University Medical Center Freiburg

High-dose glucocorticoid regimes do not improve outcomes compared to standard dose but carry greater risk of side effects Glucocorticoid treatment does not result in complete recovery in 60% of patients New treatment options for sudden hearing loss patients are urgently needed BERLIN--(BUSINESS WIRE)-- High-dose glucocorticoids are no more effective than the standard-dose in treating patients with sudden hearing loss. They are also associated with more side effects and significantly worse outcomes for speech recognition and tinnitus perception. Additionally, 60% of patients treated with the standard dose had not fully recovered by the end of the study. This clinical study, led by Prof. Stefan Plontke from the University Medicine Halle, evaluated the efficacy of different doses of glucocorticoids in over 300 sudden hearing loss patients and is published in NEJM Evidence. These results raise the possibility that glucocorticoids may not be sufficiently effective in treating this condition. This press release features multimedia. View the full release here: Prof. Stefan Plontke, principal investigator of the study at the University Medical Center Halle (Photo: University Medicine Halle). Sudden hearing loss can drastically impair speech understanding and affect a patient’s daily life. Glucocorticoids are prescribed worldwide as the standard-of-care. However, in certain circumstances their side effects can be severe, and it remains unclear whether they provide meaningful improvement for patients. "These drugs have been used globally for 50 years as the standard of care for sudden hearing loss, still there is no reliable scientific evidence for this practice.", explains study leader Stefan Plontke, underscoring the increasing need for new treatments. Many companies are exploring alternatives. However, there is currently only one clinical trial with a new active substance in which patients can participate: The compound AC102 outperformed the widely used cortisone-like dexamethasone in preclinical models of hearing loss, likely because it specifically targets damaged sensory cells and the auditory nerve. Clinical trials are now testing whether this effect is comparable in humans. "We are not surprised by the HODOKORT study results. Glucocorticoids as anti-inflammatory drugs are a good treatment option for many conditions. However, there is no convincing mode-of-action for the treatment of sudden hearing loss with steroids, as our own research has shown," says Dr. Reimar Schlingensiepen, CEO of AudioCure Pharma. After 50 years of treating sudden hearing loss with glucocorticoids, a new and effective drug for this condition would represent a much-needed paradigm shift. Original Study: Plontke, et al. NEJM Evid 2024;3(1) DOI:10.1056/EVIDoa2300172 View source version on businesswire.com: Contacts AudioCure Pharma GmbH Frauke Luers Phone: +49 30 2218 397-0 E-Mail: pr@ac-clinical.com Web: Source: AudioCure Pharma GmbH Smart Multimedia Gallery Photo Prof. Stefan Plontke, principal investigator of the study at the University Medical Center Halle (Photo: University Medicine Halle). Logo View this news release and multimedia online at:

Older people may be at greater risk of developing pancreatic cancer and have poorer prognoses because of age-related changes in cells in the pancreas called fibroblasts, according to new research. Older people may be at greater risk of developing pancreatic cancer and have poorer prognoses because of age-related changes in cells in the pancreas called fibroblasts, according to research led by investigators from the Johns Hopkins Kimmel Cancer Center, the Johns Hopkins Bloomberg School of Public Health and the Bloomberg~Kimmel Institute for Cancer Immunotherapy. The study, published online Feb. 8 in Cancer Research, provides clues as to why pancreatic cancer is more common and aggressive in older people. It may also help scientists develop new therapeutic approaches for this difficult-to-treat cancer. The study showed that aging alters fibroblasts in ways that enable them to promote pancreatic cancer tumor growth. "Older fibroblasts release proteins that directly affect pancreatic cancer cells and ultimately lead to the growth and spread of pancreatic cancer tumors," says the study's lead author, Daniel Zabransky, M.D., Ph.D., assistant professor of oncology at the Johns Hopkins University School of Medicine. "The younger fibroblasts did not have these capabilities. We think this is a key reason why we see pancreatic cancer more commonly in older patients." Zabransky and his colleagues compared samples of pancreatic fibroblasts from patients older than 55 with pancreatic fibroblasts from patients younger than 35. They discovered that the cells from older patients behave very differently than younger ones. To find out why, they compared the proteins released by the younger and older cells and noted profound differences. They determined that a critical change in older pancreatic fibroblasts is that they release more of a protein called growth/differentiation factor 15 (GDF-15). When the team treated young mice with pancreatic tumors with GDF-15, it caused the tumors to grow more rapidly, just as they do in older mice. Older mice that were genetically engineered to lack the gene encoding GDF-15 had reduced pancreatic tumor growth. Experiments in human cells and mouse models revealed that GDF-15 activates the AKT signaling pathway in an age-dependent manner. The discovery was a surprise because the AKT pathway is typically not very active in mouse models of pancreatic cancer, Zabransky says. However, most studies look only at young mice. Experimental drugs already exist that inhibit the AKT pathway. When the team tested AKT-inhibiting drugs in mouse models of pancreatic cancer, they found the drugs reduced tumor growth in mice with aged fibroblasts. However, it had no effect in mice with young fibroblasts. Zabransky and his colleagues next plan to study age-related changes in other cells found in pancreatic cancer tumors, including immune cells, and their impact on pancreatic cancer. Previous work by senior study author Ashani Weeraratna, Ph.D., co-chair of the Cancer Invasion and Metastasis Program and associate director for laboratory research for the Johns Hopkins Kimmel Cancer Center, demonstrated the importance of age-related changes in melanoma, a finding the team has now extended to pancreatic cancer. Weeraratna also is the E.V. McCollum Professor and chair of the Department of Biochemistry and Molecular Biology and a Bloomberg Distinguished Professor at the Johns Hopkins Bloomberg School of Public Health, and a professor of oncology at the Johns Hopkins University School of Medicine. "We have very few treatment options for pancreatic cancer," Weeraratna says. "Trying to understand how the aging microenvironment contributes to pancreatic cancer progression might open up new avenues for therapies." "Precision cancer therapy just got more complicated," adds study co-author Elizabeth Jaffee, M.D., deputy director of the cancer center, co-director of the gastrointestinal cancers program, and the Dana and Albert "Cubby" Broccoli Professor of Oncology at Johns Hopkins. "This work by Dr. Zabransky and his team points out for the first time in pancreatic cancer that there are aging-specific signals in tumors that may need to be modulated to realize the potential of current and future treatments for this deadly disease." Zabransky says age-related changes may also be critical in other types of cancers. He noted scientists test most cancer drugs in young mice, and drugs that target age-specific cancerous changes may not work in these young mouse models. It also may be vital to examine the results of clinical trials of cancer drugs to see if the effects vary in different age groups, he says. Other study co-authors were Yash Chhabra, Mitchell E. Fane, Emma Kartalia, James L. Leatherman, Laura Hu?ser, Jacquelyn W. Zimmerman, Todd D. Armstrong, Soren Charmsaz, Samantha Guinn, Sneha Pramod and Elizabeth D. Thompson of Johns Hopkins. Other authors were from the Fox Chase Cancer Center in Philadelphia; the German Cancer Research Center in Heidelberg, Germany; the University Medical Center Mannheim and Ruprecht-Karl University of Heidelberg in Mannheim, Germany; the Stanford School of Medicine in California; the University of Florida College of Medicine in Gainesville; and the National Institute on Aging in Baltimore. The study was supported in part by the National Institutes of Health (grants T32 5T32CA009071, U01CA227550, P01CA114048, R01CA207935, K99CA263017, P01CA247886, P01CA114046, U01CA227550, and R01CA232256), a Conquer Cancer Foundation/ASCO Young Investigator Award, a MacMillan Pathway to Independence Award, the MD Anderson GI SPORE, the Maryland Cancer Moonshot Research Grant to the Johns Hopkins Medical Institutions (FY24), a Lustgarten Foundation Cancer Convergence Grant, and a Team Science Award from the Melanoma Research Alliance. Zabransky and Zimmerman receive support from Roche and Genentech. Jaffee receives personal fees from Achilles, Dragon Fly, Parker Institute, Surge, Mestag, and Medical Group Home; grants from Lustgarten, Genentech, BMS, and Breakthrough Cancer; and other support from Abmeta and Adventris. Weeraratna serves on the board of Regain Therapeutics. These relationships are managed by The Johns Hopkins University in accordance with its conflict-of-interest policies.

Tumor vaccines can help the body fight cancer. These vaccines alert the patient's immune system to proteins that are carrying cancer-typical alterations. Physicians and cancer researchers have now treated adult patients with advanced midline gliomas, difficult-to-treat brain tumors, with a peptide vaccine for the first time. The vaccine mimicked a mutational change in a histone protein typical of this type of cancer. The vaccine proved to be safe and induced the desired immune responses directed against the brain tumor. Tumor vaccines can help the body fight cancer. These vaccines alert the patient's immune system to proteins that are carrying cancer-typical alterations. Physicians and cancer researchers from Heidelberg and Mannheim have now treated adult patients with advanced midline gliomas, difficult-to-treat brain tumors, with a peptide vaccine for the first time. The vaccine mimicked a mutational change in a histone protein typical of this type of cancer. The vaccine proved to be safe and induced the desired immune responses directed against the brain tumor. Crucial for the success of cancer vaccinations are protein structures by which the immune cells can recognize the cancer -- and which are not present (or only to a small extent) on healthy cells. Mutations in the tumor genome often lead to protein structures that are altered in a way typical of cancer. Diffuse midline gliomas are among the most aggressive brain tumors. They usually occur in children and young adults near the brain stem and are therefore difficult to access surgically. Chemotherapy or radiation therapy also have limited effectiveness. In this type of cancer, mutations characteristically occur in the gene encoding histone H3 (H3K27M), a packaging protein of DNA. The mutation gives rise to a novel protein structure -- a so-called neoepitope -- that can be recognized as foreign by the patient's immune system. "Such mutations, which occur in identical form in many patients, are rare in cancer. They literally lend themselves to the development of tumor vaccines because they occur in all cancer cells, since the mutated histone is causative for the development of midline gliomas. This means that vaccination against the mutated protein gets to the root of the problem," explains Michael Platten, Director of the Department of Neurology at the University Medical Center Mannheim and Head of Department at the German Cancer Research Center (DKFZ). The researchers led by Katharina Sahm and Michael Platten synthetically reconstructed the section of the histone H3 protein with the characteristic mutation. Using this peptide, they were able to curb the growth of H3K27M-mutated tumors in a mouse model. Encouraged by the results, the team decided to test the mutation-specific vaccine produced at the University of Tübingen in patients in a phase I-trial*, which is still ongoing. In parallel, the physicians, together with colleagues from Munich, Berlin, Bonn and Münster, treated eight adult patients with the peptide vaccine in time-limited individual curative trials. These patients, who could not be enrolled in the trial protocol, suffered from diffuse midline gliomas with H3K27M mutation that progressed after standard therapy. Some of the affected individuals received therapy with immune checkpoint inhibitors in addition to tumor vaccination. No serious side effects were observed in any of the vaccinated patients. Five of the eight treated patients developed specific immune responses against the mutant protein, which were dominated by CD4 T-helper cells. In one of the patients who had shown a strong immune response, the tumor regressed completely and she remained tumor-free for 31 months. The vaccine peptide, which is comparatively long at 27 amino acids, worked in patients with different HLA variants. HLA proteins are responsible for the presentation of the mutant peptide on the cell surface and differ from person to person depending on their genetic background. Supported by the HI-TRON Mainz -- Helmholtz Institute of the DKFZ, the researchers also observed that immune responses decreased over time, so repeated administration of the vaccine could support a sustained effect. "We cannot make any further statements about the efficacy of the vaccination based on these treatments. In any case, the current study has given us valuable information that will help us to further optimize the development of brain tumor vaccines in the future," explains the study's senior author Katharina Sahm, senior physician at the Neurological University Hospital Mannheim and DKFZ researcher. A phase I-trial is currently underway to test the vaccine against the H3K27M mutation in patients with newly diagnosed midline gliomas. Evaluation is expected to begin around 2025. The project was funded by the Translational Oncology funding program of German Cancer Aid (Deutsche Krebshilfe). * INTERCEPT-H3 trial: