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Tag: Immunology
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CHOP Researchers Identify Molecules that Optimize Immune Presentation of Antigens across the Human Population
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Newswise — Philadelphia, February 24, 2023—Researchers at Children’s Hospital of Philadelphia (CHOP) have identified variants of a chaperone molecule that optimizes the binding and presentation of foreign antigens across the human population, which could open the door to numerous applications where robust presentation to the immune system is important, including cell therapy and immunization. The findings were published today in Science Advances.
Class I major histocompatibility complex (MHC-I) proteins are found on the surface of cells from all jawed vertebrates and play an essential role in the immune system. The MHC-I displays peptide fragments of proteins from within the cell on the cell surface, effectively “presenting” them to the immune system, which is constantly scanning the body for foreign or toxic antigens. When foreign peptides are identified, they trigger a cascade that allows cytotoxic T cells to eliminate intruders.
For a peptide to be presented to the immune system, it needs to be loaded on a folded MHC-I protein. Several molecules facilitate this process, including proteins known as molecular chaperones, which assist with MHC-I folding. Tapasin and a similar molecule known as TAPBPR are both molecular chaperones that facilitate MHC-I folding and peptide loading. Because TAPBR functions independently outside of the peptide-loading complex, it is well-suited for clinical applications that involve peptide exchange, such as loading immunogenic peptides on MHC-I molecules and generating libraries to detect T-cells that recognize peptides or antigens from infected or cancerous cells.
However, TAPBPR-mediated peptide exchange has thus far only worked for a limited set of common allotypes of human MHC-I, known as human leukocyte antigen (HLA), which has limited wider use of these technologies in biomedical applications. Over time, HLA subtypes, which include HLA-A, HLA-B, and HLA-C, have evolved such that not all alleles interact equally well with TAPBPR. This has been a roadblock in developing and enhancing novel therapies with the help of molecular chaperones, as some HLA allotypes do not interact with these molecules.
To solve this problem, the CHOP researchers analyzed three different TAPBPR proteins: one from humans, one from chickens, and one from mice. They found that unlike human TAPBPR, chicken TAPBPR co-evolved with its class I genes, so that it maintains high affinity across MHC-I allotypes. In their analysis, they found that chicken TAPBPR was able to react with multiple HLA allotypes, many of which were not able to bind to human TAPBPR. They also demonstrated that TAPBPR stabilizes the empty MHC-I groove in an “open” conformation, boosting its affinity for peptide loading.
Simultaneously, in close collaboration with researchers at the University of Illinois led by Erik Procko, PhD, the research team used deep mutational scanning to characterize the effects from 100s of point mutations on human TAPBPR and found a variant that mimics the chicken sequence. Like the chicken TAPBPR, this variant enhanced peptide exchange across a broad range of HLA types.
“Although the highly polymorphic nature of MHC-I molecules makes it challenging to engineer ‘universal’ chaperones, our research team demonstrated that both a chicken ortholog of TAPBPR and a human variant with minor adjustments could enhance peptide exchange across multiple disease-relevant HLAs,” said senior author Nikolaos G. Sgourakis, PhD, Associate Professor in the Center for Computational and Genomic Medicine at Children’s Hospital of Philadelphia. “These TAPBPR orthologs could be utilized in various cancer immunotherapeutic settings to narrow the peptide repertoire and increase immunogenicity. The knowledge gained by our studies can guide the design of engineered TAPBPR variants with tailored HLA specificity and catalytic efficiency for peptide exchange applications both in vitroand in vivo.”
This research was supported by funding from the National Institute of Allergy and Infectious Diseases (5R01AI143997) and National Institute of General Medical Sciences (5R35GM125034).
Yi Sun, Georgia F. Papadaki, Christine A. Devlin, Julia N. Danon, Michael C. Young, Trenton J. Winters, George M. Burslem, Erik Procko, and Nikolaos G. Sgourakis. “Xeno-interactions between MHC-I proteins and molecular chaperones enable ligand exchange on a broad repertoire of HLA allotypes,” Science Advances, February 24, 2023, DOI: 10.1126/sciadv.ade7151
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About Children’s Hospital of Philadelphia: A non-profit, charitable organization, Children’s Hospital of Philadelphia was founded in 1855 as the nation’s first pediatric hospital. Through its long-standing commitment to providing exceptional patient care, training new generations of pediatric healthcare professionals, and pioneering major research initiatives, the 595-bed hospital has fostered many discoveries that have benefited children worldwide. Its pediatric research program is among the largest in the country. The institution has a well-established history of providing advanced pediatric care close to home through its CHOP Care Network, which includes more than 50 primary care practices, specialty care and surgical centers, urgent care centers, and community hospital alliances throughout Pennsylvania and New Jersey, as well as a new inpatient hospital with a dedicated pediatric emergency department in King of Prussia. In addition, its unique family-centered care and public service programs have brought Children’s Hospital of Philadelphia recognition as a leading advocate for children and adolescents. For more information, visit http://www.chop.edu.
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Children’s Hospital of Philadelphia
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Immunotherapy After Surgery Provides Significant, Durable Benefit for High-Risk Bladder Patients
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Newswise — New York, NY (February 17, 2023)—Immunotherapy after surgery increased bladder cancer patients’ chance of staying cancer-free compared to patients who received a placebo, according to clinical trial results shared in a late-breaking oral presentation at the American Society of Clinical Oncology (ASCO) 2023 Genitourinary Cancers Symposium in February.
Matthew Galsky, MD, Co-Director of the Center of Excellence for Bladder Cancer at The Tisch Cancer Institute at Mount Sinai, presented three-year follow-up results from the Phase 3 CheckMate 274 trial. Patients on the trial had urothelial cancer of the bladder or upper urinary tract and had tumor features indicating a high risk for recurrence.
“Adjuvant nivolumab became a standard of care based on the initial results of CheckMate 274,” Dr. Galsky said. “These results, showing patients’ continued survival three years out, reinforce adjuvant nivolumab as a standard of care for patients with muscle-invasive urothelial cancer of the bladder or upper urinary tract. Normally, patients with this cancer face a high chance of recurrence, especially within the first three years after surgical removal of the bladder or kidney.”
This new data showed that at approximately three years of follow-up, nivolumab increased these patients’ chance of staying cancer-free after surgery compared to patients who received a placebo. The average length of time before relapse doubled in patients who received nivolumab, which is a monoclonal antibody immune checkpoint inhibitor that harnesses the immune system to fight cancer. For a subset of clinical trial patients who received the immunotherapy, disease-free survival was more than six times that of patients on placebo.
Among the 699 patients in the trial, half received nivolumab, and the other half received a placebo every two weeks for one year. Adjuvant nivolumab versus placebo was not associated with a detriment to quality of life. This trial was conducted with support from Bristol Myers Squibb, the maker of the immunotherapy, in collaboration with ONO Pharmaceutical Company Ltd.
About the Mount Sinai Health System
Mount Sinai Health System is one of the largest academic medical systems in the New York metro area, with more than 43,000 employees working across eight hospitals, over 400 outpatient practices, nearly 300 labs, a school of nursing, and a leading school of medicine and graduate education. Mount Sinai advances health for all people, everywhere, by taking on the most complex health care challenges of our time — discovering and applying new scientific learning and knowledge; developing safer, more effective treatments; educating the next generation of medical leaders and innovators; and supporting local communities by delivering high-quality care to all who need it.
Through the integration of its hospitals, labs, and schools, Mount Sinai offers comprehensive health care solutions from birth through geriatrics, leveraging innovative approaches such as artificial intelligence and informatics while keeping patients’ medical and emotional needs at the center of all treatment. The Health System includes approximately 7,300 primary and specialty care physicians; 13 joint-venture outpatient surgery centers throughout the five boroughs of New York City, Westchester, Long Island, and Florida; and more than 30 affiliated community health centers. We are consistently ranked by U.S. News & World Report‘s Best Hospitals, receiving high “Honor Roll” status, and are highly ranked: No. 1 in Geriatrics and top 20 in Cardiology/Heart Surgery, Diabetes/Endocrinology, Gastroenterology/GI Surgery, Neurology/Neurosurgery, Orthopedics, Pulmonology/Lung Surgery, Rehabilitation, and Urology. New York Eye and Ear Infirmary of Mount Sinai is ranked No. 12 in Ophthalmology. U.S. News & World Report’s “Best Children’s Hospitals” ranks Mount Sinai Kravis Children’s Hospital among the country’s best in several pediatric specialties. The Icahn School of Medicine at Mount Sinai is one of three medical schools that have earned distinction by multiple indicators: It is consistently ranked in the top 20 by U.S. News & World Report‘s “Best Medical Schools,” aligned with a U.S. News & World Report “Honor Roll” Hospital, and top 20 in the nation for National Institutes of Health funding and top 5 in the nation for numerous basic and clinical research areas. Newsweek’s “The World’s Best Smart Hospitals” ranks The Mount Sinai Hospital as No. 1 in New York and in the top five globally, and Mount Sinai Morningside in the top 20 globally.
For more information, visit https://www.mountsinai.org or find Mount Sinai on Facebook, Twitter and YouTube.
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Mount Sinai Health System
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Major genetic study reveals unexpectedly high variation in T-cell receptor genes between persons
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Newswise — T-cells that are part of our immune system are central in the protection against infections and cancer. With the help of TCRs, the cells recognize foreign invaders and tumor cells.
“It was previously unknown how variable human TCR genes are”, says Gunilla Karlsson Hedestam, professor at the department of microbiology, tumor and cell biology at Karolinska Institutet and the study’s lead author.
Using deep sequencing of blood samples, the researchers examined TCR genes in 45 people originating from sub-Saharan Africa, East Asia, South Asia and Europe. The researchers showed that these genes vary greatly between different persons and population groups. The results were confirmed by analyses of several thousand additional cases from the 1000 Genomes project.
“We found that every individual, other than identical twins, has a unique set of TCR gene variants. These differences reveal possible mechanisms underlying the wide range of responses to infections and vaccines that we observe at the population level”, says Martin Corcoran, the first author of the study.
“We discovered 175 new gene variants, which doubles the number of known TCR gene variants. An unexpected and surprising finding is that certain gene variants originate from Neanderthals and one of these is present in up to 20% of modern humans in Europe and Asia.”
Gunilla Karlsson Hedestam explains that the variation in these genes cannot be detected with the standard methods used in whole genome sequencing, but with the development of specialized deep sequencing methods and analysis software that allow highly precise definition of B- and T-cell receptor genes, this is now possible.
“As these genes are among the most variable in our genome, the results also provide new information about how our immune system has developed over the course of history, says Martin Corcoran. We are particularly interested in uncovering the function of the TCR variants we have inherited from Neanderthal ancestors. The frequency of these variants in modern humans suggests an advantageous function in our biology and we are keen to understand this”, adds Martin Corcoran.
The findings and the new TCR gene database the researchers now publish can be of great importance in the development of new therapeutic approaches in the future.
“Understanding human genetics is fundamental for the development of targeted treatments. The methods described in the study provide new opportunities, not the least in the cancer field where T-cells are central to several promising forms of immunotherapy”, says Gunilla Karlsson Hedestam.
The results can also shed light on other areas of research.
“The findings can lead to the development of new diagnostics and therapies in a range of medical disciplines, including precision medicine”, says Gunilla Karlsson Hedestam.
What is the next step in your research?
“We are now investigating the functional significance of several of the newly discovered gene variants and how this variation impacts our T-cell responses. We are also planning extended studies involving large groups of individuals to examine the role of TCR gene variation in diseases we know involve T cells, such as infectious diseases, cancer, and autoimmune disorders”, says Gunilla Karlsson Hedestam.
Main funding for the study comes from an ERC Advanced Grant and the Swedish Research Council.
Publication: “Archaic humans have contributed to large-scale variation in modern human T cell receptor genes”, Martin Corcoran, Mark Chernyshev, Marco Mandolesi, Sanjana Narang, Mateusz Kaduk, Kewei Ye, Christopher Sundling, Anna Färnert, Taras Kreslavsky, Carolina Bernhardsson, Maximilian Larena, Mattias Jakobsson, Gunilla B. Karlsson Hedestam, Immunity, online February 15, doi: 10.1016/j.immuni.2023.01.026
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Karolinska Institute
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‘Natural killer’ immune cells can modify tissue inflammation: study
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Newswise — Melbourne researchers have improved our understanding of how the immune system is regulated to prevent disease, identifying a previously unknown role of ‘natural killer’ (NK) immune cells.
The Monash University-led study identified a new group of immune cells, known as tissue-resident memory natural killer (NKRM) cells. NKRM cells limited immune responses in tissues and prevented autoimmunity, which is when the immune system makes a mistake and attacks the body’s own tissues or organs.
While additional research is required, the discovery may ultimately be used to treat autoimmune diseases like Sjogren’s Syndrome and possibly chronic inflammatory conditions.
Published in Immunity, the preclinical research is led by senior author Professor Mariapia Degli-Esposti and first author Dr Iona Schuster from the Monash Biomedicine Discovery Institute (BDI), in close ongoing collaboration with the Lions Eye Institute.
Originally, NK cells were thought to be short lived cells that circulate in the blood with the sole function of identifying and quickly killing virally infected or damaged cells.
The team’s previous research established that NK cells’ role is far more complex, and the latest study demonstrates for the first time that a subset of NK cells, NKRM, are critical in regulating immune responses in tissues.
“This is key to preserving tissue function and preventing autoimmunity from developing,” Dr Schuster said. “While long-lived tissue resident memory T cells (TRM) have been described, the primary known function of these cells is to protect the host against reinfection.
“Our discovery of tissue-resident memory natural killer (NKRM) cells establishes that the function of some memory cells that live in tissues is to protect from excessive inflammation rather than protect against recurring infection.”
Professor Degli-Esposti, BDI Head of Experimental and Viral Immunology, said the findings significantly improved our fundamental understanding of how the immune system is regulated to prevent disease.
“One of the main obstacles in cancer immunotherapy … is the development of immune related adverse events, which include the development or flare-up of autoimmune complications,” she said.
“These events are due to ‘super’ or ‘uncontrolled’ activation of the immune system as a result of the brakes being removed by the therapeutic strategy.“Furthermore, many therapies cause collateral damage to tissues where tumours are localised. Thus, NKRM may be an adjunct or follow-up therapy to restore immune balance and bring back tissue health.”
Read the full paper in Immunity: Infection induces tissue resident memory NK cells that safeguard tissue health. https://www.cell.com/immunity/fulltext/S1074-7613(23)00026-2
Key findings
1. Following infection with a common virus, cytomegalovirus, ‘natural killer’ (NK) cells were recruited from the circulation into inflamed tissues where they were retained and developed into a long-lived population of cells that researchers called tissue-resident memory natural killer (NKRM) cells.
2. Unlike NK cells, NKRM did not participate in virus control.
3. In the absence of NKRM, infection led to tissue damage and the development of autoimmunity which presented as Sjogren’s Syndrome, one of the most common autoimmune diseases.
Therefore, researchers identified a new population of cells that specifically localise to tissues to modulate immune responses to prevent immune pathology and autoimmunity.About the immune system
Dysregulated immune or inflammatory processes contribute to many diseases. While the immune system protects against infection, a dysregulated immune response can lead to chronic inflammation, and in some instances cause tissue damage. Viral infections can trigger these processes, as the Covid pandemic has highlighted.
About autoimmune diseases
Autoimmune diseases arise when immune responses are misdirected and the immune system attacks host tissues and organs. Appropriate regulation of immune responses is therefore critical. As an example, Sjogren’s Syndrome is one of the most common autoimmune diseases and severely affects vision as patients are not able to produce tears. In most cases this leads to severe discomfort, but complications can lead to corneal damage and compromise vision. There is no cure for Sjogren’s Syndrome or its ocular complications.
About the Monash Biomedicine Discovery Institute
Committed to making the discoveries that will relieve the future burden of disease, the Monash Biomedicine Discovery Institute (BDI) at Monash University brings together more than 120 internationally-renowned research teams. Spanning seven discovery programs across Cancer, Cardiovascular Disease, Development and Stem Cells, Infection, Immunity, Metabolism, Diabetes and Obesity, and Neuroscience, Monash BDI is one of the largest biomedical research institutes in Australia. Our researchers are supported by world-class technology and infrastructure, and partner with industry, clinicians and researchers internationally to enhance lives through discovery.About the Lions Eye Institute
At the Lions Eye Institute, we make a difference to people’s lives through excellent patient care and by pushing the frontiers of science to discover new treatments and cures for eye disease. As a not for profit organisation, the Lions Eye Institute spans the dual complementary pathways of research and clinical care. We bring together a globally recognised team of researchers and clinicians who continually build on each other’s discoveries, knowledge and expertise to deliver sight-saving treatment and care around the world. The quest for knowledge and its life-changing applications for patients is what drives our work.
For more Lions Eye Institute media stories, visit our news site.For more Monash media stories, visit our news and events site.
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Monash University
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Scientists discover receptor that blocks COVID-19 infection
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Newswise — University of Sydney scientists have discovered a protein in the lung that blocks SARS-CoV-2 infection and forms a natural protective barrier in the human body.
This protein, the leucine-rich repeat-containing protein 15 (LRRC15), is an inbuilt receptor that binds the SARS-CoV-2 virus without passing on the infection.
The research opens up an entirely new area of immunology research around LRRC15 and offers a promising pathway to develop new drugs to prevent viral infection from coronaviruses like COVID-19 or deal with fibrosis in the lungs.
The study has been published in the journal PLOS Biology. It was led by Professor Greg Neely with his team members Dr Lipin Loo, a postdoctoral researcher, and PhD student Matthew Waller at the Charles Perkins Centre and the School of Life and Environmental Sciences.
The University study is one of three independent papers that reveal this specific protein’s interaction with COVID-19.
“Alongside two other groups, one at Oxford, the other at Brown and Yale in the USA, we found a new receptor in the LRRC15 protein that can stop SARS-CoV-2. We found that this new receptor acts by binding to the virus and sequestering it which reduces infection,” Professor Neely said.
“For me, as an immunologist, the fact that there’s this natural immune receptor that we didn’t know about, that’s lining our lungs and blocks and controls virus, that’s crazy interesting.
“We can now use this new receptor to design broad acting drugs that can block viral infection or even suppress lung fibrosis.”
What is LRRC15?
The COVID-19 virus infects humans by using a spike protein to attach to a specific receptor in our cells. It primarily uses a protein called the angiotensin-converting enzyme 2 (ACE2) receptor to enter human cells. Lung cells have high levels of ACE2 receptors, which is why the COVID-19 virus often causes severe problems in this organ of infected people.
Like ACE2, LRRC15 is a receptor for coronavirus, meaning the virus can bind to it. But unlike ACE2, LRRC15 does not support infection. It can, however, stick to the virus and immobilise it. In the process, it prevents other vulnerable cells from becoming infected.
“We think it acts a bit like Velcro, molecular Velcro, in that it sticks to the spike of the virus and then pulls it away from the target cell types,” Dr Loo said.
“Basically, the virus is coated in the other part of the Velcro, and while it’s trying to get to the main receptor, it can get caught up in this mesh of LRRC15,” Mr Waller said.
LRRC15 is present in many locations such as lungs, skin, tongue, fibroblasts, placenta and lymph nodes. But the researchers found human lungs light up with LRRC15 after infection.
“When we stain the lungs of healthy tissue, we don’t see much of LRRC15, but then in COVID-19 lungs, we see much more of the protein,” Dr Loo said.
“We think this newly identified protein could be part of our body’s natural response to combating the infection creating a barrier that physically separates the virus from our lung cells most sensitive to COVID-19.”
Implications of the research
“When we studied how this new receptor works, we found that this receptor also controls antiviral responses, as well as fibrosis, and could link COVID-19 infection with lung fibrosis that occurs during long COVID,” Mr Waller said.
“Since this receptor can block COVID-19 infection, and at the same time activate our body’s anti-virus response, and suppress our body’s fibrosis response, this is a really important new gene,” Professor Neely said.
“This finding can help us develop new antiviral and antifibrotic medicines to help treat pathogenic coronaviruses, and possibly other viruses or other situations where lung fibrosis occurs.
“For fibrosis, there are no good drugs: for example, idiopathic pulmonary fibrosis is currently untreatable.”
Fibrosis is a condition in which lung tissue becomes scarred and thickened, causing breathing difficulties. COVID-19 can cause inflammation and damage to the lungs, leading to fibrosis.
The authors said they are developing two strategies against COVID-19 using LRRC15 that could work across multiple variants – one which targets the nose as a preventative treatment, and another aimed at the lungs for serious cases.
The researchers also said that the presence or lack of LRRC15, which is involved in lung repair, is an important indication of how severe a COVID-19 infection might become.
“A group at Imperial College London independently found that absence of LRRC15 in the blood is associated with more severe COVID, which supports what we think is happening.” Dr Loo said. “If you have less of this protein, you likely have serious COVID. If you have more of it, your COVID is less severe.
“We are now trying to understand exactly why this is the case.”
The research involved screening human cell cultures for genes and investigating the lungs of human COVID-19 patients.
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University of Sydney
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How a high fat diet allows expulsion of intestinal parasite worms
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Newswise — Scientists have discovered that a high-fat diet allows the immune system to eliminate a parasitic worm which is a major cause of death and illness in the developing world.
Parasitic worms affect up to a billion people, particularly in developing nations with poor sanitation. One of these parasites known as “whipworm” can cause long lasting infections in the large intestine.
Researchers from Lancaster University and the University of Manchester in the UK have discovered that a high-fat diet allows the immune system to eliminate the parasite.
Lead author Dr Evelyn Funjika, formerly at Manchester and now at the University of Zambia, said: “Just like the UK, the cheapest diets are often high in fat and at-risk communities to whipworm are increasingly utilising these cheap diets. Therefore, how worm infection and western diets interact is a key unknown for developing nations.
“In order to be able to study how nutrition affects parasite worm infection, we have been using a mouse model, Trichuris muris, closely related to the human whipworm Trichuris trichiura and seeing how a high-fat diet impacts immunity.”
It has been previously shown that immune responses which expel the parasite rely on white blood cells called T-helper 2 cells, specialised for eliminating gastrointestinal parasites.
The findings, published in the journal “Mucosal Immunology”, demonstrate how a high-fat diet, rather than obesity itself, increases a molecule on T-helper cells called ST2 and this allows an increased T-helper 2 response which expels the parasite from the large intestinal lining.
Dr John Worthington from the Department of Biomedical and Life Science at Lancaster University co-led the research.
“We were quite surprised by what we found during this study. High-fat diets are mostly associated with increased pathology during disease. However, in the case of whipworm infection this high fat diet licenses the T-helper cells to make the correct immune response to expel the worm.”
Co-lead Professor Richard Grencis from the University of Manchester said: “Our studies in mice on a standard diet demonstrate that ST2 is not normally triggered when expelling the parasite, but the high-fat diet boosts the levels of ST2 and hence allows expulsion via an alternative pathway”.
Co-lead Professor David Thornton from the University of Manchester added: “It was really fascinating that simply altering the diet completely switched the immune response in the gut from one that fails to expel the parasite, to one that brings about all the correct mechanisms to eliminate it.”
However, Dr Worthington added caution to the findings.
“Before you order that extra take-away, we have previously published that weight loss can aid the expulsion of a different gut parasite worm. So these results may be context specific, but what is really exciting is the demonstration of how diet can profoundly alter the capacity to generate protective immunity and this may give us new clues for treatments for the millions who suffer from intestinal parasitic infections worldwide.”
The research was funded by the Commonwealth Scholarship Commission, The Wellcome Trust and EPSRC (Engineering and Physical Sciences Research Council).
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Lancaster University
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Immunotherapy with two novel drugs shows activity in colorectal cancer
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Newswise — BOSTON –A combination of two next-generation immunotherapy drugs has shown promising clinical activity in treating patients with refractory metastatic colorectal cancer, a disease which has not previously responded well to immunotherapies, according to a Dana-Farber Cancer Institute researcher.
The results of an expanded phase 1 trial of the two drugs, botensilimab and balstilimab, are to be presented at the ASCO Gastrointestinal Cancers Symposium Jan. 19-21 in San Francisco. The study is led by Benjamin L. Schlechter, MD, a senior physician in the Gastrointestinal Cancer Treatment Center at Dana-Farber.
The trial included 70 patients with metastatic colorectal cancer who had been previously treated with several lines of drugs, including immunotherapies. These patients all had tumors termed microsatellite stable, or MSS, meaning that their genes for repairing certain types of DNA damage were intact. MSS colorectal tumors account for the vast majority of colorectal cancers, and the first generation of immunotherapy drugs have had little effect on them. While immunotherapy has succeeded in microsatellite unstable (MSI) colorectal cancers, only about 3-5% advanced colorectal cancers are MSI and there are no approved immunotherapies for the far more common MSS colorectal cancers.
The two-drug combination being tested in the expanded phase 1a/1b trial of patients with metastatic MSS colorectal cancers were novel, next-generation antibodies. Botensilimab is an antibody directed against the T-cell receptor cytotoxic T-lymphocyte-associated antigen 4, or CTLA-4, which is an immune checkpoint that regulates T-cell activation. Balstilimab is a novel monoclonal antibody designed to block PD-1 – another immune checkpoint protein – from interacting with PD-L1 and PD-L2. By inhibiting this interaction, balstilimab is aimed at freeing the immune system to attack cancers.
The patients in the trial were followed for a median of 7 months after receiving the drug combination. During that period, 23% of the patients had a reduction in the size of their tumors, and the median duration of response was not reached. The disease control rate – the percentage of patients with metastatic cancer who had a complete or partial response and stable disease – was 76%. The 12-month overall survival was 63%. The main population of patients who benefited from the combination were those who did not have active metastatic cancer in their liver.
Treatment-related adverse events occurred in 91% of patients, including grade 3 in 40% and grade 4 in 3%. Twelve percent of patients discontinued both drugs because of adverse events.
The researchers concluded that “in patients with heavily pretreated metastatic MSS colorectal cancer, botensilimab plus balstilimab continues to demonstrate promising clinical activity with durable response, and was well tolerated, with no new immune-mediated safety signals.”
“Harnessing the power of immune therapy in refractory colorectal cancer has been a key goal of multiple clinical trials in advanced colorectal cancer, but in MSS colorectal cancer efforts have been universally disappointing,” said Schlechter. “These data are a meaningful and important advance in the care of this very sick population.”
Based on these findings, a randomized phase 2 trial in patients with MSS colorectal cancer is currently enrolling.
Funding for this research comes from Agenus, Inc.
About Dana-Farber Cancer Institute
Dana-Farber Cancer Institute is one of the world’s leading centers of cancer research and treatment. Dana-Farber’s mission is to reduce the burden of cancer through scientific inquiry, clinical care, education, community engagement, and advocacy. Dana-Farber is a federally designated Comprehensive Cancer Center and a teaching affiliate of Harvard Medical School.
We provide the latest treatments in cancer for adults through Dana-Farber Brigham Cancer Center and for children through Dana-Farber/Boston Children’s Cancer and Blood Disorders Center. Dana-Farber is the only hospital nationwide with a top 5 U.S. News & World Report Best Cancer Hospital ranking in both adult and pediatric care.
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Dana-Farber Cancer Institute
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Commonly used antiretroviral drugs used to treat HIV and hepatitis B reduce immune cells’ energy production
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FINDINGS
New UCLA-led research suggests that antiretroviral drugs called TAF and TDF directly reduce energy production by mitochondria, structures inside cells that generate the power that cells use to function. Both drugs led to reduced cellular oxygen consumption rates, a measure of the ability of the mitochondria to produce energy, compared with controls. But in combination with other antiretrovirals, TAF appeared to result in a larger energy reduction than TDF did. Whether this is a cause for concern is not known at this point.
BACKGROUND
The antiretroviral drugs tenofovir alafenamide (TAF) and tenofovir disoproxil fumarate (TDF) are used to treat HIV and hepatitis B infection in millions of people around the world. These drugs are also used as pre-exposure prophylaxis (PrEP) against HIV in uninfected people.
METHOD
Using both a human clinical trial and experimental lab studies, the researchers assessed the impact of TAF and TDF in combination with other antiretrovirals on the ability of blood immune cells to make energy. In the clinical trial, 26 people with HIV switched antiretrovirals over nine months and the researchers assessed how the drugs affected their cells’ energy production. The investigators confirmed these findings experimentally in the lab by directly adding the drugs to healthy immune cells and analyzing their impact on the cells’ metabolism.
IMPACT
The clinical implications of the findings are unclear at this point, a question that requires more research. These drugs are well tolerated by millions of people worldwide, but the long-term clinical implications of these drugs on the ability of human cells to make energy is unclear.
COMMENT
“Mitochondria are key structures inside the cells. This is the among the first demonstrations that antiretrovirals used in humans in HIV and hepatitis B directly change the function of mitochondria to make energy,” said senior author Dr. Theodoros Kelesidis, associate professor-in-residence of medicine in the division of infectious diseases at the David Geffen School of Medicine at UCLA. “We utilized independent research methods to confirm our findings. This is an important message, given that millions of people are on these antiretrovirals. It remains to be shown whether the effects of these antiretrovirals on mitochondria are mechanistically linked to certain metabolic changes that may be seen with the use of these antiretrovirals such as weight gain.”
AUTHORS
Study co-authors are Eleni Ritou, Sandro Satta, Anton Petcherski, Maria Daskou, Madhav Sharma, Hariclea Vasilopoulos, and Dr. Orian Shirihai of UCLA, and Eisuke Murakami of Gilead Sciences.
JOURNAL
The study is published in the peer-reviewed journal Metabolism.
FUNDING
The study was supported by Gilead Sciences, Inc. (CO-US-311-4393) and the National Institutes of Health (R01AG059501).
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University of California, Los Angeles (UCLA), Health Sciences
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Using paleogenomics to elucidate 10,000 years of immune system evolution
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Newswise — Scientists from the Institut Pasteur, Université Paris Cité, the CNRS and the Collège de France have used paleogenomics to trace 10,000 years of human immune system evolution. They analyzed the genomes of more than 2,800 individuals who lived in Europe over the past ten millennia. They were able to date the increase in frequency of most of the mutations that are advantageous in defending against pathogens to after the Bronze Age, 4,500 years ago. The scientists also observed that mutations conferring a higher risk of developing inflammatory disorders have become more frequent over the past 10,000 years. These enlightening results on the effects of natural selection on immunity genes were published in the journal Cell Genomics on January 13, 2023.
In the 1950s, the geneticist J.B.S. Haldane attributed the maintenance or persistence of the mutation responsible for anomalies in red blood cells commonly observed in Africa to the protection these anomalies provided against malaria, an endemic infection that claims millions of lives. This theory suggested that pathogens are among the strongest selective pressures faced by humans. Several population genetics studies subsequently confirmed the theory. But major questions remained, especially regarding the specific epochs during which the selective pressures exerted by pathogens on human populations were strongest and their impact on the present-day risk of developing inflammatory or autoimmune disorders.
To address these questions, scientists from the Institut Pasteur, Université Paris Cité, the CNRS and the Collège de France, in collaboration with the Imagine Institute and The Rockefeller University (United States), adopted an approach based on paleogenomics. This discipline, which studies the DNA from fossil remains, has led to major discoveries about the history and evolution of humans and human diseases, as illustrated by the decision to award the 2022 Nobel Prize in Physiology or Medicine to the paleogeneticist Svante Pääbo. In the study led by the Institut Pasteur, published on January 13 in the journal Cell Genomics, the scientists analyzed the variability of the genomes of more than 2,800 individuals who lived in Europe over the past ten millennia – a period covering the Neolithic, the Bronze Age, the Iron Age, the Middle Ages and the present.
By reconstituting the evolution over time of hundreds of thousands of genetic mutations, the scientists initially identified mutations that rapidly increased in frequency in Europe, indicating that they were advantageous. These mutations that evolved under “positive” natural selection are mainly located in 89 genes enriched in functions relating to the innate immune response, including especially the OAS genes – which are responsible for antiviral activity – and the gene responsible for the ABO blood group system. Surprisingly, most of these positive selection events, which demonstrate a genetic adaptation to the pathogenic environment, began recently, from the start of the Bronze Age, around 4,500 years ago. The scientists explain this “acceleration” in adaptation by the growth in the human population during this period and/or by strong selective pressures exerted by pathogens in the Bronze Age, probably linked to the spread of severe infectious diseases such as plague.
At the same time, the scientists also looked at the opposite situation, in other words, mutations whose frequency fell significantly over the past ten millennia. These mutations are probably subject to “negative” selection because they increase the risk of disease. They noted that once again, these selection events mainly began in the Bronze Age. Many of these disadvantageous mutations were also located in genes associated with the innate immune response, such as TYK2, LPB, TLR3 and IL23R, and have been confirmed in experimental research to have a deleterious effect in terms of infectious disease risk. The results emphasize the value of adopting an evolutionary approach in research on genetic susceptibility to infectious diseases.
Finally, the scientists explored the theory that the selection exerted by pathogens in the past gave an advantage to alleles conferring resistance to infectious diseases, but that in turn these alleles have increased the present-day risk of autoimmune or inflammatory disorders. They investigated the few thousand mutations known to increase susceptibility firstly to tuberculosis, hepatitis, HIV or COVID-19, and secondly to rheumatoid arthritis, systemic lupus erythematosus or inflammatory bowel disease. By looking at the evolution of these mutations over time, they observed that those associated with an increased risk of inflammatory disorders – including Crohn’s disease – became more frequent over the past 10,000 years, while the frequency of those associated with a risk of developing infectious diseases decreased. “These results suggest that the risk of inflammatory disorders has increased in Europeans since the Neolithic period because of a positive selection of mutations improving resistance to infectious diseases,” explains Lluis Quintana-Murci, director of the study and Head of the Human Evolutionary Genetics Unit (Institut Pasteur/CNRS Evolutionary Genomics, Modeling and Health Unit/Université Paris Cité).
The results of the study, which harnessed the huge potential of paleogenomics, show that natural selection has targeted human immunity genes over the past ten millennia in Europe, especially since the start of the Bronze Age, and contributed to present-day disparities in terms of the risk of infectious and inflammatory diseases.
As well as the institutions mentioned above, this research was supported by the French Foundation for Medical Research (FRM), the Allianz-Institut de France Foundation and the Fondation de France.
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Institut Pasteur
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More than two billion are infected with this disease; Vitamin D can help
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Newswise — Sarcomas are cancer tumours found in e.g. the bones, muscles or fatty tissue. It is a rare type of cancer seen in only one per cent of cancer patients. It is complex and difficult to treat.
However, a new study may have found a new treatment that can help the sickest sarcoma patients.
“We have learned that sarcoma patients whose cancer cells have a high expression of the cep135 protein are worse off. But inhibiting a gene called plk1 also inhibits growth of the sarcoma cells, and this suggests that we can target the treatment of the sickest sarcoma patients,” says Associate Professor Morten Scheibye-Knudsen from the Center for Healthy Aging at the Department of Cellular and Molecular Medicine, who is responsible for the new study.
Methods for identifying sarcoma patients’ prognoses are already available, as are different forms of treatment. But the new study has identified a new method.
“This is a new way of stratifying and possibly a new and better way of treating sarcoma. And the introduction of yet another method is always good news to patients. Because no two cancers are alike. Ideally, treatment should always be tailored to the individual patient,” Morten Scheibye-Knudsen stresses.
He hopes other researchers with access to the necessary test facilities will study his results in more detail and eventually design a new treatment. If the method turns out to work, he believes a new treatment may be available to patients in five to 10 years.
Grey hair, wrinkles and loss of fatty tissue at an early age
Morten Scheibye-Knudsen and his colleagues started out by studying patients suffering from the rare neurological disorders Werner’s syndrome, Nijmegen breakage syndrome and Ataxia-telangiectasia syndrome.
These patients experience symptoms of early ageing such as grey hair, wrinkles and loss of fatty tissue – and they have a high risk of developing cancer at an early age.
“Age-associated diseases such as cancer is one of my main areas of interest as a researcher at the Center for Healthy Aging. As we grow older, a lot of things happen to the body, and determining causality can be difficult. But in people suffering from e.g. Werner’s syndrome it is easier to see which genes are responsible for which processes. This gives us a molecular handle, so to speak,” says Morten Scheibye-Knudsen.
In order to establish why these patients develop cancer at an early age, the researchers compared gene expressions across the three disorders. Here they worked together with the company Insilico Medicine, whose large Pandaomics platform made it possible to identify gene mutations in thousands of different disorders. It turned out that cep135 is a common denominator for the cancer genes of the three disorders.
“This made us study the gene expressions of various cancers, and we learned that cep135 is associated with high mortality in i.a. sarcoma, but also in bladder cancer. Sarcoma was particularly interesting, as many Werner’s syndrome patients develop sarcoma,” explains Morten Scheibye-Knudsen.
Finally, the researchers sought to find ways to inhibit the sarcoma. Cep135 is not a useful target, as it is a so-called structural protein, which are difficult to target. Instead, the researchers learned that by inhibiting the plk1 gene they were able to target the sarcoma.
“The study indicates that we can use genetic diseases that exhibit accelerated aging to identify new treatment targets. In this study, we investigated cancer, but the method can in principle be used for all age-related diseases such as dementia, cardiovascular diseases and others,” says Morten Scheibye-Knudsen.
Read the entire study, ”High-confidence cancer patient stratification through multiomics investigation of DNA repair disorders”, in CDDpress.
What are sarcomas?
Sarcomas are cancer tumours found in i.a. the bones, muscles or fatty tissue. There are two main types: bone sarcoma and soft tissue sarcoma (muscles, fatty tissue, connective tissue, blood vessels and neurilemma).
Sarcoma affects one per cent of cancer patients. In Denmark, around 45 people are diagnosed with bone sarcoma each year and 220 with soft tissue sarcoma. Adults diagnosed with bone sarcoma have a 60-per cent five-year survival rate, while adults diagnosed with bone sarcoma have a 50-70-per cent five-year survival rate.
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University of Copenhagen, Faculty of Health and Medical Sciences
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Vaccine and prior SARS-CoV-2 infection confer long-lasting protection against omicron BA.5
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Newswise — A new study led by Luís Graça, group leader at the Instituto de Medicina Molecular João Lobo Antunes (iMM, Lisbon) and full professor at the Medical School of the University of Lisbon, and Manuel Carmo Gomes, associate professor with aggregation at the Faculty of Sciences of the University of Lisbon (Ciências ULisboa), both members of the Direção Geral de Saúde (DGS) Technical Committee for Vaccination against COVID-19 (CTVC), and published today in the scientific journal Lancet Infectious Diseases*, shows that the protection conferred by hybrid immunity against the SARS-CoV-2 subvariant omicron BA.5, obtained by the infection of vaccinated people, lasts for at least eight months after the first infection.
This study follows the results published in September by the same researchers in the New England Journal of Medicine** where they showed, by studying the widely vaccinated Portuguese population, that infection by the first omicron subvariants of SARS-CoV-2, circulating in January and February 2022, conferred considerable protection against the omicron BA.5 subvariant circulating in Portugal since June and which remains the predominant variant in many countries. However, the stability of the protection conferred by the so-called hybrid immunity, the immunity conferred by the combination of vaccination and infection, was not yet known.
“In September, we had observed that infection by the first omicron subvariants conferred protection for the BA.5 subvariant about four times higher than vaccinated people who were not infected on any occasion, showing the importance of hybrid immunity for protection against new infections. Now, we show that this protection conferred by vaccination together with previous infections is stable and maintained until at least eight months after the first infection”, explains Luís Graça, co-leader of the study.
As in the previous study, the researchers used the national COVID-19 case registry until September 2022, which is especially comprehensive due to the legal requirement to register all cases of SARS-CoV-2 infection at the time to gain access to sick leave during mandatory isolation days. “We used the national COVID-19 case registry to obtain the information of all cases of SARS-CoV-2 infections in the population over 12 years old residing in Portugal. These data from the Portuguese population allows us to conclude about hybrid immunity because vaccination had already covered 98% of this population by the end of 2021. The virus variant of each infection was determined considering the date of infection and the dominant variant at that time”, explains Manuel Carmo Gomes, co-leader of the study.
About the calculations performed with these data, João Malato, first author of the study, explains: “With these data, we calculated the relative risk of reinfection over time in people vaccinated with previous infections by the first omicron subvariants of SARS-CoV-2, allowing us to conclude on the level of protection against reinfection. We found that protection remains high 8 months after contact with the virus.”
“The protection afforded by hybrid immunity is initially about 90%, reducing after 5 months to about 70%, and showing a tendency to stabilize at a value of around 65% after 8 months, compared to the protection in vaccinated persons that were never infected by the virus. These results show that hybrid immunity conferred by infection with previous subvariants of SARS-CoV-2 in vaccinated people is quite stable”, adds Luís Graça about the protection conferred by hybrid immunity.
This study shows that infection by previous subvariants of the SARS-CoV-2 virus, which causes COVID-19, has the ability to confer additional protection compared to the protection conferred by vaccination alone, and that this protection is stable.
This work was developed at the Instituto de Medicina Molecular João Lobo Antunes (iMM, Lisboa) and the Direção Geral de Saúde, in colaboration with researchers from the Centro de Estatística e Aplicações da Universidade de Lisboa, the Faculdade de Ciências da Universidade de Lisboa and Los Alamos National Laboratory (USA). This work was funded by the Horizon 2020 research and innovationfrom the European Union, Fundação para a Ciência e a Tecnologia (FCT, Portugal) and the National Institute of Health.
* João Malato, Ruy M Ribeiro, Eugénia Fernandes, Pedro P Leite, Pedro Casaca, Carlos Antunes, Válter R Fonseca, Manuel Carmo Gomes, Luís Graça. (2022) Stability of hybrid vs. vaccine immunity against BA.5 infection over 8 months. Lancet Infectious Diseases.
** João Malato, Ruy M Ribeiro, Pedro P Leite, Pedro Casaca, Eugénia Fernandes, Carlos Antunes, Válter R Fonseca, Manuel C Gomes, Luís Graça. (2022) Risk of BA.5 Infection among Persons Exposed to Previous SARS-CoV-2 Variants. New England Journal of Medicine.387(10):953-954. Doi: 10.1056/NEJMc2209479.
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Instituto de Medicina Molecular
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Does COVID change the body’s response to other threats? Depends on your sex
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Newswise — New Haven, Conn. — The long-term effects of infection on the immune system have long intrigued John Tsang, a Yale immunobiologist. After the body has faced down a pathogen, does the immune system return to the previous baseline? Or does a single infection change it in ways that alter how it will respond not only to a familiar virus but also to the next new viral or bacterial threat it faces?
Tsang, a professor of immunobiology and biomedical engineering at Yale, has long believed that the immune system reverts to the previous stable baseline after viral infection.
The emergence of the COVID-19 pandemic in 2020 allowed him and colleagues to test that theory. The answer, they found, depends on the individual’s sex, according to a study published Jan. 4 in the journal Nature.
For the study, a team led by Tsang, who at the time was at the National Institute of Allergy and Infectious Diseases (NIAID), and colleagues, including lead author Rachel Sparks, also from NIAID, systematically analyzed immune responses of healthy people who had received the flu vaccine. From that data, they then compared the responses between those who had never been infected by SARS-CoV-2, the virus that causes COVID-19, and those who experienced mild cases but recovered.
To their surprise, they found that immune systems of men who had recovered from mild cases of COVID-19 responded more robustly to flu vaccines than women who had had mild cases or men and women who had never been infected.
In essence, the baseline immune statuses in men previously infected with SARS-CoV-2 was altered in ways that changed the response to an exposure different from SARS-CoV-2, the authors said.
“This was a total surprise,” Tsang said. “Women usually mount a stronger overall immune response to pathogens and vaccines, but are also more likely to suffer from autoimmune diseases.”
The findings may also be linked to an observation made early in the pandemic: Men were much more likely to die from a runaway immune response than women after contracting the COVID-19 virus. Even mild cases of COVID-19, the new findings suggest, might trigger stronger inflammatory responses in males than females, resulting in more pronounced functional changes to the male immune system, even long after recovery.
Their unbiased analysis of immune system status down to the individual cell level revealed several differences between COVID-recovered males and healthy controls and COVID-recovered females, both before and after receiving flu vaccinations. For instance, previously infected males produced more antibodies to influenza and produced increased levels of interferons, which are produced by cells in response to infections or vaccines. Generally, healthy females have stronger interferon responses than their male counterparts.
Understanding the lingering effects of COVID-19 on the immune system is crucial, the authors say, since more than 600 million people worldwide have been infected so far, and the emergence of “long-COVID” symptoms in some people continues to be a major health concern.
“Our findings point to the possibility that any infection or immune challenge may change the immune status to establish new set points,” said Sparks. “The immune status of an individual is likely shaped by a multitude of prior exposures and perturbations.”
Tsang thinks these findings may also help scientists create better vaccines against diverse threats by, for instance, mimicking how mild COVID-19 changes the male immune baseline.
Other researchers included William Lau, a computational biologist at the National Institutes of Health, and Can Liu, a systems immunology graduate student at the University of Maryland who is also affiliated with NIAID.
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Yale University
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International recommendations for diagnosis and treatment of new-onset refractory status epilepticus (NORSE)
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Newswise — The following is the transcript from an episode of ILAE’s podcast, Sharp Waves.
Sharp Waves episodes are meant for educational purposes only, and not as medical or clinical advice.
You can listen to and download all Sharp Waves episodes, including this one, on Spotify, Apple Podcasts, Google Podcasts, Amazon Music, or the ILAE website.
First-line immunotherapy and the ketogenic diet are two main recommendations for treatment of NORSE of unknown cause, according to results from an international consensus group. Dr. Maryam Nabavi Nouri interviews first author Dr. Ronny Wickstrom.
Dr. Nabavi Nouri: So thank you for joining us on this episode of Sharp Waves – I’m joined by Dr. Ronny Wickstrom from Stockholm. He’s going to tell us about the international consensus recommendation for management of new-onset refractory status epilepticus (NORSE) and febrile infection-related epilepsy syndrome (FIRES), and I know there are two papers published: one is on summary and clinical tools and the other one statements and supporting evidence.
Dr. Wickstrom: Thanks for the opportunity to present these papers. I’m Ronny Wickstrom; I’m a pediatric neurologist and epileptologist in Stockholm in Sweden. I’m also professor of child neurology at Karolinska.
So my field for a long time has been working with neuroinflammatory diseases, both demyelinating diseases and also encephalitis cases of different kinds, and then I work with epilepsy. And these have been my two fields, and these two fields meet in FIRES, so that’s how I came to start with this.
I had a case actually, six or seven years ago, a FIRES case, that did not end well, of course, like they often do not. He survived but he had severe sequelae. It sort of puzzled me, this whole FIRES thing and I wasn’t aware of FIRES until then. I’d heard of it, but this is an epilepsy phenotype where we believe that autoimmune or some sort of immunological at least components are involved. So that’s where I came into it, because those were my two worlds met anyway.
But when it started out, it started as a FIRES discussion. And we in the pediatric field had some FIRES communities. And what’s happened over the last couple of years, and which I’ve had the privilege of being involved in, is that this has merged with the NORSE community, which was also existing. So NORSE was perceived as an adult disease and FIRES as a pediatric disease, and one of the things we want to emphasize here is that that’s probably not true.
One of the things we were doing in the FIRES field and also in the NORSE field is there’s a lot of research trying to be done, and there’s some data coming out, but it’s very hard, these are hard areas to study. One of course is that this is new onset, so there’s no population to study until they end up in refractory status epilepticus. And this, it’s very rare, and also it’s rare in a very hyperacute thing, so if you try to set up clinical trials, with standardized sampling and standardized testing and standardized treatment for these patients, it’s very difficult because you’re in a hyperacute situation where you have to do everything for your patient. So designing trials is extremely difficult.
We went through all the data before we started this and there’s a lot of case series and case presentations, and even in the larger case series and the ones we tried to compile, for instance, all the children that have been treated with IL-1 inhibition – one of the lessons we learned from that is even though we tried to standardize the data when we looked at it, it really ended up being 26 children, 26 individuals. It’s really, really difficult. That means what you’re left with as a clinician is there’s not a lot of solid data to base anything on.
So what we wanted to do with this Delphi approach, which, I’d been a part of another Delphi approach where we tried to summarize treatment in NMDA encephalitis. So I thought one way to do this or to try to summarize what we do know and give some sort of recommendations — we’ve been careful not to call these guidelines or anything like that because they’re not — we don’t have any evidence to say that they are guidelines. This is a recommendation, something to hold onto as a clinician and as a researcher. And we tried to compile this group of people that we thought for one or another reason were important to have as a part of it, and compile recommendations that covered everything from what is NORSE and FIRES, and also diagnostics and workup, treatment and long-term treatment, and then, and that’s the second part of why we undertook this and why I thought it was important, it also provided a possibility to try to bring everyone together because that’s the next step here.
This is a very rare and hyperacute and complicated thing. We at least need to try to, I mean we obviously need to study it better and we need large consortia to do this, and we need a common understanding, and common data elements, and speak the same language, and tests standardized and things like that, even if it’s only real-world studies. So the second idea of bringing this together was to create a platform like a solid ground, and this is the first step, to start a research consortium and international consortium where we can do these studies.
Dr. Nabavi Nouri: Thank you. I understand there was a core group, and then a bigger group, an expert panel of 48 people internationally. Of course the Delphi method is quite interesting too, in that in this particular project there was a pre-set of questions and then it led to a stage 1 and a stage 2.
Dr. Wickstrom: Yeah, so the Delphi methodology is an interesting way of doing things. It’s a standardized way of reaching a consensus, basically that’s what that is. You can be very orthodox or less orthodox and there are different ways of doing it. But the basic principle is the same. The idea is that rather than asking questions, you try to phrase statements like a recommendation or a guideline, if you have enough data for that. And for statements where you reach a consensus that’s all fine, and in statements where you do not reach a consensus for some reason, the idea is that you try to mold or adjust these statements until they are acceptable by the group as a consensus.
So a couple of things here. One is of course how do you select the group, how do you choose what group? How do you form the questions or the statements? And then, what is a consensus? I mean 100% is obviously a consensus but is 70% a consensus? There’s no definition, I mean no clear definition on this. We chose the methods that had most often been used in how to do this.
So a couple of things were unusual in this case. One is that for a Delphi process, having 48 experts is a very large group. It’s almost impossible. Of course this gives you so much input, and so that’s not the problem. The problem of course is if there’s too much input, and trying to get a consensus, and also trying to get all of these people together is very difficult. The other side of that is that I think the people in this group were perfect. I think we could have probably found 48 others too that should have been on this group. Looking at representation, it’s very heavy in Europe and North America and there’s a lot of great research coming out of Asia, for instance, and we have suboptimal representation from Japan, Korea, China, and other places.
And then what we did, which is also unusual, is that we had this initial question of, we’re dealing with two things, there are two ways of slicing this if you want to. We’re dealing with adults and children, and should we, are the questions usable for both groups or should we divide them?
And also we’re dealing with NORSE and FIRES and those are more or less the same, because NORSE children are perceived to have FIRES and adults have NORSE. So we asked the group, and we were divided on this: Should we perform one Delphi, which is what we did, or should we divide it and do a pediatric and an adult one?
The reason we actually decided to go with the Delphi, one Delphi, is that there’s not a whole lot of evidence supporting that this is pediatric disease on one hand and NORSE is different. A lot of evidence points to this being very overlapping diseases or conditions. And if nothing else the traditional or the use of anti-inflammatory treatment in children as, for instance, IL-1 inhibition using anakinra, whereas in adults it’s IL-6 inhibition and in this case it was tocilizumab. There’s no real reason for this, it’s just in adults that’s been used more and it’s different traditions. We felt in this case the differences, we can probably learn more from the differences from the adult and pediatrics sides that it won’t cause a problem.
Joining or defining FIRES as a part of NORSE, we corroborated that here. But that’s in the definitions that was published in 2019 and 2018, even. So that was nothing new, but it’s important to emphasize that if you look at adults with NORSE in the Yale cohort for instance right now, their preliminary data show that more than half of the adult NORSE patients actually fulfill FIRES criteria as well. And conversely there are children who don’t fulfill FIRES criteria. But it’s quite rare. It’s obvious that the children, in children, in younger ages, the prevalence of an infection preceding the illness is much higher. It’s not 100% but it’s getting there.
The important things in this is to try to look at all kinds of NORSE, including FIRES, as a potentially immunological problem. Especially cryptogenic NORSE. So NORSE today is a condition that can include infectious diseases, it can include autoimmune diseases, and if you find that of course you treat that. If you don’t find that and then you’re stuck with, so you have inconclusive results, cases of no etiology, we want to emphasize the importance of trying to break a vicious circle which is probably, I’m not going to say it’s inflammatory but at least it’s immunological. And that’s been more used in the pediatric field because it’s so obvious, I mean from a preceding illness, that this could be some sort of activation, whereas that’s not the case in adults. There are some data looking at refractory status epilepticus in adults showing that immunological treatments are not really on the table, or definitely not as early as they should be.
So to think that this is possibly immunological, there’s an immunological component in this and you have to target that, because if you don’t break that circle, none of your regular anti-seizure medications are going to work. So that’s one of the things, to start early with first-line immunotherapy, and escalate early and aggressively to second-line immunotherapy.
The other thing that’s also in this, which is not primarily immunological, is that we advocate the use of ketogenic diet as early as possible. And that’s also used in pediatrics but not so much in adults. The reason for advocating that is that’s one of the few treatments that has actually been shown in small but still case series to be effective. So we believe that adding ketogenic diet early, which is in this case was defined in the recommendations as seven days, is of importance.
Dr. Nabavi Nouri: Thank you. What would be the implications of the results?
Dr. Wickstrom: The important implication is to look at your local guidelines on how you treat status epilepticus and refractory status epilepticus in your hospitals. We can see, we haven’t shown that here but there’s data showing that a lot of hospitals don’t have clear guidelines on this and the ones that do have them rarely include immunotherapy. So looking at these guidelines, this would affect your local guidelines for refractory status epilepticus and super-refractory status epilepticus, if these are new onset, during the first week of treatment.
When it comes to workup and diagnostics, there’s a lot of recommendations on how to do this. And this also differs a little bit. We know that in pediatrics, for instance, we sometimes don’t take all the antibodies that we should do. We know in adult situations, it’s perceived as not so important to look at genetics or metabolic disease, of course because it’s not as prevalent, but it should be part of your workup. So during the first couple of days, during the workup, the implications of these papers is that that it can give you recommendations on where to look and try to widen your screening.
And then the big implications is of course the treatment implication from day three, and that includes primary immunotherapy or first line immunotherapy, and then escalating that by day seven.
Dr. Nabavi-Nouri: Well I think having those timeframes arguably could be altering outcomes, especially when we’re really dealing with, as you mentioned you had one case and it will never leave you for the rest of your career, always trying to understand what you can do better. What would be the next steps of this, next steps of this very impressive consensus group?
Dr. Wickstrom: So the next step everyone is dreaming about, which we were thinking about, I mean it’s been a couple of years that we’ve been thinking that this should have been started, is clinical trials of treatments. It’s just it’s very, very difficult it turns out. It’s difficult to agree on if we do a treatment, how do we do it, is it head-to-head treatment and if so, what do we use? It’s going to be really, really hard to design those trials at this point. I don’t think we have enough data for anyone because you as a treating clinician, you need to treat your patient the way you think is best, and it’s hard to randomize patients. You have to have compliance from the group. And that was part of doing this, was to increase compliance and let everyone have a say in how to design these clinical trials.
I’m hoping we can fairly soon arrive at clinical trials, but I also think we need to think differently than that and think about how we can design real-life studies that are usable. For instance, can we look at some sort of clinical decision support that can serve both the purpose of filling up a biobank of data and possibly samples, at the same time that it offers you as a clinician help.
But I hope the work that we’ve done is to create awareness in this group and in other groups that there is a consortium or there will be a consortium and this is open – the more people who want to join the better the stronger we can get. And we can use this to do good research, to get funding to do research and also to try to help these children and adults. And hopefully expand into refractory status epilepticus (RSE), because I mean – one debate now is, what actually differs? Why is NORSE different from other RSE? That’s a valid question. I think in many cases it will be, for instance if you have structural, some sort of etiologies, or if you have an ongoing epilepsy, that’s probably a different sort. But immunological components may be a part even in that case.
But I think what NORSE as a concept offers is it offers a sort of umbrella that can help us in forwarding and advancing our knowledge. And maybe in 2 years or 5 or 10 years we’ll decide there’s no such thing as NORSE, it’s just RSE that happens to be new onset and we understand what it is.
Dr. Nabavi Nouri: Lastly, and second to last question would be about the CSF cytokines. I’m very intrigued that it made it to the consensus. It’s been a big point of debate for two reasons: one is for clinical availability in terms of using reliable labs that can give you a clinical turnaround time as quickly as you would like to use it as a biomarker to guide treatment, and the other one is always timing, I find, because the cytokine profile can change quite drastically. I see there were two questions in the consensus – one whether it would be used for a biomarker of disease progression and response to treatment, and the other one was a choice of medication.
Dr. Wickstrom: So one of the hypotheses concerning FIRES and also NORSE is that it at least involves, maybe that’s not the whole mechanism, but it involves cytokine release. And that part of the immunological activation is actually the problem. There is some evidence to support that from animal data, and also there’s evidence in humans from blocking IL-1 and IL-6 mainly, with good results. So that’s the idea why cytokines appear to be important.
Just as you mentioned, there are several problems with cytokines. One is that it’s hugely complex – it’s really a web of different cytokines and they affect one another. For instance, we know that IL-1, which is a regulator of the proinflammatory system, we hardly ever see it because it has a very short half-life. Just by looking at lab data we have for IL-1, for instance, you would never use an IL-1 blocker, that would be a logical result of that, and still we know that it works. Looking at IL-1 levels doesn’t really help.
The second problem with cytokines is that they’re hard to analyze, if you don’t have access to a lab, but they’re also hard to sample. Whereas antibodies are very stable, cytokines are not stable, so you really, if you don’t sample it the right way for instance from the start, then you go to your bacterial or microbiology lab and say do you have any CSF left, and it’s been standing on a lab bench for two hours and cytokines have degenerated.
I would love to say you should look at cytokines and you should use that, but we don’t know that. But tentatively, if we believe that cytokines are involved in this, it should or could be possible to have it both as a marker of disease and also as disease progression. But just like you said, it’s not a question of whether this goes up and then it goes down and then it’s gone. Inflammation is a tricky thing because it’s an endogenous response you want to have. And one of the consequences of a proinflammatory response – when we say inflammation, we usually mean proinflammation – the other thing is we have anti-inflammation. The proinflammatory cytokines will increase the anti-inflammatory response and we know for instance in studies of encephalitis cases, you really need to look at the ratio between pro- and anti-inflammatory to understand it.
Dr. Nabavi Nouri: What do young clinician researchers listening, how can they get more involved in this type of research? Are there any organizations or consensus groups with in the ILAE or within this consortium that they could approach and explore being more involved in this type of research?
Dr. Wickstrom: Right now this consortium that I’m referring to isn’t really a consortium, it’s something we want to evolve into. But people are there and it’s open, 100% open to everyone who wants to join, both from a learning perspective and because this is an area to which you want to contribute is fantastic.
One way of accessing this or being involved is via the NORSE Institute. And that’s NORSEinstitute.org. It’s a North American institute that was started by the mother of a patient who died from this, and she’s done a fantastic job in trying to promote this research and bringing all of us together. You can find the names and email addresses of many of the people who have been part of this, and we regularly update it with published literature and how to find your way to the different ongoing studies, and that’s a way in.
Dr. Nabavi-Nouri: To conclude, I’d like to ask if there’s anything more that you’d like to add and most importantly any take home messages that we’d like to leave our listeners with.
Dr. Wickstrom: I really, really want to emphasize the immunological treatment because I can see that’s not working perfectly, of course not, but it could be improved a lot in kids, but even more so in adults, because they’re not using immunological treatment at all, and I’m convinced it will help so many adults with NORSE. And FIRES, probably both NORSE and FIRES. That’s an important take-home message.
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The recommendations and clinical tools are available now:
Families affected by NORSE/FIRES can join the NORSE Family Registry and contribute information that may help shape and initiate research. NORSE Family Registry registration is available in multiple languages: English | français | Mandarin | español
Founded in 1909, the International League Against Epilepsy (ILAE) is a global organization with more than 125 national chapters.
Through promoting research, education and training to improve the diagnosis, treatment and prevention of the disease, ILAE is working toward a world where no person’s life is limited by epilepsy.
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CRISPR Technology Improves Huntington’s Disease Symptoms in Models
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Newswise — Huntington’s disease (HD) is a neurological disorder that causes progressive loss of movement, coordination and cognitive function. It is caused by a mutation in a single gene called huntingtin or HTT. More than 200,000 people worldwide live with the genetic condition, approximately 30,000 in the United States. More than a quarter of a million Americans are at risk of inheriting HD from an affected parent. There is no cure.
But in a new study, published December 12, 2022 in Nature Neuroscience, researchers at University of California San Diego School of Medicine, with colleagues elsewhere, describe using RNA-targeting CRISPR/Cas13d technology to develop a new therapeutic strategy that specifically eliminates toxic RNA that causes HD.
CRISPR is known as a genome-editing tool that allows scientists to add, remove or alter genetic material at specific locations in the genome. It is based on a naturally occurring immune-defense system used by bacteria. However, current strategies run the risk of off-target edits at unintended sites that may cause permanent and inheritable chromosomal insertions or genome alterations. Because of this, significant efforts have focused on identifying CRISPR systems that target RNA directly without altering the genome.
In the case of HD, the condition is caused by repetitive and damaging sequences in the HTT gene.
Our cells have a hard time copying repetitive DNA, and these copying errors can cause repetitive sequences to grow longer with each generation,” said senior study author Gene Yeo, PhD, professor of cellular and molecular medicine at UC San Diego School of Medicine.
“In the Huntingtin gene, these repeats can sometimes grow to many times their normal length, with the resulting repeat-expanded protein tending to aggregate and form toxic clumps in a part of the brain called the striatum that is important for regulating movement. The loss of functional neurons in the striatum ultimately leads to HD symptoms.”
With colleagues at UC Irvine and Johns Hopkins University, Yeo and his team investigated whether recently described RNA-targeting CRISPR technology could be used to affect RNA (a chemical intermediate between DNA instructions and protein production) accumulation associated with HD.
They used viral vehicles to deliver the therapy to neuronal cultures, which were developed from stem cells derived from patients with HD, and found that the approach not only targeted and destroyed mutant RNA molecules, but also cleared out toxic protein buildup. They also demonstrated that expression of other human genes was generally not disrupted by the therapy.
“Our goal was to engineer a type of therapy that would only target the toxic RNA that causes HD and could keep the rest of the human genome and transcriptome intact,” said co-first author Kathryn Morelli, PhD, a research fellow in Yeo’s lab. “We specifically screened our top therapeutic constructs in HD patient cell lines to make sure of it.”
Development of effective therapies for HD has proven challenging. In 2021, for example, two clinical trials for promising gene therapies were halted following disappointing results performance. Both potential drugs had been touted as game-changers for HD. Currently, no treatments can alter the course of the disease, though medications can lessen some symptoms.
“The Huntington’s community was devastated when the clinical trials failed, primarily due to target specificity and toxic effects,” said Yeo. “But their termination has only re-energized the scientific community to find alternative strategies.”
Yeo’s lab collaborated with Wenzhen Duan, MD, PhD, professor of psychiatry and behavioral sciences, at Johns Hopkins Medicine to conduct preclinical testing in mice. Duan, with co-first author Qian Wu, PhD, found that the therapy improved motor coordination, attenuated striatal degradation and reduced toxic protein levels in a mouse model of HD. The improvements lasted for at least 8 months without adverse effects and minimal off-target effects on other RNA molecules.
Co-authors include: Maya L. Gosztyla, Ryan J. Marina, Kari Lee, Krysten L. Jones, Megan Huang and Allison Li, all at UC San Diego; Hongshuai Liu, Minmin Yao and Chuangchuang Zhang, Johns Hopkins University; Jiaxu Chen, Beijing University of Chinese Medicine; and Charlene Smith-Geater and Leslie M. Thompson, UC Irvine.
Funding for this research came, in part, from the National Institutes of Health (grants EY029166, NS103172,MH107367, AI132122, HG004659, HG009889, NS099397, NS124084, T32GM008666 ) the Bev Hartig Huntington’s Disease Foundation, an NIH NS112654-03 postdoctoral fellowship, a University of California President’s Postdoctoral Fellowship, the Paul G. Allen Foundation, the China Scholarship Council and the National Natural Science Foundation of China (82174278 and 81973748), the Hereditary Disease Foundation, an NIH predoctoral fellowship (NS111859), a National Science Foundation Graduate Research Fellowship (DGE-2038238),a Myotonic Dystrophy Foundation Doctoral Research Fellowship, an Association for Women in Science Scholarship and a Triton Research and an Experiential Learning Scholarship from Eureka! Research Scholarship.
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Disclosures: Gene Yeo is a scientific advisory board member of Jumpcode Genomics and a co-founder, member of the Board of Directors, scientific advisory board member, equity holder and paid consultant for Locanabio and Eclipse BioInnovations. He is also a Distinguished Visiting Professor at the National University of Singapore.
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Investigators Develop Model to Predict Overall Survival in Adults Diagnosed with Advanced Stage Hodgkin Lymphoma
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********** UNDER EMBARGO UNTIL Saturday, December 10 at 5:10 PM EST (4:10 PM CST) ***********
Newswise — New Brunswick, NJ and Boston, MA, December 10, 2022 – Investigators from Rutgers Cancer Institute of New Jersey, the state’s only NCI-designated Comprehensive Cancer Center and leading cancer program along with Tufts Medical Center in Boston, developed and validated the Advanced-stage Hodgkin lymphoma International Prognostication Index (A-HIPI). A-HIPI is a state-of-the-art clinical decision model to predict five-year progression-free and overall survival in adults with advanced-stage classic Hodgkin lymphoma using comprehensive individual patient data from international clinical trials and large prospective cancer registries. To enhance the use of A-HIPI, the team developed an online calculator to assist clinicians and patients in estimating individualized prognosis. This work was published in the Journal of Clinical Oncology (DOI: https://ascopubs.org/doi/full/10.1200/JCO.22.02473) simultaneously with an oral abstract presentation at the 2022 American Society of Hematology (ASH) Annual Meeting and Exposition.
For the last 25 years, the International Prognostic Score (IPS) has been the most commonly used risk stratification tool for patients with advanced Hodgkin lymphoma, however, more modern tools to help inform individualized treatment and promote personalized cancer care are needed. Significant debate remains about the optimal treatment for Hodgkin lymphoma patients in the modern era, in part as its treatment comes at human cost, including an increased risk of treatment-related late effects like secondary malignant neoplasms and cardiovascular disease, compromised health-related quality of life, and the potential loss of young lives.
A-HIPI is the inaugural work of the HoLISTIC project (Hodgkin Lymphoma International Study for Individual Care), building on detailed multi-source individual patient data from more than 15,000 Hodgkin lymphoma patients. A-HIPI development was performed on eight recent seminal phase 3 clinical trials conducted around the world. External validation was performed from contemporaneously treated patients in four “real-world” Hodgkin lymphoma registries across North America and Australia.
HoLISTIC is spearheaded by Andrew M. Evens, DO, MBA, MSc, associate director for clinical services at Rutgers Cancer Institute and system director of medical oncology and oncology lead, RWJBarnabas Health and Susan K. Parsons, MD, MRP, medical director of the adolescent and young adult (AYA) program and research director of the Center for Health Solutions at Tufts Medical Center, who are co-principal investigators on the work.
“Through continued collaboration with worldwide Hodgkin lymphoma clinical experts, decision scientists, statisticians, epidemiologists, and patient advocates, we’re one step closer to improving individualized prognostication and enhancing personalized medicine for Hodgkin lymphoma patients across all ages and disease stages,” notes Dr. Evens, who is also a professor of medicine at Rutgers Robert Wood Johnson Medical School, vice chancellor of clinical innovation and data analytics at Rutgers Biomedical and Health Sciences. “Through HoLISTIC, we will continue to develop innovative and evidence-based decision support models to guide Hodgkin lymphoma patients and their families and healthcare providers.”
“The A-HIPI model is an exciting first step for the HoLISTIC Consortium,” notes Dr. Parsons, who is also professor of medicine and pediatrics at Tufts University School of Medicine. “The next phase of the project will be significant, as we will extend the rigorous clinical modeling methodology to early-stage Hodgkin lymphoma and relapsed/refractory disease. We will also explore the impact of treatment selection and integrate PET imaging results and important biologic factors into the model.” The investigators plan to synthesize all of this information into a comprehensive and robust clinical decision model that estimates the likelihood of cure, life expectancy, post-acute and late effects, and quality-adjusted life expectancy for individual patients across varied treatment options.
The dynamic and interactive decision support models generated by the HoLISTIC Consortium will guide individual patients and clinicians during initial diagnosis, relapse, and through survivorship in addition to serving as a strong basis for future health outcomes analyses, including patient preference and cost of care. The authors note limitations of the study include a lack of data in adults older than 65 who were treated in the clinical trials utilized for model development. Efforts are underway to identify other sources of information on older adults, as well as younger patients (adolescents and young adults), who are also often less represented in adult clinical trials.
This work was presented as an oral presentation at the 2022 American Society of Hematology (ASH) Annual Meeting and Exposition and is supported in part by a National Cancer Institute Grant (R01CA262265). Author acknowledgements, disclosures and other information can be found here.
About Rutgers Cancer Institute of New Jersey As New Jersey’s only National Cancer Institute-designated Comprehensive Cancer Center, Rutgers Cancer Institute, together with RWJBarnabas Health, offers the most advanced cancer treatment options including bone marrow transplantation, proton therapy, CAR T-cell therapy and complex surgical procedures. Along with clinical trials and novel therapeutics such as precision medicine and immunotherapy – many of which are not widely available – patients have access to these cutting-edge therapies at Rutgers Cancer Institute of New Jersey in New Brunswick, Rutgers Cancer Institute of New Jersey at University Hospital in Newark, as well as through RWJBarnabas Health facilities. To make a tax-deductible gift to support Rutgers Cancer Institute, call 848-932-8013 or visit www.cinj.org/giving.
About Tufts Medicine and Tufts Medical Center Tufts Medicine is the parent organization of Tufts Medical Center, a world renowned 415-bed academic medical center in Boston that cares for the sickest patients in the region, includes a level one trauma center and one of the largest heart transplant centers in New England, and also serves as the principal teaching hospital for Tufts University School of Medicine. Tufts Medicine is also the parent organization of Lowell General Hospital, MelroseWakefield Healthcare, an expansive home care and hospice network, and a large clinically integrated physician network that cares for more than one million patients per year. The health system is dedicated to providing patients with the highest quality of care as close to home as possible.
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For patient appointments/inquiries – contact: 844-CANCERNJ (844-226-2376)
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Experimental Cancer Therapy Shows Success in More Than 70 Percent of Patients in Global Clinical Trials
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Newswise — New York, NY (December 10, 2022) — A new therapy that makes the immune system kill bone marrow cancer cells was successful in as many as 73 percent of patients in two clinical trials, according to researchers from The Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai.
The therapy, known as a bispecific antibody, binds to both T cells and multiple myeloma cells and directs the T cells—white blood cells that can be enlisted to fight off diseases—to kill multiple myeloma cells. The researchers described this strategy as “bringing your army right to the enemy.”
The success of the off-the-shelf immunotherapy, called talquetamab, was even seen in patients whose cancer was resistant to all approved multiple myeloma therapies. It uses a different target than other approved therapies: a receptor expressed on the surface of cancer cells known as GPRC5D.
Talquetamab was tested in phase 1 and phase 2 trials. The phase 1 trial, which was reported in The New England Journal of Medicine (NEJM), established two recommended doses that were tested in the Phase 2 trial. The results of the Phase 2 trial were reported at the American Society of Hematology annual meeting on Saturday, December 10. The study participants had all been previously treated with at least three different therapies without achieving lasting remission, suggesting talquetamab could offer new hope for patients with hard-to-treat multiple myeloma.
“This means that almost three-quarters of these patients are looking at a new lease on life,” said Ajai Chari, MD, Director of Clinical Research in the Multiple Myeloma Program at The Tisch Cancer Institute and lead author of both studies. “Talquetamab induced a substantial response among patients with heavily pretreated, relapsed, or refractory multiple myeloma, the second-most-common blood cancer. It is the first bispecific agent targeting the protein GPRC5d in multiple myeloma patients.”
Nearly all patients with myeloma who receive standard therapies continually relapse. Patients who relapse or become resistant to all approved multiple myeloma therapies have a poor prognosis, so additional treatments are urgently needed. This study, while an early-phase trial designed to detect tolerability and find a safe dose, is an important step in meeting that need.
This Phase 1 clinical trial enrolled 232 patients at several cancer centers across the world between January 2018 and November 2021. Patients received a variety of doses of the therapy either intravenously or injected under their skin; future studies will focus on doses only administered under the skin either weekly or every other week
The efficacy and safety findings in the phase 1 study were validated in the phase 2 trial presented at ASH. The phase 2 trial included 143 patients treated on a weekly dose and 145 patients treated at a higher biweekly dose.
The overall response rate in these two groups was about 73 percent, Dr. Chari said. The response rate was maintained throughout various subgroups examined, with the exception of patients with a rare form of multiple myeloma that also extends to organs and soft tissues. More than 30 percent of patients in both groups had a complete response (no detection of myeloma-specific markers) or better, and nearly 60 percent had a “very good partial response” or better (indicating the cancer was substantially reduced but not necessarily down to zero).
The median time to a measurable response was approximately 1.2 months in both dosing groups and the median duration of response to date is 9.3 months with weekly dosing. Researchers are continuing to collect data on the duration of response in the group receiving 0.8 mg/kg every other week and for patients in both dosing groups who had a complete response or better.
Side effects were relatively frequent, but typically mild. About three-quarters of patients experienced cytokine release syndrome, which is a constellation of symptoms including fever that is common with immunotherapies. About 60 percent experienced skin-related side effects such as rash, about half reported taste changes, and about half reported nail disorders. The researchers said very few patients (5 to 6 percent) stopped talquetamab treatment because of side effects.
The response rate observed in the study, which Dr. Chari explained is higher than that for most currently accessible therapies, suggests talquetamab could offer a viable option for patients whose myeloma has stopped responding to most available therapies, offering a chance to extend life and benefit from other new and future therapies as they are developed.
These trials were sponsored and funded by Janssen.
About the Mount Sinai Health System
Mount Sinai Health System is one of the largest academic medical systems in the New York metro area, with more than 43,000 employees working across eight hospitals, over 400 outpatient practices, nearly 300 labs, a school of nursing, and a leading school of medicine and graduate education. Mount Sinai advances health for all people, everywhere, by taking on the most complex health care challenges of our time — discovering and applying new scientific learning and knowledge; developing safer, more effective treatments; educating the next generation of medical leaders and innovators; and supporting local communities by delivering high-quality care to all who need it.
Through the integration of its hospitals, labs, and schools, Mount Sinai offers comprehensive health care solutions from birth through geriatrics, leveraging innovative approaches such as artificial intelligence and informatics while keeping patients’ medical and emotional needs at the center of all treatment. The Health System includes approximately 7,300 primary and specialty care physicians; 13 joint-venture outpatient surgery centers throughout the five boroughs of New York City, Westchester, Long Island, and Florida; and more than 30 affiliated community health centers. We are consistently ranked by U.S. News & World Report‘s Best Hospitals, receiving high “Honor Roll” status, and are highly ranked: No. 1 in Geriatrics and top 20 in Cardiology/Heart Surgery, Diabetes/Endocrinology, Gastroenterology/GI Surgery, Neurology/Neurosurgery, Orthopedics, Pulmonology/Lung Surgery, Rehabilitation, and Urology. New York Eye and Ear Infirmary of Mount Sinai is ranked No. 12 in Ophthalmology. U.S. News & World Report’s “Best Children’s Hospitals” ranks Mount Sinai Kravis Children’s Hospital among the country’s best in several pediatric specialties. The Icahn School of Medicine at Mount Sinai is one of three medical schools that have earned distinction by multiple indicators: It is consistently ranked in the top 20 by U.S. News & World Report‘s “Best Medical Schools,” aligned with a U.S. News & World Report “Honor Roll” Hospital, and top 20 in the nation for National Institutes of Health funding and top 5 in the nation for numerous basic and clinical research areas. Newsweek’s “The World’s Best Smart Hospitals” ranks The Mount Sinai Hospital as No. 1 in New York and in the top five globally, and Mount Sinai Morningside in the top 20 globally.
For more information, visit https://www.mountsinai.org or find Mount Sinai on Facebook, Twitter and YouTube.
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LJI scientists confirm smallpox vaccine also teaches T cells to fight mpox
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Newswise — LA JOLLA, CA—There’s even more reason to think a vaccine developed against smallpox can help the body fight against mpox (monkeypox virus disease) as well, according to researchers at La Jolla Institute for Immunology (LJI). Their new study, published in Cell Host & Microbe, is the first to provide evidence that the vaccinia vaccine MVA-BN (brand name JYNNEOS) should also train virus-fighting T cells to recognize mpox sequences.
“This study gives us confidence that T cell response induced by the JYNNEOS vaccine should be able to also recognize mpox virus,” says LJI Professor Alessandro Sette, Dr.Biol.Sci., who co-led the new study with LJI Instructor Alba Grifoni, Ph.D.
The study comes as more than 100 countries reported unprecedented mpox outbreaks. In the United States, there have been more than 28,000 reported cases and 11 deaths attributed to mpox since May 2022.
Why we need mpox vaccine data
Although the JYNNEOS vaccine, based on a non-live attenuated orthopox virus called modified vaccine ankara (MVA), is approved to prevent mpox infection and severe disease, researchers don’t yet have clinical efficacy data from human trials. Still, researchers know that mpox virus is similar enough to other orthopoxviruses that immunization against an orthopoxvirus called vaccinia (VACV) can also train the immune system to fight mpox.
Mpox (termed “monkeypox” until recently) is a member of the orthopox family of viruses. The deadliest, of course, was variola virus,causing the disease known as smallpox. Smallpox was eradicated worldwide in 1980 thanks to a massive and successful vaccination campaign to administer the Dryvax vaccine, based on VACV.
VACV and variola virus have a lot of immune system targets (called antigens), in common. This means training the body to recognize VACV also taught immune cells to recognize variola virus. But there was a downside—Dryvax (and a newer version called Acambis 2000) had harmful side effects, especially in immunocompromised people.
JYNNEOS was designed to have a better safety profile. While the vaccine performed well in pre-clinical tests, the eradication of smallpox meant scientists couldn’t see how JYNNEOS performed in human patients in real-world infection scenarios, such as a smallpox outbreak or possible case of smallpox-based biological warfare (a concern in the early days of the Iraq War).
How a smallpox vaccine protects against mpox
For the new study, the LJI team set out to study if the viral proteins known to be targeted by T cells induced by VACV vaccination, would also be conserved in JYNNEOS and in mpox. As Grifoni explains, while antibodies are key for vaccine efficacy and preventing reinfections, T cells are essential for both preventing severe infections and “remembering” past infections.
“By recognizing infected cells, T cells are able to limit how much viruses can spread inside the body modulate disease severity, and ultimately terminate the infection” says Grifoni. “T cell responses also tend to be long lasting, and resilient to viral mutations to escape immune recognition. What we have seen in the context of SARS-CoV-2 is that even if the virus mutates somewhat, T cells reactivity is still largely preserved.”
The researchers demonstrated that the known targets of T cell responses seen in the VACV proven -efficacy vaccine, are also found in JYNNEOS and mpox, suggesting that the JYNNEOS vaccine can indeed trigger an effective T cell response against mpox infection. The initial test of their hypothesis was based on developing viral peptide “megapools,” or reagents designed to detect T cell reactivity to mpox antigens. The experiments further showed that these megapools can be used to accurately detect specific T cells.
“Vaccines such as JYNNEOS should be able to induce T cells that also recognize mpox and can provide protection from severe disease,” says Grifoni.
Could the vaccine work in immunocompromised patients?
“The majority of mpox cases have been in men who have sex with men,” Sette explains. “In that community, a significant fraction of the people that have been infected with mpox also happened to be HIV-positive. So it is important to learn how people who are HIV-positive respond to infection and vaccination compared to HIV-negative individuals. The present study enables future study to establish this key point”
Sette emphasizes that most HIV-positive individuals are not necessarily at greater risk of mpox infection or severe disease. “We do not expect that HIV-positive individuals will respond differently to infection and vaccination, because in most cases, people who live with HIV live with a controlled HIV because of the available therapies,” he says. “Nevertheless, it’s important to provide these data to the community affected by this outbreak and to the general scientific community.”
Whether the JYNNEOS vaccine sparks a similar immune response in people with and without HIV—and the role of T cells—will have to be determined in future studies. “We also expect to see no difference in the duration of protection between HIV positive and HIV negative individuals, but that still all needs to be proven and evaluated experimentally. We are actively engaging the community most affected by the outbreak and the scientific community at large ” says Sette.
Next steps for the LJI team
The researchers are now working to characterize the T cell response to mpox in more detail. They are especially interested in how T cell responses differ after vaccination versus natural infection. Sette and Grifoni would also like to compare T cell responses following JYNNEOS vaccination with the older Dryvax vaccination.
Just as they’ve done throughout the COVID-19 pandemic, Sette and his colleagues hope to share their reagents freely to and spur more life-saving studies around the globe. “We want to make these reagents widely available to whoever asks,” says Sette.
Additional authors of the study, “Defining antigen targets to dissect vaccinia virus (VACV) and Monkeypox virus (MPXV)-specific T cell responses in humans,” include Yun Zhang, Alison Tarke, John Sidney, Paul Rubiro, Maria Reina-Campos, Gilberto Filaci, Jennifer Dan, and Richard H. Scheuermann.
This research was supported by the National Institutes of Health’s National Institute of Allergy and Infectious Diseases (Contract No. 75N93019C00001, 75N9301900065, and HHS75N93019C00076) and through a Ph.D. student fellowship from the Clinical and Experimental Immunology Course at the University of Genoa, Italy, and with support from other private foundations.
DOI: 10.1016/j.chom.2022.11.003
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La Jolla Institute for Immunology
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Common immune cells can prevent intestinal healing
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Newswise — B cells are critical to the proper functioning of the immune system. However, researchers at Karolinska Institutet have shown that they can sometimes do more harm than good, as their numbers greatly increase after bowel damage, preventing the tissue from healing. The results, which are presented in the journal Immunity, can be of significance to the treatment of inflammatory bowel disease.
B cells are a type of white blood cell that have an important function in the immune system, in part by producing the antibodies that attack bacteria and viruses. Previous research has shown that people with chronic inflammatory bowel disease (IBD), such as Crohn’s disease or ulcerative colitis, have many more B cells in their intestines than healthy individuals. It has therefore been proposed that B cells might affect the severity of these diseases. Researchers at Karolinska Institutet in Sweden have now tried to discover if, and if so how, B cells contribute to IBD.
Sharp increase during healing
“We’ve been able to show that the B cell population increases sharply in the colon during the healing of colonic lesions, and that these cells mainly accumulate in areas where the damage is severe,” says principal investigator Eduardo Villablanca, associate professor at the Department of Medicine (Solna), Karolinska Institutet. “This prevents, in turn, the interaction between two other cell types – stromal and epithelial cells – which is needed for the tissue to heal.”
The researchers studied an experimental model of colitis and tissue from patients with ulcerative colitis, using a range of methods to analyse cell populations. Focusing particularly on how B cells affect healing in the intestinal mucosa, they found that mice lacking B cells recovered much more quickly after bowel damage than regular mice. The finding that the B cells seem to do more harm than good in colonic inflammation can be of significance to the treatment of IBD.
Drugs that affect B cells
“There are already approved drugs that affect the B cell response and that are used for other diseases,” says Gustavo Monasterio, postdoc in Dr Villablanca’s research group at Karolinska Institutet and one of the leading authors. “We now want to test if depleting B cells at specific time windows could also work with IBD. We also need to find out if the accumulation of B cells can have a long-term beneficial effect, such as by changing the composition of bacteria in the gastrointestinal tract.”
The study was supported by grants from the Swedish Research Council, the Swedish Cancer Society, the Knut and Alice Wallenberg Foundation (the Wallenberg Academy Fellow programme) and the German research foundation DFG. Eduardo Villablanca has received research grants from the pharmaceutical company F. Hoffmann-La Roche and co-author Camilla Engblom is scientific consultant for the biotech company 10X Genomics Inc. Julio Saez-Rodriguez receives funding from Glaxo Smith Kline and Sanofi and consultancy fees from Travere Therapeutics.
Publication: “B cell expansion hinders the stroma-epithelium regenerative crosstalk during mucosal healing”. Annika Frede, Paulo Czarnewski, Gustavo Monasterio, Kumar P. Tripathi, David A Bejarano, Ricardo O. Ramirez Flores, Chiara Sorini, Ludvig Larsson, Xinxin Luo, Laura Geerlings, Claudio Novella-Rausell, Chiara Zagami, Raoul Kuiper, Rodrigo A Morales, Francisca Castillo, Matthew Hunt, Livia Lacerda Mariano, Yue O. O. Hu, Camilla Engblom, Ana-Maria Lennon-Dumenil, Romy Mittenzwei, Nadine Hövelmeyer, Joakim Lundeberg, Julio Saez-Rodriguez, Andreas Schlitzer, Srustidhar Das, Eduardo J. Villablanca. Immunity, online 2 December 2022, doi: 10.1016/j.immuni.2022.11.002.
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Mitochondria transmit signals in the immune and nervous systems
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Newswise — New insights into the function of mitochondria reveal interfaces between the nervous and immune systems.
Mitochondria are primarily known as the powerhouse of the cell. However, these cellular organelles are required not only for providing energy: Professor Konstanze Winklhofer and her group at the Faculty of Medicine at Ruhr University Bochum, Germany, recently discovered that mitochondria play an important role in signal transduction in innate immune pathways. They regulate a signalling pathway that helps to eliminate pathogens, but can cause damage through inflammation upon overactivation. The research team published their findings in the EMBO Journal of 17. November 2022.
Protection from bacteria and viruses
Certain cytokines but also intracellular pathogens, such as viruses and some bacteria, activate the transcription factor NF-κB, which regulates the expression of various genes. “Depending on the stimulus and the cell type, NF-κB activation results in protection from cell death and increased synthesis of proteins required for the elimination of bacteria or viruses,” explains Konstanze Winklhofer. However, upon excessive and prolonged activation, this basically protective pathway can cause chronic inflammation. “Hence, a fine-tuned regulation of these signalling processes is of great medical relevance, in order to prevent pathophysiological conditions caused by either inefficient or overshooting NF-κB activation.”
Two advantages of mitochondria: they are mobile and have a large surface area
The new study has revealed that mitochondria play a crucial role in the regulation of the NF-κB signalling pathway. Within minutes after pathway activation, a signalling platform assembles at the outer mitochondrial membrane, resulting in the activation of NF-κB. “This allows signal amplification, based on the large surface of mitochondria,” says Konstanze Winklhofer. “Moreover, mitochondria have another capacity that qualifies them as organelles for signal transduction: they are mobile and can dock onto motor proteins in the cell.” The research team observed that mitochondria escort the activated transcription factor NF-κB to the nuclear membrane, thus facilitating the translocation of NF-κB into the nucleus.
However, mitochondria are not only involved in the efficient activation of the NF-κB signalling pathway; they also contribute to the deactivation and thus regulation of the signal. This is accomplished by an enzyme located at the outer mitochondrial membrane, which counteracts ubiquitination, a posttranslational modification required for NF-κB activation.
Why Parkinson’s disease patients are more susceptible to some infections
Two genes causally linked to Parkinson’s disease are involved in the mitochondrial regulation of the NF-κB signalling pathway: PINK1 and Parkin. “Our findings explain why mutations resulting in a loss of PINK1 or Parkin function promote neuronal cell death under stress conditions,” points out Konstanze Winklhofer. “Remarkably, our findings show that Parkinson’s disease patients with mutations in the PINK1 or Parkin gene show an increased vulnerability to various infections caused by intracellular pathogens. Thus, our study also helps to gain a better understanding of the interfaces between the nervous and immune system.”
Funding
The research was funded by the German Research Foundation as part of the research unit FOR 2848 and the Excellence Strategy of the German Federal and State Governments – EXC 2033 – 390677874 – RESOLV and by the Michael J. Fox Foundation for Parkinson’s Research.
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Ruhr-Universitat Bochum
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