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NEWS
Data from the FOCUS trial published
12 Apr 2025
Head and neck squamous cell carcinoma (HNSCC) is a prevalent cancer with growing incidences globally. Immune checkpoint therapy has been approved, but durable responses are only achieved in a subset of patients while a majority not even exhibits short-term responses. One contributing factor are insufficient T cell effector responses caused by the complex tumor microenvironment in HNSCC. To overcome this obstacle, research is focused on therapeutic cancer vaccines, like UV1, that target human telomerase (hTERT), which is commonly reactivated in cancers, including HNSCC. UV1 consists of three highly immunogenic peptides that specifically target hTERT to stimulate T cell responses.
To test efficacy of this vaccination approach in combination with immune checkpoint blockade in patients with metastatic or recurrent HNSCC, we designed the two-armed, open-label, randomized, multicenter phase 2 FOCUS study. While most patients developed robust UV1-directed T cell responses, the median overall survival was comparable to patients who only received immune therapy.
Congratulations to Anna Brandt and the whole team for this effort!
Read the whole story at MED.
New immune repertoire data for DADA2 patients published in JACI
08 Feb 2025
Deficiency of adenosine deaminase 2 (DADA2) is an autoinflammatory disease with a broad range of immune-related clinical features. DADA2 is caused by hypomorphic mutations in the ADA2 gene that encodes a protein acting in extracellular adenosine metabolism.
To better understand the immunological underpinnings, we profiled immunoglobulin and cytokine levels as well as peripheral B and T cell phenotypes in 52 DADA2 patients and combined these data with a BCR/TCR immune repertoire analysis.
A high proportion of patients presented with hypogamma-globulinemia and cytopenias and displayed high levels of TNF, BAFF and soluble CD40 that persisted under anti-TNF therapy. Moreover, DADA2 patients exhibited immuno-genetic imprints, especially in the B cell compartment, that are related to autoimmunity and lymphoma. Using these data, we trained a machine learning algorithm that was able to separate DADA2 with high accuracy from healthy individuals based on immunogenetic parameters like B cell clone fraction, CDR3 length, and selected Kidera factors alone.
These observations highlight the unique immune architecture in DADA2 and may open up new perspectives on early lymphoma development. Congratulations to Christoph and Paul who led this work and a big 'thank you!' to Ivona Aksentijevich and Daniel L Kastner from NIH for providing this cohort.
Read here.
First data for our IGLV3-21-R110-directed bispecific antibody is now preprinted
07 Feb 2025
We are very happy to introduce our new anti-IGLV3-21-R110-directed bispecific antibody!
Based on our R110-targeting CAR T cells published last year in Nature Communications, we developed a heterodimeric IgG1-based antibody consisting of a fragment crystallizable region (Fc) attached to an anti-IGLV3-21-R110 Fab and an anti-CD3 single chain variable fragment (scFv).
The IGLV3-21-R110l ight chain mutation is found in 10-15% of all patients with chronic lymphocytic leukemia (CLL) and associated with an aggressive disease course. This point mutation is of particular interest since it generates an antigen receptor configuration that acts as driver of neoplastic transformation. Since CLL is a disease of the elderly who may not in every case eligible for CAR T cell therapy, we engineered a bispecific antibody variant as alternative treatment approach.
Claudia demonstrated in diverse in vitro and in vivo models that the anti-IGLV3-21-R110 bispecific antibody mediates selective and very effective killing of cell lines expressing this neoepitope or patient-derived CLL cells, while sparing healthy B cells and CD34+ stem cells.
The now published results underpin the potential value of such precision approaches and warrant clinical investigations. Many thanks also to Matthias Peipp (Kiel), Heinz Läubli (Basel), Marie Follo (Freiburg), Nicholas Chiorazzi (New York) and Obinna Chijioke (Basel/Zürich) for this joint effort!
Read here.
New preprint comparing transposon- and lentivirus-based CAR T production approaches
22 Jan 2025
CAR T cell therapy is a transformative treatment for hematological malignancies and autoimmune diseases but is often limited by the challenge of using dysfunctional patient-derived T cells for production. In addition, the currently approved CAR T products are manufactured using viral vectors, which are expensive and present regulatory challenges.
To better understand these problems, we directly comparee a Sleeping Beauty transposon-based CAR T manufacturing approach with a lentiviral approach using two models: a CAR targeting the CLL-specific surface driver point mutation IGLV3-21-R110 and an anti-CD19 CAR. Using flow cytometry, bulk and single-cell RNA/VDJ sequencing, we identified production-dependent phenotypic differences, even in the absence of target antigen. Moreover, CAR transposition exhibits disadvantages with patient-derived T cells, likely due to the harsher manufacturing conditions and the fragility of the patient-derived cells. Furthermore, we provide evidence that the transposon-based production mode may promote T cell differentiation towards a more exhausted-like phenotype, primarily driven by RIG-I-mediated sensing of the transposase-encoding mRNA.
Congratulations to Simon and Christoph who led this project together. Huge thank you also to all Binder Lab co-authors, Heinz Läubli and Andreas Zingg from the DBM Basel and Sarah Adamo from Karolinska Institute. Read the whole story at bioRxiv.
A20 haploinsufficiency disturbs immune homeostasis and drives the transformation of lymphocytes with permissive antigen receptors.
21 Aug 2024
Our new paper is out now at Science Advances.
While somatic mutations in TNFAIP3 (coding for A20) are known drivers of many B and T cell lymphomas, their relevance for early lymphoma genesis is not established. Using biomaterial from rare individuals with TNFAIP3 gremlin loss-of-funciton alterations (haploinsufficiency of A20, HA20) as well as engineered mouse models, we demonstrate that loss of A20 is sufficient to generate lymphoma-like B and T cell repertoire shifts. These shifts were driven by TNF and could be reversed by therapeutic TNF antagonism. In addition, single-cell RNA sequencing revealed transcriptional patterns in HA20-derived B and T cells that were similar to signatures found in lymphomas.
Moreover, we report the surprising observation that healthy B cells with antigen receptor configurations common for neoplastic or autoreactive clones (e. g. IGHV4-34) exhibit lower TNFAIP3 levels. The link between a distinct receptor configuration and expression of a lymphoma driver suggests a gene dosis model that may explain the antigen-independent enrichment of the receptors in lymphoma patients.
Congratulations to Christoph for this long-term effort and also a huge thank you to all co-authors and collaborators, especially Ari Waisman from University Medical Center Mainz and Ivona Aksentijevich from NIH in Bethesda. Read the whole story here.
B cells expressing mutated IGHV1-69–encoded antigen receptors related to virus neutralization show lymphoma-like transcriptomes in patients with chronic HCV infection
31 Jul 2024
New paper published at Hepatology Communications.
Chronic Hepatitis C virus (HCV) infection can have long-term extrahepatic consequences like cryoglobulinemia or B cell lymphoma. While the introduction of direct-acting antiviral (DAA) treatment has largely transformed our ability to encounter the global threat caused by HCV and greatly reduced the burden of severe liver damage, its effect on the elimination of extrahepatic HCV manifestations remains to be defined.
To address this problem, we analyzed the immune repertoires of patients with chronic HCV or after DAA treatment. We show that complementarity-determining region 1 (CDR1) and framework region 3 mutations characterizing highly neutralizing HCV antibodies correspond to recurrent point mutations found in the clonotypic BCRs of HCV-unrelated high-grade lymphomas. Using single-cell sequencing, we demonstrate that these point mutations confer a persisting oncogenic signature on B cells that can be interpreted as a mechanistic basis for HCV-related B cell dyscrasias and that highlights the elevated lymphoma risk in these patients even years after HCV cure.
Congratulations to Christoph and Edith and a huge thank you to all co-authors and collaborators for their invaluable contributions and dedication. Special thanks to Julian Schulze zur Wiesch who co-supervised this project. Read the whole story here.
Detection of disease-specific signatures in B cell repertoires of lymphomas using machine learning
3 Jul 2024
Congratulations to Paul for his first first-author paper now published in PLOS Computational Biology.
The classification of B cell lymphomas is mainly based on light microscopy evaluation by a pathologist and requires many years of training. Since the B cell receptor (BCR) of the lymphoma clonotype and the microenvironmental immune architecture are important features discriminating different lymphoma subsets, we asked whether BCR repertoire next-generation sequencing (NGS) of lymphoma-infiltrated tissues in conjunction with machine learning algorithms could have diagnostic utility in the subclassification of these cancers.
Paul trained different machine learning algorithms using the immense immune repertoire data we collected over the years for different high-grade lymphomas. He could show that based on patterns of clonal distribution, VDJ gene usage and physico-chemical properties of the top-n most frequently represented clonotypes in the BCR, nodular lymphocyte predominant B cell lymphoma (NLPBL), diffuse large B cell lymphoma (DLBCL) and chronic lymphocytic leukemia (CLL) could be differentiated with high accuracy.
A special thanks to Maria Kalweit from CRIION in Freiburg for co-supervising this work and a huge thank you to all co-authors and collaborators for their invaluable contributions and dedication. Read here.
Post-infection SARS-CoV-2 vaccination is associated with fewer gastrointestinal symptoms in long COVID-19
5 Feb 2024
Congratulations to Christoph for his first paper as corresponding author and Claudia for her first publication now published in npj Vaccines.
They analyzed serological markers in 540 individuals with or without post-COVID-19 condition (PCC; "long COVID-19") and looked especially on association with vaccination status. They found that post-infection vaccination with one or more doses does not increase symptom burden or any pro-inflammatory marker associated with PCC. Vaccination with mRNA vaccines or seasonal influenza vaccine in control cohorts did also not result in any PCC-like persisting symptoms.
Importantly, they observed that patients with ongoing PCC symptoms less often reported gastrointestinal symptoms when receiving one or two doses of a SARS-CoV-2 mRNA vaccine. This was associated with substantially lower plasma levels of IL-1 family cytokines (IL-1beta/IL-18) known players in SARS-CoV-2 clearance within the intestine.
This work further corroborates the safety of SARS-CoV-2 vaccines and also demonstrates the potential benefit for a subset of patients with PCC.
IGLV3-21-R110 targeting CAR T cells published
2 Feb 2024
We are very happy that our manuscript on IGLV3-21-R110-targeting CAR T cells is now published in Nature Communications.
The IGLV3-21-R110 light chain mutation is found in 10-15% of all patients with chronic lymphocytic leukemia (CLL) and defines a patient subset with aggressive disease. This point mutation is of particular interest since it generates an antigen receptor configuration that acts as driver of neoplastic transformation.
We now developed CAR T cells targeting this oncogenic light chain and provide provide proof-of-concept for the targeting of a single point mutation using CAR T cells. Notably, we demonstrate the lack of CAR T-mediated cytotoxicity towards healthy B cells, which is a major advancement as compared to other CAR T approaches that eradicate the complete B cell compartment. These results underpin the potential value of such precision approaches and warrant clinical investigations.
Huge congratulations to the first authors Florian Märkl from Sebastian Kobold's lab at TUM in Munich and Christoph for this achievement! Very special thanks to Sebastian for this joint effort! Thanks also to Nicholas Chiorazzi (New York), Obinna Chijioke (Basel/Zurich), Susana Minguet (Freiburg), Heinz Läubli (Basel) and Michael Hudecek (Würzburg).
SARS-CoV-2-associated T cell infiltration in the central nervous system
31 Jan 2024
Congratulations to Malte Mohme from UKE in Hamburg and Christoph for their recent publication in Clinical & Translational Immunology on SARS-CoV-2-associated T cell infiltration in the brain.
They analyzed eight different brain regions from deceased patients with COVID-19 and found T cell infiltration especially in the olfactory bulb, medulla and cerebellum. These were mainly CD8+ T cells exhibiting a perivascular infiltration pattern.
The immunogenetic analysis of these T cells revealed high homology to known clonotypes with SARS-CoV-2 spike (44%), ORF1ab (21%), NCP (17%) and NSP3 (10%) reactivity.
Future studies are needed to define the precise role of these infiltrating T cells for COVID-19-related neuropathology and potential long-term consequences on patients' cognitive and mental health.
RAP trial published
24 Jan 2024
The results from the AIO RAP trial with Peter Thus-Patience are now published at JAMA Network Open.
Gastric cancer is responsible for 1 million new cancer diagnoses every year and ranks fourth for cancer-related mortality worldwide. Most patients are diagnosed at late stages with metastatic disease and are amenable only to palliative systemic therapy.
The AIO RAP trial was desigend to compare the efficacy and tolerability of ramucirumab and paclitaxel combined with the checkpoint inhibitor avelumab (PDL-1 inhibitor) in the second-line treatment of patients with esophagogastric adenocarcinoma.
This study demonstrates that the combination of ramucirumab, avelumab, and paclitaxel is well tolerated and highly effective in the second-line treatment of a patient population with heavy pretreatment. In addition, patients with low levels of cfDNA and high T cell richness ware associated with favorable outcomes, while high levels of cfDNA were associated with a significantly shorter overall survival. These findings suggests cfDNA and T cell repertoire richness as potential markers to select patients for therapy.
Best Abstract Award for Christoph
5 Dec 2023
Congratulations to Christoph for his fantastic talk on targeting high-risk IGLV3-21-R110 positive CLL patients using point mutation-specific CAR T cells at this year`s SOHC congress in Basel and for winning the prize of SOHC and SSMO for best abstract in experimental hematology and oncology - well done!!
Preliminary data available as preprint at bioRxiv - check out!
New study from the lab characterizes immune signatures of variant syndromes of primary biliary cholangitis and autoimmune hepatitis
26 April 2023
We are excited to share our new study on the (patho)immunology of variant syndromes of PBC and AIH.
We found that immunogenetic features of B and T cells were good general separators for autoimmune liver disease but less robust for the individual disease subset. However, plasma profiling revealed that the soluble forms of CD25, LAG-3, CD86, and Tim-3 may represent important discriminators between AIH and PBC that could be used to complement established clinical and laboratory parameters such as liver function tests, autoantibodies and Ig levels.
Link to the study published in Hepatology communications.
Mascha Binder is now head of Medical Oncology at University Hospital Basel
01 April 2023
We are very happy to announce that Mascha was appointed Professor of Medical Oncology at the Faculty of Medicine at the University Basel and now also heads the Medical Oncology at the University Hospital of Basel.
The Binder Lab is very proud and excited to continue our work at the Department of Biomedicine soon!
Link to the press release of the University Basel.
Results from the INTEGA study are published in JAMA Oncology
23 June 2022
The results from the AIO INTEGA trial with Alex Stein are now published at JAMA Oncology.
Gastric cancer can remain undetected for a long time because of the often non-specific symptoms in the early stages thus complicating therapy when the cancer is diagnosed in advanced stages. ​For HER2-positive esophagogastric adenocarcinomas, the current standard of care is the combination of the HER2 antibody trastuzumab and chemotherapy with an average survival of 15 months after diagnosis.
The AIO INTEGA trial was desigend to compare HER2 antibody therapy and potent immuno-therapy (nivolumab and ipilimumab) with the current standard of care plus nivolumab. While the first regimen showed comparable results to the current standard of care, patients in the second group lived an average of 22 months - 7 months longer than when treated without the use of immunotherapy.
This study demonstrates that immunotherapy as addition to the previous standard of care has a positive impact on disease progression and can prolong the survival of patients with HER2-positive gastric cancer.
Our study on post-acute sequelae of COVID-19 (PASC) is now published
21 June 2022
Data from the COVID-19 module of the DigiHero trial addressing post-acute sequelae of COVID-19 (PASC) is now published in Cell Reports Medicine.
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It has become increasingly clear that in a substantial number of COVID-19 patients who cleared the underlying SARS-CoV-2 infection, severe health impairments can persist for months. The pathophysiology of PASC ("longCOVID") is still largely unknown and may depend on acute severity and course of COVID-19.
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By using a digital epidemiology approach including blood sampling, we show that PASC persists in up to 60% of patients with mild COVID-19 up to 24 months. We also found that PASC is associated with persistent elevation of IL-1β, IL-6 and TNF plasma levels.
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Single-cell RNA sequencing analyses of samples from acute COVID-19 suggest that these cytokine levels are potentially secreted from overactivated monocytes/macrophages.
New publication on B cell maturation after SARS-CoV-2 mRNA vaccination
09 May 2022
The first data from the DigiHero is now officially published in Frontiers in Immunology.
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We tracked B cells from individuals participating in the DigiHero study through their vaccination series including a third "booster" shot.
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The percentage of antigen experienced SARS-CoV-2-specific B cells was low after the first two vaccinations but evolved over months and increased steeply after boosting. The third vaccination mobilized not only naïve, but also antigen-experienced B cell clones into further rapid somatic hypermutation trajectories indicating increased affinity.
These findings may explain why the third, but not the primary vaccination series, offers some protection against immune-escape variants such as Omicron.
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For more info on the DigiHero trial click here.
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Welcome Denis!
01 April 2022
The Binderlab welcomes its newest member Denis Owczarek!
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Denis has lots of academic and industry experience in antibody discovery and production.
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We are really happy that he will help us to develop new CAR T cells.
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Happy new year 2022
01 January 2022
The Binderlab wishes all of you and your friends and families a happy new year and a good start into 2022!
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We have some big plans and are looking forward for the things to come.
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Meanwhile, we celebrate this with a little gift to ourseleves and finally launch this website.
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