Markus W. Löffler

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Verified

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• PD Dr.
• Physician/ Researcher at University of Tübingen

Immune cell infiltrates have proven highly relevant for colorectal carcinoma (CRC) prognosis, making CRC a promising candidate for immunotherapy. Since tumors interact with the immune system via HLA-presented peptide ligands, exact knowledge of the peptidome constitution is fundamental for understanding this relationship. Here we comprehensively de...

Background Although mutated HLA ligands are considered ideal cancer-specific immunotherapy targets, evidence for their presentation is lacking in hepatocellular carcinomas (HCCs). Employing a unique multi-omics approach comprising a neoepitope identification pipeline, we assessed exome-derived mutations naturally presented as HLA class I ligands in...

Background The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery is poorly understood. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods This international, multicentre, cohort study at 235 hospitals in 24 countries includ...

Immune-checkpoint inhibition provides an unmatched level of durable clinical efficacy in various malignancies. Such therapies promote the activation of antigen-specific T cells, although the precise targets of these T cells remain unknown. Exploiting these targets holds great potential to amplify responses to treatment, such as by combining immune-...

Background: The COVID-19 pandemic has disrupted routine hospital services globally. This study estimated the total number of adult elective operations that would be cancelled worldwide during the 12 weeks of peak disruption due to COVID-19. Methods: A global expert-response study was conducted to elicit projections for the proportion of elective...

Despite intensive efforts to improve early cancer detection, to date 30% of all solid tumors are still diagnosed at a metastasized and incurable stage. Molecular mechanisms underlying early metastasis are poorly understood, and thus far there are no strategies to suppress it. Here, using high-plex spatial protein profiling of human and murine tumou...

Cytoreductive surgery followed by hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) is a treatment concept for highly selected patients with peritoneal metastases and primary tumors (PMT). A challenge from the perspective of hospitals is the cost intensity of this promising multimodal treatment option. Which factors influence the cost and reven...

The emergence of SARS-CoV-2 has necessitated the development of versatile vaccines capable of addressing evolving variants. Prime-2-CoV_Beta, a novel Orf virus-based COVID-19 vaccine, was developed to express the SARS-CoV-2 spike and nucleocapsid antigens. This first-in-human, phase I, dose-finding clinical trial was conducted to assess the safety,...

Among the common strategies to design next-generation COVID-19 vaccines is broadening the antigenic repertoire thereby aiming to increase efficacy against emerging variants of concern (VoC). This study describes a new Orf virus-based vector (ORFV) platform to design a multiantigenic vaccine targeting SARS-CoV-2 spike and nucleocapsid antigens. Vacc...

Two hypermutated colon cancer cases with patient-derived cell lines, peripheral and tumor-infiltrating T cells available were selected for detailed investigation of immunological response. T cells co-cultured with autologous tumor cells showed only low levels of pro-inflammatory cytokines and failed at tumor recognition. Similarly, treatment of co...

Neutrophil extracellular traps (NETs) are a key antimicrobial feature of cellular innate immunity mediated by polymorphonuclear neutrophils (PMNs). NETs counteract microbes but are also linked to inflammation in atherosclerosis, arthritis, or psoriasis by unknown mechanisms. Here, we report that NET-associated RNA (naRNA) stimulates further NET for...

(1) Background: Laparoscopic staging is essential in gastric cancer (GC) to rule out peritoneal metastasis (PM). Hypericin, a plant-derived fluorescent compound, has been suggested to improve laparoscopic visualization of PM from GC. This prospective, single-arm, open-label clinical trial aimed to assess the feasibility and safety of oral hypericin...

More than 5 years previous to this report, a female patient in her 60s underwent oncological left-sided pancreatic resection and adrenalectomy including splenectomy for locally advanced pancreatic adenocarcinoma (PDAC), recommended by a multidisciplinary tumour board (MDT). Additionally, she was treated with gemcitabine-containing hyperthermic intr...

Two hypermutated colon cancer cases with patient-derived cell lines, peripheral and tumor-infiltrating T cells available were selected for detailed investigation of immunological response. T cells co-cultured with autologous tumor cells showed only low levels of pro-inflammatory cytokines and failed at tumor recognition. Similarly, treatment of co-...

This study presents a high-dimensional immunohistochemistry approach to assess human γδ T cell subsets in their native tissue microenvironments at spatial resolution, a hitherto unmet scientific goal due to the lack of established antibodies and required technology. We report an integrated approach based on multiplexed imaging and bioinformatic ana...

Cytotoxic T lymphocytes are key for controlling viral infection. Unravelling CD8⁺ T cell-mediated immunity to distinct influenza virus strains and subtypes across prominent HLA types is relevant for combating seasonal infections and emerging new variants. Using an immunopeptidomics approach, naturally presented influenza A virus-derived ligands res...

Simple Summary Effective treatment options for malignant diseases affecting the peritoneum, the inner surface of the abdominal cavity and organs, are scarce. Oncolytic virotherapy uses self-replicating viruses that target malignant cells and kill them selectively. In our work, we investigated the ability and potential of modified vaccinia viruses t...

T-cell immunity is central for control of COVID-19, particularly in patients incapable of mounting antibody responses. CoVac-1 is a peptide-based T-cell activator composed of SARS-CoV-2 epitopes with documented favorable safety profile and efficacy in terms of SARS-CoV-2-specific T-cell response. We here report a Phase I/II open-label trial (NCT049...

Background The 2015 Lancet Commission on global surgery identified surgery and anaesthesia as indispensable parts of holistic health-care systems. However, COVID-19 exposed the fragility of planned surgical services around the world, which have also been neglected in pandemic recovery planning. This study aimed to develop and validate a novel index...

Background Patients with cancers that exhibit extraordinarily high somatic mutation numbers are ideal candidates for immunotherapy and enable identifying tumor-specific peptides through stimulation of tumor-reactive T cells (Tc). Methods Colorectal cancers (CRC) HROC113 and HROC285 were selected based on high TMB, microsatellite instability and HL...

Background The 2015 Lancet Commission on global surgery identified surgery and anaesthesia as indispensable parts of holistic health-care systems. However, COVID-19 exposed the fragility of planned surgical services around the world, which have also been neglected in pandemic recovery planning. This study aimed to develop and validate a novel index...

Background The 2015 Lancet Commission on global surgery identified surgery and anaesthesia as indispensable parts of holistic health-care systems. However, COVID-19 exposed the fragility of planned surgical services around the world, which have also been neglected in pandemic recovery planning. This study aimed to develop and validate a novel index...

Background The 2015 Lancet Commission on global surgery identified surgery and anaesthesia as indispensable parts of holistic health-care systems. However, COVID-19 exposed the fragility of planned surgical services around the world, which have also been neglected in pandemic recovery planning. This study aimed to develop and validate a novel index...

Background The 2015 Lancet Commission on global surgery identified surgery and anaesthesia as indispensable parts of holistic health-care systems. However, COVID-19 exposed the fragility of planned surgical services around the world, which have also been neglected in pandemic recovery planning. This study aimed to develop and validate a novel index...

Background The 2015 Lancet Commission on global surgery identified surgery and anaesthesia as indispensable parts of holistic health-care systems. However, COVID-19 exposed the fragility of planned surgical services around the world, which have also been neglected in pandemic recovery planning. This study aimed to develop and validate a novel index...

Cytoreductive surgery, often in combination with hyperthermic intraperitoneal chemotherapy (HIPEC), has been instrumental in improving the survival of patients with peritoneal metastases from colorectal cancer. Recent studies have highlighted the benefits of complete cytoreduction, while the role of the HIPEC treatment remains unclear. An oxaliplat...

Upon recognition of aberrantly located DNA, the innate immune sensor cyclic GMP-AMP synthase (cGAS) activates stimulator of IFN genes (STING)/IFN regulatory factor (IRF)3–driven antiviral responses. In this study, we characterized the ability of a specific variant of the human cGAS-encoding gene MB21D1, rs610913, to alter cGAS-mediated DNA sensing...

Neutrophil extracellular traps (NETs) have emerged as a key feature of cellular innate immunity mediated by polymorphonuclear neutrophils (PMNs), the primary leukocyte population in humans. Forming web-like structures composed of DNA, histones, and antimicrobial proteins, NETs trap and kill microbial invaders and thus enhance host defense. However,...

Background: The SARS-CoV-2 pandemic has led to restrictions in surgical care worldwide and therefore also posed new challenges to liver surgery. The respective procedures often entail high perioperative risks and resource requirements. However, the indication for liver surgery is frequently without alternatives. To date, there is little knowledge...

Introduction: Point-of-care (POC) platelet function tests are faster and easier to perform than in-depth assessment by flow cytometry. At low platelet counts, however, POC tests are prone to assess platelet function incorrectly. Lower limits of platelet count required to obtain valid test results were defined and a testing method to facilitate com...

Individuals with impaired ability to mount a humoral immune response, either during natural infection or upon prophylactic vaccination, are at high risk for a severe course of COVID-19. Besides humoral immunity mediated by B cells, T cell immunity is key for the control of viral infections. We developed the peptide-based vaccine candidate CoVac-1,...

Purpose: Immunotherapy for hepatocellular carcinoma (HCC) shows considerable promise in improving clinical outcomes. HepaVac-101 represents a single-arm, first-in-man Phase I/II multicenter cancer vaccine trial for HCC (NCT03203005). It combines multi-peptide antigens (IMA970A) with the TLR7/8/RIG I agonist CV8102. IMA970A includes 5 HLA-A*24 and...

Cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) was considered a promising treatment for patients with peritoneal metastasis from colorectal cancer. However, the recently published randomized controlled PRODIGE 7 trial failed to demonstrate survival benefits through the addition of short-term oxaliplatin-based...

Conformational change of the β2 integrin lymphocyte function‐associated antigen 1 (LFA‐1) is an early marker of T cell activation. A protocol using the mAb clone m24 recognizing the active, extended high‐affinity conformation has been previously described for the assessment of functional CD4⁺ and CD8⁺ T cells in response to MHC‐peptide stimulation....

T cell immunity is central for the control of viral infections. CoVac-1 is a peptide-based vaccine candidate, composed of SARS-CoV-2 T cell epitopes derived from various viral proteins1,2, combined with the Toll-like receptor 1/2 agonist XS15 emulsified in Montanide ISA51 VG, aiming to induce profound SARS-CoV-2 T cell immunity to combat COVID-19....

Background The SARS-CoV‑2 pandemic has extensively challenged healthcare systems all over the world. Many elective operations were postponed or cancelled, changing priorities and workflows in surgery departments. Aims The primary aim of this cross-sectional study was to assess the workload and psychosocial burden of surgeons and anesthesiologists,...

Members of the COVIDSurg Collaborative are co-authors of this study and are listed under the heading Collaborators. For details of role see Appendix S1. Dear Editor During the COVID-19 pandemic, multiple theories were proposed based on the observation that countries with an ongoing national Bacillus Calmette-Gué rin (BCG) immunization programme had...

Drug repurposing is a complementary pathway for introducing new drugs against cancer. Broad systematic assessments of ongoing repurposing efforts in oncology are lacking, but may be helpful to critically appraise current and future efforts. Hence, we conducted a systematic PubMed search encompassing 100 frequently prescribed and 100 randomly select...

Background Anti-programmed cell death protein 1 (PD-1) antibodies are now routinely administered for metastatic melanoma and for increasing numbers of other cancers, but still only a fraction of patients respond. Better understanding of the modes of action and predictive biomarkers for clinical outcome is urgently required. Cancer rejection is most...

We aimed to determine the impact of pre-operative isolation on postoperative pulmonary complications after elective surgery during the global SARS-CoV-2 pandemic. We performed an international prospective cohort study including patients undergoing elective surgery in October 2020. Isolation was defined as the period before surgery during which pati...

Background: Surgery is the main modality of cure for solid cancers and was prioritised to continue during COVID-19 outbreaks. This study aimed to identify immediate areas for system strengthening by comparing the delivery of elective cancer surgery during the COVID-19 pandemic in periods of lockdown versus light restriction. Methods: This internati...

Zusammenfassung Hintergrund Die SARS-CoV-2-Pandemie hat zu einer globalen Gesundheitskrise mit hohen Mortalitätsraten insbesondere bei Betroffenen in Hochrisikogruppen geführt. Eine stetig wachsende Zahl klinischer Fallberichte zeigt die Folgen von COVID-19 bei Patienten nach solider Organtransplantation (SOT) und deutet auf schwerwiegende klinisch...

Activity of the NLRP3 inflammasome, a critical mediator of inflammation, is controlled by accessory proteins, posttranslational modifications, cellular localization, and oligomerization. How these factors relate is unclear. We show that a well-established drug target, Bruton's tyrosine kinase (BTK), affects several levels of NLRP3 regulation. BTK d...

Background: Preoperative SARS-CoV-2 vaccination could support safer elective surgery. Vaccine numbers are limited so this study aimed to inform their prioritization by modelling. Methods: The primary outcome was the number needed to vaccinate (NNV) to prevent one COVID-19-related death in 1 year. NNVs were based on postoperative SARS-CoV-2 rates an...

Upon recognition of aberrantly located DNA, the innate immune sensor cGAS activates STING/IRF-3-driven antiviral responses. Here we characterized the ability of a specific variant of the cGAS-encoding gene MB21D1, rs610913, to alter cGAS-mediated DNA sensing and viral infection. rs610913 is a frequent G>T polymorphism resulting in a P261H exchange...

T-cell immunity is central for the control of viral infections. CoVac-1 is a peptide-based vaccine candidate, composed of SARS-CoV-2 T-cell epitopes derived from various viral proteins, combined with the toll-like receptor 1/2 agonist XS15 emulsified in Montanide TM ISA51 VG, aiming to induce superior SARS-CoV-2 T-cell immunity to combat COVID-19....

Summary We aimed to determine the impact of pre-operative isolation on postoperative pulmonary complications after elective surgery during the global SARS-CoV-2 pandemic. We performed an international prospective cohort study including patients undergoing elective surgery in October 2020. Isolation was defined as the period before surgery during wh...

Background : The SARS-CoV-2 pandemic is challenging health systems all over the world. Particularly high-risk groups show considerable mortality rates after infection. In 2020, an inexorable number of case reports, case series and ultimately various systematic reviews have been published reporting on morbidity and mortality risk of SARS-CoV-2 in so...

To support the global restart of elective surgery, data from an international prospective cohort study of 8492 patients (69 countries) was analysed using artificial intelligence (machine learning techniques) to develop a predictive score for mortality in surgical patients with SARS-CoV-2. We found that patient rather than operation factors were the...

Background Pancreatic ductal adenocarcinoma (PDAC) is a common fatal disease with unfavorable prognosis, even after oncological resection. To improve survival, adding hyperthermic intraperitoneal chemotherapy (HIPEC) has been suggested. Whether HIPEC entails disproportional short-term mortality is unknown and a prospectively determined adverse even...

Peri-operative SARS-CoV-2 infection increases postoperative mortality. The aim of this study was to determine the optimal duration of planned delay before surgery in patients who have had SARS-CoV-2 infection. This international, multicentre, prospective cohort study included patients undergoing elective or emergency surgery during October 2020. Su...

We describe the results of two vaccinations of a self-experimenting healthy volunteer with SARS-CoV-2-derived peptides performed in March and April 2020, respectively. The first set of peptides contained eight peptides predicted to bind to the individual's HLA molecules. The second set consisted of ten peptides predicted to bind promiscuously to se...

Background The human leucocyte antigen (HLA) complex controls adaptive immunity by presenting defined fractions of the intracellular and extracellular protein content to immune cells. Understanding the benign HLA ligand repertoire is a prerequisite to define safe T-cell-based immunotherapies against cancer. Due to the poor availability of benign ti...

Background Preoperative SARS-CoV-2 vaccination could support safer elective surgery. Vaccine numbers are limited so this study aimed to inform their prioritization by modelling. Methods The primary outcome was the number needed to vaccinate (NNV) to prevent one COVID-19-related death in 1 year. NNVs were based on postoperative SARS-CoV-2 rates and...

Background Preoperative SARS-CoV-2 vaccination could support safer elective surgery. Vaccine numbers are limited so this study aimed to inform their prioritization by modelling. Methods The primary outcome was the number needed to vaccinate (NNV) to prevent one COVID-19-related death in 1 year. NNVs were based on postoperative SARS-CoV-2 rates and...

Background: During the initial COVID-19 outbreak up to 28.4 million elective operations were cancelled worldwide, in part owing to concerns that it would be unsustainable to maintain elective surgery capacity because of COVID-19-related surgeon absence. Although many hospitals are now recovering, surgical teams need strategies to prepare for future...

Aim This study aimed to describe the change in surgical practice and the impact of SARS-CoV-2 on mortality after surgical resection of colorectal cancer during the initial phases of the SARS-CoV-2 pandemic. Method This was an international cohort study of patients undergoing elective resection of colon or rectal cancer without preoperative suspicio...

Background: Surgical services are preparing to scale up in areas affected by COVID-19. This study aimed to evaluate the association be- tween preoperative SARS-CoV-2 testing and postoperative pulmonary complications in patients undergoing elective cancer surgery. Methods: This international cohort study included adult patients undergoing elective s...

Background: Surgical services are preparing to scale up in areas affected by COVID-19. This study aimed to evaluate the association between preoperative SARS-CoV-2 testing and postoperative pulmonary complications in patients undergoing elective cancer surgery. Methods: This international cohort study included adult patients undergoing elective sur...

Background During the initial COVID-19 outbreak up to 28.4 million elective operations were cancelled worldwide, in part owing to concerns that it would be unsustainable to maintain elective surgery capacity because of COVID-19-related surgeon absence. Although many hospitals are now recovering, surgical teams need strategies to prepare for future...

Background Surgical services are preparing to scale up in areas affected by COVID-19. This study aimed to evaluate the association between preoperative SARS-CoV-2 testing and postoperative pulmonary complications in patients undergoing elective cancer surgery. Methods This international cohort study included adult patients undergoing elective surge...

Zusammenfassung Bereits der Arzt und Forscher Paul Ehrlich stellte die These auf, dass das Immunsystem nicht nur Infektionen bekämpft, sondern auch gegen Krebs vorgehen kann. Über die möglichen positiven Auswirkungen einer simultanen Infektion auf den Verlauf einer Krebserkrankung wurde bereits im alten Ägypten ca. 2600 v. Chr. berichtet. Jedoch wu...

Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are a multimodal treatment approach combining surgical interventions of varying extent with administration of heated cytostatic drugs flushed through the abdominal cavity. Hitherto, this treatment has been popular for peritoneal metastasis (PM), e.g. from colorectal c...

Background and Aims: Hepatocellular carcinoma (HCC) is the third leading cause of death from cancer globally with an extremely variable 5-year survival rate. Immunotherapy strategies for HCC may represent a key therapeutic tool to improve clinical outcome in HCC patients. HepaVac-101 (EudraCT Number: 2015-003389-10; NCT03203005), is a single-arm, f...

Context Pancreatic steatosis leading to beta-cell failure might be involved in type 2 diabetes (T2D) pathogenesis. Objective We hypothesized that the genetic background modulates the effect of pancreatic fat on beta-cell function and investigated genotype x pancreatic fat interactions on insulin secretion. Design Two observational studies. Setti...

Zusammenfassung Tumorzellen weisen immer Veränderungen im Vergleich zu normalen Zellen auf. Die Veränderungen können vom Immunsystem erkannt werden, was zur Zerstörung der Tumorzellen durch T‑Zellen führen kann. Der Erfolg der Immuncheckpointinhibition beispielsweise beim malignen Melanom hat dies eindrucksvoll gezeigt. Viele Tumorerkrankungen spre...

3128 Background: The human leukocyte antigen (HLA) complex regulates the adaptive immune response by showcasing the intracellular and extracellular protein content to the immune system, which is the basis for T cell-dependent tumor rejection. Therefore, a comprehensive map of the entirety of both HLA class I- and class II-presented peptides from va...

Here, we describe the preliminary results of an experimental vaccination of a self-experimenting healthy volunteer with eight SARS-CoV-2-derived peptides: five predicted to bind to HLA class I molecules (CD8 peptides) and three predicted to bind to HLA-DR molecules (CD4 peptides). The vaccine formulation also included one long and one short CMV-pp6...

Dissection of the role and function of human γδ T cells and their heterogeneous subsets in cancer, inflammation, and auto‐immune diseases is a growing and dynamic research field of increasing interest to the scientific community. Therefore, harmonization and standardization of techniques for the characterization of peripheral and tissue‐resident γδ...

Psoriasis is an inflammatory skin disease with strong neutrophil (PMN) infiltration and high levels of the antimicrobial peptide, LL37. LL37 in complex with DNA and RNA is thought to initiate disease exacerbation via plasmacytoid dendritic cells. However, the source of nucleic acids supposed to start this initial inflammatory event remains unknown....

Activity of the NLRP3 inflammasome, a critical mediator of inflammation ( 1 ), is controlled by accessory proteins (2, 3) , post-translational modifications (4, 5) , cellular localization (6, 7) and oligomerization (8) . How these factors relate, is unclear. We show that the established drug target, Bruton’s Tyrosine Kinase (BTK) (2, 9) , integrate...

Background: Radiofrequency ablation (RFA) is an established treatment option for malignancies located in the liver. RFA-induced irreversible coagulation necrosis leads to the release of danger signals and cellular content. Hence, RFA may constitute an endogenous in situ tumor vaccination, stimulating innate and adaptive immune responses, including...

Background: We previously showed that the bacterial lipopeptide Pam3Cys-Ser-Ser, meanwhile established as a toll-like receptor (TLR) 1/2 ligand, acts as a strong adjuvant for the induction of virus specific CD8+ T cells in mice, when covalently coupled to a synthetic peptide. Case presentation: We now designed a new water-soluble synthetic Pam3C...

The Human Leukocyte Antigen (HLA) regulates the adaptive immune response by showcasing the intracellular and extracellular protein content to the immune system, where T cells, in particular, are able to distinguish between self and foreign. Therefore, a comprehensive mapping of the entirety of both HLA class I- and class II-presented peptides is a...

Psoriasis is a frequent systemic inflammatory autoimmune disease characterized primarily by skin lesions with massive infiltration of leukocytes, but frequently also presents with cardiovascular comorbidities. Especially polymorphonuclear neutrophils (PMNs) abundantly infiltrate psoriatic skin but the cues that prompt PMNs to home to the skin are n...