Refine
Has Fulltext
- yes (92)
Is part of the Bibliography
- yes (92)
Year of publication
Document Type
- Journal article (92)
Language
- English (92) (remove)
Keywords
- multiple myeloma (22)
- Aspergillus (6)
- cytokines (5)
- Aspergillus fumigatus (4)
- fungal infection (4)
- refractory (4)
- relapse (4)
- CXCR4 (3)
- T cells (3)
- allogeneic stem cell transplantation (3)
- cancer (3)
- immunotherapy (3)
- invasive aspergillosis (3)
- medicine (3)
- survival (3)
- 18F-FDG PET/CT (2)
- B cells (2)
- Bone marrow transplantation (2)
- CCL4 (2)
- COVID-19 (2)
- GVHD (2)
- Multiple myeloma (2)
- NK cells (2)
- T cell (2)
- adaptive immunity (2)
- amplicon sequencing (2)
- aspergillus fumigatus (2)
- autologous transplantation (2)
- biomarker (2)
- cell staining (2)
- dendritic cells (2)
- extramedullary disease (2)
- galactomannan (2)
- immunoassay (2)
- inflammation (2)
- lenalidomide (2)
- leukemia (2)
- pomalidomide (2)
- quality of life (2)
- regulatory T cells (2)
- stem-cell transplantation (2)
- theranostics (2)
- transplantation (2)
- 11C-Methionine PET/CT (1)
- 68Ga-Pentixafor PET/CT (1)
- ABL gene (1)
- AKT-signaling (1)
- AML (1)
- Active disease (1)
- Acute lymphoblastic leukemia (1)
- Acute myeloid leukemia (1)
- Acute myeloid leukemia (AML) (1)
- Akt (1)
- Allogeneic stem cell transplantation (1)
- Allogeneic transplantation (1)
- Alpha therapy (1)
- Ascaris lumbricoides (1)
- Autoimmune diseases (1)
- B cell (1)
- B cell receptors (1)
- BCOR (1)
- BCORL1 (1)
- BRAF mutation (1)
- Bacteria (1)
- Bioluminescence (1)
- Bioluminescence imaging (1)
- Blood (1)
- Bone marrow cells (1)
- Bone marrow transplantantation (1)
- Bone-marrow-transplantation (1)
- C-X-C motif chemokine receptor 4 (1)
- CAPA (1)
- CAR T cell (1)
- CAR T cells (1)
- CAR-T-cell (1)
- CCL3 (1)
- CCL5 (1)
- CD11b+ myeloid cells (1)
- CD319 (1)
- CD38 (1)
- CD4(+) (1)
- CMV (1)
- CS1 (1)
- CXCR4/SDF-1 (1)
- Cancer genetics (1)
- Cancer risk factors (1)
- Cancer treatment (1)
- Candida albicans (1)
- Capicua transcriptional repressor (1)
- Chronic lymphoblastic leukemia (1)
- Chronic myeloid leukaemia (1)
- Chronic myeloid leukemia (1)
- Conditioning regimen (1)
- Dara-KDT-P(A)CE (1)
- Dendritische Zelle (1)
- Drug resistance (1)
- European experts (1)
- European group (1)
- Expression (1)
- Extramedullary disease (1)
- FDG (1)
- FDG PET/CT (1)
- Factor receptor (1)
- Fludarabine (1)
- Fludarabine-treosulfan (FT) (1)
- Fungal (1)
- Fusarium (1)
- GVL (1)
- Genome-wide association studies (1)
- Graft versus Tumor (1)
- Graft-versus-host disease (1)
- Graft-versus-leukemia (1)
- Gruppo-italiano (1)
- GvHD (1)
- HBV (1)
- HCV (1)
- HD (1)
- HIV (1)
- HLA antigens (1)
- HLA-E matching (1)
- HSTC outcome (1)
- Haematology (1)
- Hematopoietic stem cell transplantation (1)
- Hepatitis B virus (1)
- Hepatitis B virus reactivation (1)
- Herpes simplex virus (1)
- Hsp90 (1)
- Human immunodefiency virus (1)
- Immune receptor signaling (1)
- Infections (1)
- Infectious Diseases (1)
- Influenzae type B (1)
- Interleukin-2 (1)
- Invasive Aspergillosis (1)
- KRAS (1)
- Killer cell immunoglobulin-like receptors (1)
- LATE DEATHS (1)
- LPS (1)
- Late mortality (1)
- Low-dose acyclovir (1)
- Lymphomas (1)
- MAPKAPK2 (1)
- MEK/ERK-signaling (1)
- MIP-1β (1)
- MOR202 (1)
- MTB (1)
- MTX (1)
- MUST-Score (1)
- Medizin (1)
- Midollo-Osseo (1)
- Minor histocompatibility antigen mismatch transplantation (1)
- Molecularly targeted therapy (1)
- Multivariate analysis (1)
- Myeloma (1)
- NF-κB/NFAT reporter cells (1)
- NFkB-relatedgenes (1)
- NK-cells (1)
- PET (1)
- PET/CT (1)
- Pneumocystis-carinii-pneumonia (1)
- Pom‐PAD‐Dara (1)
- Prognostic scoring system (1)
- R-CHOP (1)
- RNA extraction (1)
- ROR1 (1)
- Regulatory-cells (1)
- Respiratory syncytial virus (1)
- Rheumatoid arthritis (1)
- Rhizopus (1)
- Risk factors (1)
- Ruxolitinib (1)
- SLAMF7 (1)
- Sibling donor (MSD) (1)
- Societe Francaise (1)
- Spleen (1)
- Stem cell transplantation (1)
- Suppression (1)
- Survival (1)
- T-cells (1)
- TNF (1)
- TNFR2 (1)
- TNFSF14 (1)
- TNFSF4 (1)
- TSLP (1)
- Thiotepa-busulfan-fludarabine (TBF) (1)
- Translational research (1)
- Tumor-necrosis-factor (1)
- Unrelated donor (UD) (1)
- Varicella-Zoster-Virus (1)
- Viral (1)
- [177Lu]PentixaTher (1)
- [68Ga]PentixaFor (1)
- [90Y]PentixaTher (1)
- \(^{11}\)C-methionine (1)
- actin (1)
- activation (1)
- acute Graft versus Host Disease (1)
- acute graft-versus-host disease (1)
- acute kidney injury (1)
- acute leukemia (AL) (1)
- acute lymphoblastic leukaemia (1)
- acute lymphoblastic leukemia (1)
- acute myeloid leukaemia (1)
- acute myeloid leukemia (1)
- acute myeloid-leukemia (1)
- adoptive cell therapy (1)
- adoptive transfer (1)
- adrenocortical carcinoma (1)
- agonist (1)
- alloSCT patients (1)
- allogeneic hematopoietic stem cell transplantation (1)
- alloreactive T cells (1)
- alveolar epithelium (1)
- amsacrine (1)
- antigen loss (1)
- antigens (1)
- apoptosis (1)
- artificial intelligence (1)
- aspergillosis (1)
- bacterial infection (1)
- beta-D-glucan (1)
- biophosphonate (1)
- bispecific antobodies (1)
- blinatumomab (1)
- blinatumoman (1)
- bone disease (1)
- bone marrow transplantation (1)
- bone-disease (1)
- bone-mineral density (1)
- bortezomib (1)
- bortezomib plus dxamethasone (1)
- breakpoint (1)
- bridge-to-transplant (1)
- bronchoalveolar lavage fluid (1)
- cancer care (1)
- cancer immunotherapy (1)
- cancer treatment (1)
- carfilzomib (1)
- caspase-3 (1)
- cell binding (1)
- cells (1)
- cereblon expression (1)
- chemokine receptor (1)
- chemokines (1)
- chimeric antigen receptor (1)
- chronic myelogenous leukemia (1)
- chronic myeloid leukemia (1)
- chronic phase (1)
- clinical trial (1)
- combination therapy (1)
- complement system (1)
- consensus statement (1)
- corticosteroids (1)
- corticosteroids and cyclophosphamide (1)
- cyclophosphamide (FLAMSA) (1)
- cytogenetic response (1)
- cytotoxicity (1)
- daratumumab (1)
- daratumumab monotherapy (1)
- denritic cells (1)
- depression (1)
- diagnostics (1)
- different imatinib dose regimens (1)
- disorders (1)
- donor-cell leukemia (1)
- downstream (1)
- early applied higher imatinib dosages (1)
- elderly patients (1)
- elotuzumab (1)
- enal impairment (1)
- endoradiotherapy (1)
- enzyme-linked immunoassays (1)
- erythropoiesis-stimulating agents (1)
- fungal host response (1)
- fungal molecular diagnostics (1)
- fungi (1)
- galectin-2 (1)
- gene expression (1)
- gene expression data (1)
- gene regulation (1)
- gene regulation in immune cells (1)
- gene therapy (1)
- genetic polymorphisms (1)
- genetic susceptibility (1)
- granulocytes (1)
- group consensus statement (1)
- haploidentical γδ T lymphocytes (1)
- health care (1)
- hematologic malignancies (1)
- hematological malignancies (1)
- hematology (1)
- hematopoietic (1)
- hematopoietic cell transplantation (1)
- hematopoietic stem cell transplantation (1)
- hematopoietic stem cell transplantation (HSCT) (1)
- host defense (1)
- host response (1)
- human biomarker (1)
- human leukocyte antigen-E (HLA-E) (1)
- humans (1)
- hybrid messenger RNA (1)
- hypersensitivity (1)
- immune cell recruitment (1)
- immune cells (1)
- immune control (1)
- immune impairment (1)
- immune receptors (1)
- immune reconstitution (1)
- immune response (1)
- immunohistochemistry techniques (1)
- in vitro model (1)
- in vivo cell expansion (1)
- in vivo imaging (1)
- incidence (1)
- individual mind state (1)
- induction regimen (1)
- infectious diseases (1)
- infusion (1)
- inhibition (1)
- innate immune response (1)
- innate immunity (1)
- interaction (1)
- intermediate dose Ara-C (1)
- invasive fungal infections (1)
- invasive pulmonary aspergillosis (1)
- involvement (1)
- isoforms (1)
- kidney (1)
- library screening (1)
- life-threatening side-effects (1)
- lifestyle habits (1)
- loss-of-function (1)
- lymphoma (1)
- mAb engineering (1)
- malignancies (1)
- malignant transformation (1)
- malnutrition (1)
- management (1)
- mantle cell lymphoma (1)
- marrow plasma cells (1)
- matrix metallopeptidase-1 (1)
- mebendazole (1)
- mechanism (1)
- metastasis (1)
- microenvironment (1)
- mismatch (1)
- mold exposure (1)
- monoclonal antibody (1)
- monoclonal gammopathy (1)
- monocytes (1)
- mortality (1)
- motivational level (1)
- mouse models (1)
- mucormycosis (1)
- multiparameter flow-cytometry (1)
- multiparameter flow-cytpmetry (1)
- multiparametric flow cytometry (1)
- multiplicity of infection (1)
- murine model (1)
- mycophenolic acid (1)
- natural killer cell (1)
- natural killer cells (1)
- natural language processing (1)
- network (1)
- newly-diagnosed myeloma (1)
- no correlation (1)
- novel therapies (1)
- nutritional counseling (1)
- nutritional medical needs (1)
- nutritional risk screening (1)
- obinutuzumab (1)
- observational (1)
- older patients (1)
- oncology (1)
- oncology outpatients (1)
- ontology (1)
- outcomes research (1)
- outreach (1)
- panobinostat (1)
- participation in clinical trials (1)
- pathogen-associated molecular patterns (1)
- pathophysiology (1)
- pathway (1)
- patient access (1)
- pattern (1)
- pattern recognition receptors (1)
- pediatric (1)
- phosphatidylinositol 3-kinase/Akt (1)
- phosphorylation (1)
- plasma cells (1)
- polymerase-chain-reaktion (1)
- population-based cohort (1)
- positron emission tomography (1)
- precision medicine (1)
- precision oncology (1)
- prediction (1)
- probe-based real-time PCR (1)
- progression (1)
- public health (1)
- radiogenomics (1)
- randomized controlled trial (1)
- randomized phase-3 trial (1)
- rare SNP (1)
- real life setting (1)
- real world data (1)
- real world evidence (1)
- real-time PCR (1)
- receptor tyrosine kinases (1)
- recombinant-human-erythropoietin (1)
- relapsed (1)
- relapsed and refractory (1)
- renal failure (1)
- respiratory virus (1)
- risk stratification (1)
- salvage (1)
- serum biomarkers (1)
- serum retention (1)
- significance MGUS (1)
- sirolimus (1)
- smoldering multiple-myeloma (1)
- smoldering myeloma (1)
- stem cell transplantation (1)
- stimulation (1)
- stress (1)
- susceptibility (1)
- symptom burden (1)
- term-follow-up (1)
- thalidomide maintenance (1)
- therapy (1)
- total body irradiation/busulfan (1)
- toxicity (1)
- transcripts (1)
- transient regulatory T-cell targeting (1)
- tumor‐specific antigen (1)
- tumour immunology (1)
- undetermined significance MGUS (1)
- venetoclax (1)
- venous thromboembolic disease (1)
- virus (1)
- virus-specific T-cell (1)
- zoledonic acid (1)
Institute
- Medizinische Klinik und Poliklinik II (90)
- Pathologisches Institut (12)
- Klinik und Poliklinik für Nuklearmedizin (8)
- Institut für Hygiene und Mikrobiologie (7)
- Institut für Virologie und Immunbiologie (5)
- Kinderklinik und Poliklinik (5)
- Medizinische Klinik und Poliklinik I (5)
- Theodor-Boveri-Institut für Biowissenschaften (5)
- Abteilung für Molekulare Innere Medizin (in der Medizinischen Klinik und Poliklinik II) (4)
- Comprehensive Cancer Center Mainfranken (3)
Sonstige beteiligte Institutionen
- Center for Interdisciplinary Clinical Research, Würzburg University, Würzburg, Germany (2)
- Department of Hematology and Oncology, Sana Hospital Hof, Hof, Germany (1)
- Department of Laboratory Medicine and Medicine Huddinge, Karolinska Institutet and University Hospital, Stockholm, Sweden (1)
- Department of Medicine A, University Hospital of Münster, Münster, Germany (1)
- Interdisciplinary Center for Clinical Research (IZKF), Würzburg, Germany (1)
- Mildred Scheel Early Career Center (1)
- University of Bari Medical School, Bari, Italy (1)
EU-Project number / Contract (GA) number
- 733297 (2)
- 754658 (2)
- 037602 (1)
- 19-COP-0031 (1)
- 2016 FGR 0053 (1)
- 260338 (1)
- 847507 (1)
- 853988 (1)
Long-term sequelae in hospitalized Coronavirus Disease 2019 (COVID-19) patients may result in limited quality of life. The current study aimed to determine health-related quality of life (HRQoL) after COVID-19 hospitalization in non-intensive care unit (ICU) and ICU patients. This is a single-center study at the University Hospital of Wuerzburg, Germany. Patients eligible were hospitalized with COVID-19 between March 2020 and December 2020. Patients were interviewed 3 and 12 months after hospital discharge. Questionnaires included the European Quality of Life 5 Dimensions 5 Level (EQ-5D-5L), patient health questionnaire-9 (PHQ-9), the generalized anxiety disorder 7 scale (GAD-7), FACIT fatigue scale, perceived stress scale (PSS-10) and posttraumatic symptom scale 10 (PTSS-10). 85 patients were included in the study. The EQ5D-5L-Index significantly differed between non-ICU (0.78 ± 0.33 and 0.84 ± 0.23) and ICU (0.71 ± 0.27; 0.74 ± 0.2) patients after 3- and 12-months. Of non-ICU 87% and 80% of ICU survivors lived at home without support after 12 months. One-third of ICU and half of the non-ICU patients returned to work. A higher percentage of ICU patients was limited in their activities of daily living compared to non-ICU patients. Depression and fatigue were present in one fifth of the ICU patients. Stress levels remained high with only 24% of non-ICU and 3% of ICU patients (p = 0.0186) having low perceived stress. Posttraumatic symptoms were present in 5% of non-ICU and 10% of ICU patients. HRQoL is limited in COVID-19 ICU patients 3- and 12-months post COVID-19 hospitalization, with significantly less improvement at 12-months compared to non-ICU patients. Mental disorders were common highlighting the complexity of post-COVID-19 symptoms as well as the necessity to educate patients and primary care providers about monitoring mental well-being post COVID-19.
Introduction: National and international guidelines recommend early integration of evidence-based multimodal interventions and programs, especially with a focus on relaxation techniques and other Mind–Body-based methods to maintain the quality of life of oncology patients, improve treatment tolerability, and promote healthy lifestyle behaviors. Consequently, we aim to understand what drives patients and how they navigate integrative medicine to best advise them. This study aimed to detect possible topics of particular interest to patients and identify the patient groups that could benefit most from further programs. Furthermore, we aimed to investigate if patients are open-minded toward integrative oncology concepts and learn about their motivational level to maintain or change behavior.
Methods: Between August 2019 and October 2020 we surveyed patients undergoing oncological therapy in a university oncological outpatient center using a custom-developed questionnaire based on established Mind–Body Medicine concepts.
Results: We included 294 patients with various cancers. More than half reported problems sleeping through (61%) and 42% felt stressed frequently, invariably rating this as detrimental to their health. Moreover, a slight majority (52%) felt physically limited due to their disease and only 30% performed defined exercise programs. Women were significantly more likely to feel stressed and reported with alarming frequency that they often feel “everything was up to them.” The 40–65-year-olds reported significantly less restful sleep, more stress and were more dissatisfied with their situation. However, this group already used natural remedies most frequently and was most often motivated to use relaxation techniques in the next 6 months. The lower the perceived individual energy level (EL), the less frequently patients did sport, the more frequently they felt their disease impaired their activity, mostly feeling stressed and tense. We also found significant associations between negative emotions/thoughts and the variables “sleep,” “use of relaxation techniques,” “personal stress perception,” and “successful lifestyle modification.”
Conclusion: Mind–Body programs that focus on patient’s individual resources, with tools to explore impairing patterns of self-perception and cognitive biases, can be a valuable resource for oncology patients and should therefore be part of an integrative medical treatment concept.
The COVID-19 pandemic has resulted in large numbers of patients requiring critical care management. With the established association between severe respiratory virus infection and invasive pulmonary aspergillosis (7.6% for COVID-19-associated pulmonary aspergillosis (CAPA)), the pandemic places a significant number of patients at potential risk from secondary invasive fungal disease. We described a case of CAPA with substantial supporting mycological evidence, highlighting the need to employ strategic diagnostic algorithms and weighted definitions to improve the accuracy in diagnosing CAPA.
Despite available diagnostic tests and recent advances, diagnosis of pulmonary invasive aspergillosis (IPA) remains challenging. We performed a longitudinal case-control pilot study to identify host-specific, novel, and immune-relevant molecular candidates indicating IPA in patients post allogeneic stem cell transplantation (alloSCT). Supported by differential gene expression analysis of six relevant in vitro studies, we conducted RNA sequencing of three alloSCT patients categorized as probable IPA cases and their matched controls without Aspergillus infection (66 samples in total). We additionally performed immunoassay analysis for all patient samples to gain a multi-omics perspective. Profiling analysis suggested LGALS2, MMP1, IL-8, and caspase-3 as potential host molecular candidates indicating IPA in investigated alloSCT patients. MMP1, IL-8, and caspase-3 were evaluated further in alloSCT patients for their potential to differentiate possible IPA cases and patients suffering from COVID-19-associated pulmonary aspergillosis (CAPA) and appropriate control patients. Possible IPA cases showed differences in IL-8 and caspase-3 serum levels compared with matched controls. Furthermore, we observed significant differences in IL-8 and caspase-3 levels among CAPA patients compared with control patients. With our conceptual work, we demonstrate the potential value of considering the human immune response during Aspergillus infection to identify immune-relevant molecular candidates indicating IPA in alloSCT patients. These human host candidates together with already established fungal biomarkers might improve the accuracy of IPA diagnostic tools.
Multiple myeloma remains a largely incurable disease of clonally expanding malignant plasma cells. The bone marrow microenvironment harbors treatment-resistant myeloma cells, which eventually lead to disease relapse in patients. In the bone marrow, CD4\(^{+}\)FoxP3\(^{+}\) regulatory T cells (Tregs) are highly abundant amongst CD4\(^{+}\) T cells providing an immune protective niche for different long-living cell populations, e.g., hematopoietic stem cells. Here, we addressed the functional role of Tregs in multiple myeloma dissemination to bone marrow compartments and disease progression. To investigate the immune regulation of multiple myeloma, we utilized syngeneic immunocompetent murine multiple myeloma models in two different genetic backgrounds. Analyzing the spatial immune architecture of multiple myeloma revealed that the bone marrow Tregs accumulated in the vicinity of malignant plasma cells and displayed an activated phenotype. In vivo Treg depletion prevented multiple myeloma dissemination in both models. Importantly, short-term in vivo depletion of Tregs in mice with established multiple myeloma evoked a potent CD8 T cell- and NK cell-mediated immune response resulting in complete and stable remission. Conclusively, this preclinical in-vivo study suggests that Tregs are an attractive target for the treatment of multiple myeloma.
Purpose
Patients suffering from aggressive systemic peripheral lymphoma with primary central nervous system involvement (PCL) are a rare and sparsely investigated population. Recommended treatment regimens include a combination of intrathecal and systemic chemotherapy as well as whole brain radiotherapy while offering relatively poor survival.
Methods
We conducted a single-center retrospective study that analyzed safety and outcome of 4 + 4 cycles Rituximab (R)-CHOP and R-high-dose Methotrexate (HD-MTX) for newly diagnosed, transplant-eligible patients ("Ping-Pong"), followed by Cytarabine (AraC)/Thiotepa (TT), BCNU/TT, and autologous hematologic stem cell transplantation (aHSCT). We retrospectively analyzed a set of 16 patients with high-intermediate or high-risk IPI status.
Results
Overall response rate to Ping-Pong was 100% measured by CT/MRI, including 93.75% complete remissions after BCNU/TT followed by PBSCT. One patient failed to qualify for high-dose chemotherapy due to progression when receiving Cytarabine/TT. All patients experienced grade III adverse events, 3 of them a grade IV adverse event. Estimated progression-free survival is 93.75% after a 4.8-year follow-up currently.
Conclusion
Our study suggests high effectivity of R-CHOP with mid-cycle MTX with aHSCT consolidation towards acceptable OS results in this challenging patient population.
The multi-agent therapy “VDT-PACE” represents an established regimen in relapsed/refractory multiple myeloma (RRMM). Here, we report on our experience with a “modified VDT-PACE” incorporating new generation anti-MM agents daratumumab and carfilzomib (“Dara-KDT-P(A)CE”). We retrospectively analyzed 38 patients with RRMM treated with “Dara-KDT-P(A)CE”. The median age was 62 (range 45–82) years, and the patients were heavily pretreated with a median of 5 (range 2–12) prior lines of therapy. Twenty-one (55%) patients suffered from penta-refractory MM. High-risk cytogenetics was present in 31 (81%) patients. The patients received a median of 2 (range 1–10) cycles of this therapy, and the overall response rate (ORR) was 70%. Patients with penta-refractory MM and high-risk cytogenetics showed similar ORR of 65% and 79%, respectively. The median progression-free survival (PFS) and overall survival were 4.1 (95% CI 2.7–5.4) and 8.4 (95% CI 6.7–10.0) months, respectively. Patients with lactate dehydrogenase >250 IU/L showed significantly shorter PFS in comparison with others patients (p = 0.006). We used this regimen as bridging therapy prior to chimeric antigen receptor T-cell infusion in four patients. In conclusion, “Dara-KDT-P(A)CE” is an effective salvage therapy for patients with heavily pretreated, multi-refractory, high-risk RRMM lacking alternative options.
Patients suffering from coronavirus disease-2019 (COVID-19) are susceptible to deadly secondary fungal infections such as COVID-19-associated pulmonary aspergillosis and COVID-19-associated mucormycosis. Despite this clinical observation, direct experimental evidence for severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2)-driven alterations of antifungal immunity is scarce. Using an ex-vivo whole blood stimulation assay, we challenged blood from twelve COVID-19 patients with Aspergillus fumigatus and Rhizopus arrhizus antigens and studied the expression of activation, maturation, and exhaustion markers, as well as cytokine secretion. Compared to healthy controls, T-helper cells from COVID-19 patients displayed increased expression levels of the exhaustion marker PD-1 and weakened A. fumigatus- and R. arrhizus-induced activation. While baseline secretion of proinflammatory cytokines was massively elevated, whole blood from COVID-19 patients elicited diminished release of T-cellular (e.g., IFN-γ, IL-2) and innate immune cell-derived (e.g., CXCL9, CXCL10) cytokines in response to A. fumigatus and R. arrhizus antigens. Additionally, samples from COVID-19 patients showed deficient granulocyte activation by mold antigens and reduced fungal killing capacity of neutrophils. These features of weakened anti-mold immune responses were largely decoupled from COVID-19 severity, the time elapsed since diagnosis of COVID-19, and recent corticosteroid uptake, suggesting that impaired anti-mold defense is a common denominator of the underlying SARS-CoV-2 infection. Taken together, these results expand our understanding of the immune predisposition to post-viral mold infections and could inform future studies of immunotherapeutic strategies to prevent and treat fungal superinfections in COVID-19 patients.
Tumor necrosis factor (TNF) receptor-2 (TNFR2) has attracted considerable interest as a target for immunotherapy. Indeed, using oligomeric fusion proteins of single chain-encoded TNFR2-specific TNF mutants (scTNF80), expansion of regulatory T cells and therapeutic activity could be demonstrated in various autoinflammatory diseases, including graft-versus-host disease (GvHD), experimental autoimmune encephalomyelitis (EAE) and collagen-induced arthritis (CIA). With the aim to improve the in vivo availability of TNFR2-specific TNF fusion proteins, we used here the neonatal Fc receptor (FcRn)-interacting IgG1 molecule as an oligomerizing building block and generated a new TNFR2 agonist with improved serum retention and superior in vivo activity.
Methods
Single-chain encoded murine TNF80 trimers (sc(mu)TNF80) were fused to the C-terminus of an in mice irrelevant IgG1 molecule carrying the N297A mutation which avoids/minimizes interaction with Fcγ-receptors (FcγRs). The fusion protein obtained (irrIgG1(N297A)-sc(mu)TNF80), termed NewSTAR2 (New selective TNF-based agonist of TNF receptor 2), was analyzed with respect to activity, productivity, serum retention and in vitro and in vivo activity. STAR2 (TNC-sc(mu)TNF80 or selective TNF-based agonist of TNF receptor 2), a well-established highly active nonameric TNFR2-specific variant, served as benchmark. NewSTAR2 was assessed in various in vitro and in vivo systems.
Results
STAR2 (TNC-sc(mu)TNF80) and NewSTAR2 (irrIgG1(N297A)-sc(mu)TNF80) revealed comparable in vitro activity. The novel domain architecture of NewSTAR2 significantly improved serum retention compared to STAR2, which correlated with efficient binding to FcRn. A single injection of NewSTAR2 enhanced regulatory T cell (Treg) suppressive activity and increased Treg numbers by > 300% in vivo 5 days after treatment. Treg numbers remained as high as 200% for about 10 days. Furthermore, a single in vivo treatment with NewSTAR2 upregulated the adenosine-regulating ectoenzyme CD39 and other activation markers on Tregs. TNFR2-stimulated Tregs proved to be more suppressive than unstimulated Tregs, reducing conventional T cell (Tcon) proliferation and expression of activation markers in vitro. Finally, singular preemptive NewSTAR2 administration five days before allogeneic hematopoietic cell transplantation (allo-HCT) protected mice from acute GvHD.
Conclusions
NewSTAR2 represents a next generation ligand-based TNFR2 agonist, which is efficiently produced, exhibits improved pharmacokinetic properties and high serum retention with superior in vivo activity exerting powerful protective effects against acute GvHD.
Background
Multiple myeloma (MM) is the third most common hematologic malignancy with increasing importance due to improving treatment strategies and long-term outcomes in an aging population. This study aims to analyse influencing factors on health-related quality of life (HRQoL), such as treatment strategies, participation in a clinical trial and patient characteristics like anxiety, depression, gender, and age. A better understanding of the individual factors in context with HRQoL could provide a helpful instrument for clinical decisions.
Methods
In this prospective observational study, the HRQoL of MM patients with different therapies (first-line and relapse) was quantified by standardized questionnaires (EORTC QLQ-C30 and -MY20) in the context of sociodemographic data, individual anxiety and depressiveness (PHQ-4), and a selected number of clinical parameters and symptoms at defined time-points before, during, and after therapy.
Results
In total, 70 patients were included in the study. The median age of the study cohort was 62 years. 44% were female and 56% were male patients. More than half of the patients were fully active with an ECOG 0. Global health status was significantly higher in patients with first-line treatment and even increased after start of therapy, while the pain level decreased. In contrast, patients with relapsed MM reported a decreasing global health status and increasing pain. Additionally, there was a higher global health status in less anxious/depressive patients. HRQoL decreased significantly after start of chemotherapy in the parameters body image, side effects of treatment, and cognitive functioning. Tandem stem-cell transplantation was not found to be a risk factor for higher impairment of HRQoL. Participation in a clinical study led to an improvement of most aspects of HRQoL. Among others, increased anxiety and depression, female gender, older age, impaired performance status, and recurrent disease can be early indicators for a reduced HRQoL.
Conclusion
This study showed the importance of regular longitudinal assessments of patient reported outcomes (PROs) in routine clinical care. For the first time, to our knowledge, we were able to demonstrate a potential impact between participation in clinical trials and HRQoL. However, due to frequently restrictive inclusion criteria for clinical trials, these MM patients might not be directly comparable with patients treated within standard therapy concepts. Further studies are needed to clarify the relevance of this preliminary data in order to develop an individualized, patient-centred, therapy concept.