years, these molecules were considered as the pariahs among the immune competent molecules and their characteristic properties, like low affinity, cross-reactivity and pentameric structure, were assessed as useless, difficult, nebulous, etc. Today, mainly based on a few scientists' persistent work and the key discoveries on innate immune recognition, natural IgM antibodies are bback on stageQ. Their role in the immune response against bacteria, viruses, fungi and possibly modified self-components as well as in therapy and diagnosis of malignancies is accepted. All the so far negatively judged features are seen in a different light, e.g. low affinity seems to be good for function and does not exclude specificity, and cross-reactivity is no longer judged as unspecific, but instead as a very economic way of immune recognition. And at last, with the use of natural IgM antibodies, a new field of tumor-specific targets has been encountered, the carbo-neo-epitopes. Therefore, by having learned from nature, the renaissance of natural IgM antibodies opens a new area of cancer therapeutics and diagnostics.
Journal of Clinical Oncology, 2021
9036 Background: The nNGM centralizes molecular diagnostics, treatment recommendations and follow... more 9036 Background: The nNGM centralizes molecular diagnostics, treatment recommendations and follow-up reporting in NSCLC in Germany. Uncommon EGFR mutations pose a clinical challenge because they comprise a heterogenous group and analyses of treatment outcome are still scarce. Here, we analyzed follow-up data of patients with rare EGFR mutations and performed functional characterization of recurrent mutations with unknown function. Methods: This multicenter, retrospective analysis of uncommon EGFR mutations (excluding L858R-, T790M mutations and exon 19 deletions) includes stage IV patients with NSCLC from 12 nNGM centers. We categorized EGFR-mutations into 3 groups: uncommon EGFR mutations with known driver function, for instance E709X, G719X, S768I and L861Q (group 1), exon 20 insertions (group 2) and all other very rare mutations (group 3). Functional characterization of unknown mutations was performed by insertion mutagenesis in Ba/F3 cells and monitoring of growth factor-indepen...
Journal of Clinical Oncology, 2004
4070 Background: The human IgM antibody SC-1 binds to CD55SC-1, which is exclusively expressed on... more 4070 Background: The human IgM antibody SC-1 binds to CD55SC-1, which is exclusively expressed on the surface of GC cells. After binding to CD55SC-1, SC-1 induces tumor specific apoptosis of GC cel...
Molecular Imaging and Biology, Apr 11, 2019
PurposeThe use of [18F]fluoroethyl)-l-tyrosine ([18F]FET) positron emission tomography/computed t... more PurposeThe use of [18F]fluoroethyl)-l-tyrosine ([18F]FET) positron emission tomography/computed tomography (PET/CT) has proven valuable in brain tumor management. This study aimed to investigate the prognostic value of radiotracer uptake in newly diagnosed grade II or III gliomas according to the current 2016 World Health Organization (WHO) classification.ProceduresA total of 35 treatment-naive patients (mean age, 48 ± 17 years) with histologically proven WHO grade II or III gliomas as defined by the current 2016 WHO classification were included. Static PET/CT imaging was performed 20 min after intravenous [18F]FET injection. Images were assessed visually and semi-quantitatively using regions of interest for both tumor (SUVmax, SUVmean) and background (BKGmean) to calculate tumor-to-background (TBR) ratios. The association among histological results, molecular markers (including isocitrate dehydrogenase enzyme and methylguanine-DNA methyltransferase status), clinical features (age), and PET findings was tested and compared with outcome (progression-free [PFS] and overall survival [OS]).ResultsFourteen patients presented with grade II (diffuse astrocytoma n = 10, oligodendroglioma n = 4) and 21 patients with grade III glioma (anaplastic astrocytoma n = 15, anaplastic oligodendroglioma n = 6). Twenty-seven out of the 35 patients were PET-positive (grade II n = 8/14, grade III n = 19/21), with grade III tumors exhibiting significantly higher amino acid uptake (TBRmean and TBRmax; p = 0.03 and p = 0.02, respectively). PET-negative lesions demonstrated significantly prolonged PFS (p = 0.003) as compared to PET-positive gliomas. PET-positive disease had a complementary value in prognostication in addition to patient age, glioma grade, and molecular markers.ConclusionsAmino acid uptake as assessed by [18F]FET-PET/CT imaging is useful as non-invasive read-out for tumor biology and prognosis in newly diagnosed, treatment-naive gliomas according to the 2016 WHO classification.
Purpose: Glucose-regulated protein (GRP) 78 is overexpressed in multiple myeloma, and both its su... more Purpose: Glucose-regulated protein (GRP) 78 is overexpressed in multiple myeloma, and both its surface expression and its biologic significance as key sensor of the unfolded protein response make GRP78 an ideal candidate for immunotherapeutic intervention. The monoclonal antibody PAT-SM6 targets surface GRP78 and leads to disease stabilization when used as single agent in a clinical trial. In this article, we evaluated expression of GRP78 in relapsed-refractory disease and explored PAT-SM6 therapy in combination regimens. Experimental Design: GRP78 expression was immunohistochemically analyzed during disease progression and development of drug resistance throughout different stages of multiple myeloma. Activity of PAT-SM6 was evaluated in combination with anti-multiple myeloma agents lenalidomide, bortezomib, and dexamethasone in vitro. Finally, we report on a multiple myeloma patient with relapsed-refractory disease treated with PAT-SM6 in combination with bortezomib and lenalidomide. Results: Although sGRP78 expression was present at all stages, it increased with disease progression and was even strongly elevated in patients with drug-resistant and extramedullary disease. Pretreatment with dexamethasone as well as dual combination of PAT-SM6/lenalidomide further increased sGRP78 expression and consecutively showed synergistic anti-multiple myeloma effects with PAT-SM6 in proliferation assays. As proof of concept, a 62-year-old male with triple resistant multiple myeloma treated with PAT-SM6, bortezomib, and lenalidomide experienced partial remission of both intra-and extramedullary lesions. Conclusions: PAT-SM6 therapy in combination regimens showed efficacy in relapsed-refractory multiple myeloma. Clin Cancer Res; 22(17); 4341-9. Ó2016 AACR.
Molecular Cancer Therapeutics, Nov 1, 2007
B208 Heat-shock proteins (HSPs) are critical components of a cell9s defense mechanism against inj... more B208 Heat-shock proteins (HSPs) are critical components of a cell9s defense mechanism against injury associated with adverse stresses. Although HSPs are very beneficial to the normal cell, cancer cells often over-express HSPs on the membrane and use them in response to stresses associated with various therapies (hyperthermia, chemotherapy, radiation), diminishing the treatment effects. The fully human monoclonal antibody SAM-6 is a germ-line coded IgM, isolated from a gastric cancer patient by TRIOMA technology. SAM-6 induces an excess of intracellular lipids by overfeeding malignant cells with oxidized LDL. The treated cells over-accumulate depots of cholesterol-esters and triglycerides and undergo apoptosis. Here we show that the SAM-6 antibody binds to a tumor-specific O-linked carbohydrate moiety expressed on a membrane-bound variant of GRP78, which is a member of the HSP70 family. These data show that cancer-specific modifications of cell surface protection molecules are ideal targets for immuno-therapeutical approaches.
Cancer Research, May 1, 2008
AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA 2128 Natural or innate immunity is the first... more AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA 2128 Natural or innate immunity is the first line defence against cancer. Antibodies play a major role in these processes and the majority of these germ-line coded antibodies are pentameric IgMs. Several of these natural antibodies have already been successfully used in clinical trials and for definition of new cancer targets. Natural immunity is also the bridge to immunological memory, resulting in affinity maturated IgG antibodies. We used the human hybridoma technology to screen cancer patients in a huge study on the humoral immune response for tumor-specific IgGs. Interestingly, we were able to isolate not only many cancer specific IgM antibodies, but also several tumor-reacting IgGs. We show in this study that these monomeric immunoglobulins show specific binding to carcinoma and melanoma cells, inhibit proliferation and induce apoptosis, similar to the already characterized natural IgMs. However, when sequenced, all found IgGs are not affinity-maturated. Biochemical studies on the antigens are underway. Natural IgG antibodies have been detected in sera, in quantities less than 1%, but so far, no one has been isolated, established and characterized in detail. This is the first report on natural monoclonal IgG antibodies with anti-cancer activity.
Springer eBooks, Oct 20, 2007
Introduction: The human monoclonal Ig-M antibody LM-1 was isolated by using the human hybridoma t... more Introduction: The human monoclonal Ig-M antibody LM-1 was isolated by using the human hybridoma technique with lymphocytes of lymph nodes, spleens and tumor tissue from patients with different gastrointestinal cancers. Immunohistochemical studies and apoptosis assays in colon cancer cell lines showed both the tumor specific binding of LM-1 and the induction of apoptosis in vitro. The aim of this study is the analysis of the tumoricide in vivo effects of LM-1 in a colon cancer nude mouse model. Material and methods: After intraportal injection of 5 × 106 HT-29 colon cancer cells in balb c nu/nu mice (n = 10) on day 0, the intraperitoneal injection of LM-1 was performed on days 7, 9, 11, 13, and 15 with 260 µg LM-1 in 300 µl medium. All animals were sacrificed after 8 weeks or in case of cachexy. The liver, lung, spleen and bone marrow of each animal was stored fixed in formalin of as fresh tissue. Histological and immunohistochemical analysis and TUNEL-assays were performed for the detection of liver metastases and the rate of apoptotic cells respectively. For the detection of tumor cells in the bone marrow, a ck-20 pcr-analysis was performed. Nude mice with intraportal injection of HT-29 colon cancer cells without further therapy (n = 10) and with injection of an unspecific human Ig-M antibody (n = 10) served as control group 1 and 2 respectively. Results: The nude mice without LM-1 injection showed a significant higher loss of weight with multiple liver metastases in 80 % (control group 1) and 70 % (control group 2) of all mice. In mice treated with LM-1 antibody only 20 % of the animals showed metastases in the liver with an increased rate of apoptotic tumor cells seen in the TUNEL-assay. In the bone marrow of the mice treated with LM-1, CK-20 positive cells were detectable in 30 % of all mice compared to 90 % in both control groups. Conclusion: In this in vivo study in a colon cancer liver metastases nude mouse model, the tumoricide effects of LM-1, a human, monoclonal antibody, could be demonstrated. The decrease in the number of hepatic metastases and the reduction of CK-20 positive cells (tumor cells) in the bone marrow of LM-1 treated animals are objective parameters of the anti-tumor capacity of LM-1 in vivo.
PubMed, Jul 1, 2005
Precancerous epithelial lesions are sites of uncontrolled cellular proliferation generated by irr... more Precancerous epithelial lesions are sites of uncontrolled cellular proliferation generated by irreversible genetic alterations. Not all of those lesions progress to invasive cancer, some may even regress, but the early detection of abnormal cells can be crucial for patient survival. Immune surveillance mechanisms are responsible for the removal of transformed cells and antibodies play an important role in these immune processes. In the past, analysis of the immunoglobuline repertoire has focused mainly on xenoimmunizations or the investigation of cancer patient immunity. The human hybridoma technology (Trioma technique) offers the unique possibility to study the humoral immunity of healthy people. Using this technique a series of tumor-binding antibodies could be isolated which all have several features in common: they are germ-line coded IgM antibodies, they predominantly bind to carbohydrates on post-transcriptionally modified antigens, they induce apoptosis and, most importantly, they detect not only malignant cells but also precursor stages. These data demonstrate that the body has a comprehensive defense system against malignant cells based on the production of natural antibodies.
Journal of Clinical Oncology, Jun 20, 2007
21173 Background: Pancreatic malignancies belong to the top-five killers among all cancers worldw... more 21173 Background: Pancreatic malignancies belong to the top-five killers among all cancers worldwide. The 5-year survival rate with conventional therapy is below 5%. This shows that there is a big need for new therapeutical approaches. The fully human monoclonal antibody SAM-6 is a germ-line coded IgM, isolated from a cancer patient by TRIOMA technology. SAM-6 antibody binds to a modified O-linked carbohydrate moiety expressed on a membrane-bound variant of GRP78, which is a member of the HSP70 family. Heat-shock proteins (HSPs) are critical components of a cell's defense mechanism against injury associated with adverse stresses. They can protect cells against subsequent, otherwise lethal, outcome. Although HSPs are very beneficial to the normal cell, cancer cells often over-express HSPs on the membrane. They use them in response to stresses associated with various therapies, diminishing the treatment effects. Methods: In vitro and in vivo assays were used to investigate the apoptotic effects of antibody SAM-6 on pancreas cancer cells. Results: Binding of SAM-6 antibody to GRP78 induces an overfeeding of malignant cells with oxidized LDL. The cancer cells over-accumulate depots of cholesterol and triglyceride esters and finally undergo apoptosis. The deadly effect of SAM-6 could be demonstrated in vitro and in vivo in experimental animal models. Conclusions: These data show that cancer-specific modifications of cell surface protection molecules are ideal targets for immuno-therapeutical approaches. No significant financial relationships to disclose.
International Journal of Molecular Sciences, Dec 13, 2022
Protein-Based Oncopanel as Addition to Target Sequencing in Head and Neck Squamous Cell Carcinoma... more Protein-Based Oncopanel as Addition to Target Sequencing in Head and Neck Squamous Cell Carcinoma to Individualize Treatment Decisions.
medRxiv (Cold Spring Harbor Laboratory), May 16, 2022
Background: Molecular Tumor Boards (MTBs) are crucial instruments for discussing and allocating t... more Background: Molecular Tumor Boards (MTBs) are crucial instruments for discussing and allocating targeted therapies to suitable cancer patients based on genetic findings. Currently, limited evidence is available regarding the regional impact and the outreach component of MTBs. Methods: We analyzed MTB patient data from four neighboring Bavarian tertiary care oncology centers in Würzburg, Erlangen, Regensburg, and Augsburg, together constituting the WERA Alliance. Absolute patient numbers and regional distribution across the WERA-wide catchment area were weighted with local population densities. Results: Highest MTB patient numbers were found close to the four cancer centers. However, peaks in absolute patient numbers were also detected in more distant and rural areas. Moreover, weighting absolute numbers with local population density allowed us to identify regions within our catchment area relatively underrepresented in WERA MTBs. Conclusion: Investigating patient data from four neighboring cancer centers, we comprehensively assessed the regional impact of our MTBs. The results confirmed the success of existing collaborative structures with our regional partners. Additionally, our results help identifying potential white spots in precision oncology and establishing a joint WERA-wide outreach strategy. .
Cancers, Oct 14, 2022
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
Journal of Investigative Dermatology, Oct 1, 2020
This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Journal of Molecular Biology, Jul 1, 2019
Precision medicine requires in vitro models which will both faithfully recapitulate the features ... more Precision medicine requires in vitro models which will both faithfully recapitulate the features of an individual's disease and enable drug testing on a wide variety of samples covering the greatest range of phenotypes possible for a particular disease. Organoid technology has immense potential to fulfill this demand, but it will be necessary to develop robust protocols that enable the generation of organoids in a dependable manner from nearly every patient. Here we provide a user's guide, including detailed step-by-step protocols, to the establishment, isolation and verification of gastric cancer organoids. Selection strategies include omission of growth factors, addition of drugs, isolation of distinct phenotypes and generation of monoclonal lines. For confirmation of cancer identity, we use sequencing, drug selection, karyotyping and histology. While we specify these protocols for human gastric cancer organoids here, the methods described are applicable to organoids derived from other tissues as well.
Journal of Clinical Oncology, Jun 1, 2005
7347 Background: Lung cancer is a major cause of mortality worldwide and the overall survival rat... more 7347 Background: Lung cancer is a major cause of mortality worldwide and the overall survival rate has not improved significantly in the past 20 years. Of the more than 150,000 new cases of lung cancer diagnosed in Europe every year, less than 10% of patients can be cured and enjoy long-term survival. Methods: Antibody-based targeted therapy offers a new alternative to conventional radiation and chemotherapy. The human monoclonal IgM antibody LM-1 was isolated from a lung cancer patient by using the conventional human hybridoma technology (trioma technique). Results: Sequencing of the antibodies variable regions revealed that the antibody hasn’t undergone affinity maturation and is therefore a component of the innate immunity to cancer. It binds to a N-linked carbohydrate residue on a membrane molecule of about 70 kDa that is specifically expressed on malignant cells. LM-1 reacts with a series of different tumors but shows no binding to normal tissue. Furthermore the antibody LM-1 induces apoptosis in vit...
Onkologe, May 1, 2005
ABSTRACT
Journal of Clinical Oncology, Jul 15, 2004
4070 Background: The human IgM antibody SC-1 binds to CD55SC-1, which is exclusively expressed on... more 4070 Background: The human IgM antibody SC-1 binds to CD55SC-1, which is exclusively expressed on the surface of GC cells. After binding to CD55SC-1, SC-1 induces tumor specific apoptosis of GC cel...
Human antibodies, Sep 20, 2001
Advanced Drug Delivery Reviews, Aug 1, 2006
Natural IgM antibodies are typical victims of prejudices which originated in the mid 80 s. Over t... more Natural IgM antibodies are typical victims of prejudices which originated in the mid 80 s. Over the years, these molecules were considered as the pariahs among the immune competent molecules and their characteristic properties, like low affinity, cross-reactivity and pentameric structure, were assessed as useless, difficult, nebulous, etc. Today, mainly based on a few scientists' persistent work and the key discoveries on innate immune recognition, natural IgM antibodies are bback on stageQ. Their role in the immune response against bacteria, viruses, fungi and possibly modified self-components as well as in therapy and diagnosis of malignancies is accepted. All the so far negatively judged features are seen in a different light, e.g. low affinity seems to be good for function and does not exclude specificity, and cross-reactivity is no longer judged as unspecific, but instead as a very economic way of immune recognition. And at last, with the use of natural IgM antibodies, a new field of tumor-specific targets has been encountered, the carbo-neo-epitopes. Therefore, by having learned from nature, the renaissance of natural IgM antibodies opens a new area of cancer therapeutics and diagnostics.
Journal of Clinical Oncology, 2021
9036 Background: The nNGM centralizes molecular diagnostics, treatment recommendations and follow... more 9036 Background: The nNGM centralizes molecular diagnostics, treatment recommendations and follow-up reporting in NSCLC in Germany. Uncommon EGFR mutations pose a clinical challenge because they comprise a heterogenous group and analyses of treatment outcome are still scarce. Here, we analyzed follow-up data of patients with rare EGFR mutations and performed functional characterization of recurrent mutations with unknown function. Methods: This multicenter, retrospective analysis of uncommon EGFR mutations (excluding L858R-, T790M mutations and exon 19 deletions) includes stage IV patients with NSCLC from 12 nNGM centers. We categorized EGFR-mutations into 3 groups: uncommon EGFR mutations with known driver function, for instance E709X, G719X, S768I and L861Q (group 1), exon 20 insertions (group 2) and all other very rare mutations (group 3). Functional characterization of unknown mutations was performed by insertion mutagenesis in Ba/F3 cells and monitoring of growth factor-indepen...
Journal of Clinical Oncology, 2004
4070 Background: The human IgM antibody SC-1 binds to CD55SC-1, which is exclusively expressed on... more 4070 Background: The human IgM antibody SC-1 binds to CD55SC-1, which is exclusively expressed on the surface of GC cells. After binding to CD55SC-1, SC-1 induces tumor specific apoptosis of GC cel...