Category Archives: Immunology

Immunology

Inactivation of TGF- signaling in CAR-T cells | Cellular & Molecular Immunology – Nature.com

Chong EA, Melenhorst JJ, Lacey SF, Ambrose DE, Gonzalez V, Levine BL, et al. PD-1 blockade modulates chimeric antigen receptor (CAR)-modified T cells: refueling the CAR. Blood. 2017;129:103941.

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Bell M, Gottschalk S. Engineered cytokine signaling to improve CAR T cell effector function. Front Immunol. 2021;12:684642.

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Travis MA, Sheppard D. TGF- activation and function in immunity. Annu Rev Immunol. 2014;32:5182.

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Wieser R, Attisano L, Wrana JL, Massagu J. Signaling activity of transforming growth factor beta type II receptors lacking specific domains in the cytoplasmic region. Mol Cell Biol. 1993;13:723947.

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Gorelik L, Flavell RA. Abrogation of TGFbeta signaling in T cells leads to spontaneous T cell differentiation and autoimmune disease. Immunity. 2000;12:17181.

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Gorelik L, Flavell RA. Immune-mediated eradication of tumors through the blockade of transforming growth factor-beta signaling in T cells. Nat Med. 2001;7:111822.

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Kloss CC, Lee J, Zhang A, Chen F, Melenhorst JJ, Lacey SF, et al. Dominant-negative TGF- receptor enhances PSMA-targeted human CAR T cell proliferation and augments prostate cancer eradication. Mol Ther. 2018;26:185566.

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Noh KE, Lee JH, Choi SY, Jung NC, Nam JH, Oh JS, et al. TGF-/IL-7 chimeric switch receptor-expressing CAR-T cells inhibit recurrence of CD19-positive B cell lymphoma. Int J Mol Sci. 2021;22:8706.

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Tang N, Cheng C, Zhang X, Qiao M, Li N, Mu W, et al. TGF- inhibition via CRISPR promotes the long-term efficacy of CAR T cells against solid tumors. JCI Insight. 2020;5:e133977.

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Narayan V, Barber-Rotenberg JS, Jung IY, Lacey SF, Rech AJ, Davis MM, et al. PSMA-targeting TGF-insensitive armored CAR Tcells in metastatic castration-resistant prostate cancer: a phase 1 trial. Nat Med. 2022;28:72434.

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Liang, S, Zheng R, Zuo B, Li J, Wang Y, Han Y, et al. SMAD7 expression improves the persistent and safety of CAR T cells for solid tumors. Cell Mol Immunol. 2024;21:21326.

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Li G, Liao G, Xie J, Liu B, Li X, Qiu M. Overexpression of SMAD7 improves the function of EGFR-targeted human CAR-T cells against non-small-cell lung cancer. Respirology. 2023;28:86980.

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Tu E, Chia C, Chen W, Zhang D, Park SA, Jin W, et al. T cell receptor-regulated TGF- type I receptor expression determines T cell quiescence and activation. Immunity. 2018;48:74559.e6.

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Inactivation of TGF- signaling in CAR-T cells | Cellular & Molecular Immunology - Nature.com

Immunology

Babies use their immune system differently but efficiently | Cornell Chronicle – Cornell Chronicle

Scientists have long believed that a newborns immune system was an immature version of an adults, but new research shows that newborns T cells white blood cells that protect from disease outperform those of adults at fighting off numerous infections.

These results help clarify why adults and infants respond differently to infectionsand pave the way for controlling T cells behavior for therapeutic applications.

This discovery was described in a paper, The Gene Regulatory Basis of Bystander Activation in CD8+ T cells, which published Feb. 23 in the journal Science Immunology. Brian Rudd, associate professor in the Department of Microbiology and Immunology in the College of Veterinary Medicine, and Andrew Grimson, professor in the Department of Molecular Biology and Genetics (College of Arts and Sciences), co-led the study.

The immune system is almost always viewed from an adult perspective, Rudd said. For example, adult T cells outperform newborn T cells at tasks including recognizing antigens, forming immunological memory and responding to repeat infections, which has led to the belief that infants T cells were just a weaker version of the adult ones. But during the COVID-19 pandemic, many were surprised by the apparent lack of illness in infants, bringing this long-standing belief into question.

Interested in understanding these age-related differences, Rudd and Grimson discovered that newborn T cells are not deficient. Instead, they are involved in a part of the immune system that does not require antigen recognition, the innate arm of the immune system. While adults T cells use adaptive immunity recognizing specific germs to then fight them later newborn T cells are activated by proteins associated with innate immunity, the part of the immune system that offers rapid but nonspecific protection against microbes the body has never encountered.

Our paper demonstrates that neonatal T cells are not impaired, they are just different than adult T cells and these differences likely reflect the type of functions that are most useful to the host at distinct stages of life, Rudd said.

Neonatal T cells can participate in the innate arm of the immune system. This enables newborns T cells to do something that most adult T cells cannot respond during the very first stages of an infection and defend against a wide variety of unknown bacteria, parasites and viruses.

We know that neonatal T cells dont protect as well as adult T cells against repeat infections with the same pathogen. But neonatal T cells actually have an enhanced ability to protect the host against early stages of an initial infection, Rudd said. So, it is not possible to say adult T cells are better than neonatal T cells or neonatal T cells are better than adult T cells. They just have different functions.

The team also found that these innate neonatal T cells persist into adulthood in both mice and humans and play unique roles during infection. The team believes that in adults, these neonatal T cells may respond to inflammation that occurs during an infection, in cancer and in autoimmune diseases.

As part of their research, Rudd and his collaborators identified the molecular mechanisms that allow T cells to respond to inflammation and switch between innate and adaptive functions.

We now know the key epigenetic and transcriptional programs that distinguish neonatal T cells from adult T cells at the individual cell level, Rudd said. This knowledge is essential to developing medical applications for controlling T cells behavior in specific ways.

The technology that is now available to study gene regulation of immune cells at the single-cell level allowed Rudd and Grimson to provide new insight into a poorly understood biological process at a very in-depth level.

Being able to go from observing a unique function of T cells to a molecular mechanism is really exciting, Rudd said. And this was possible because we were able to combine the expertise in cellular and developmental immunology in my lab with the tools to study gene regulation in Andrews lab.

Following up on his discovery, Rudd wants to study the neonatal T cells that persist into adulthood in humans. We are also interested in studying how changes in the relative numbers of neonatal T cells in adults contributes to variation in the susceptibility to infection and outcomes to disease, he said.

The large, multi-institution project also included collaborators at University of Rochester and University of Washington.

This work was supported by the National Institute of Allergy and Infectious Disease and the National Institute of Child Health and Human Development, in the National Institutes of Health.

Elodie Smith is a writer for the College of Veterinary Medicine.

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Babies use their immune system differently but efficiently | Cornell Chronicle - Cornell Chronicle

Immunology

Antibody reduces allergic reactions to multiple foods in NIH clinical trial – National Institutes of Health (NIH) (.gov)

News Release

Sunday, February 25, 2024

Drug can help protect kids with multiple food allergies during accidental exposure.

A 16-week course of a monoclonal antibody, omalizumab, increased the amount of peanut, tree nuts, egg, milk and wheat that multi-food allergic children as young as 1 year could consume without an allergic reaction in a late-stage clinical trial. Nearly 67% of participants who completed the antibody treatment could consume a single dose of 600 milligrams (mg) or more of peanut protein, equivalent to 2.5 peanuts, without a moderate or severe allergic reaction, in contrast with less than 7% of participants who received placebo. The treatment yielded similar outcomes for egg, milk, wheat, cashew, walnut and hazelnut at a threshold dose of 1,000 mg protein or more. This suggests the antibody therapy has the potential to protect children and adolescents if they accidentally eat a food to which they are allergic despite efforts to avoid it, according to the investigators. The findings were presented today at the American Academy of Allergy, Asthma & Immunology Annual Meeting in Washington, D.C., and published in The New England Journal of Medicine.

People with food allergies and their caregivers need to maintain constant vigilance to avoid foods that could cause a potentially life-threatening allergic reaction. This is extremely stressful, especially for parents of young children, said Jeanne Marrazzo, M.D., M.P.H., director of the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health and the trials regulatory sponsor. Although food avoidance remains critical, the findings reported today show that a medicine can help reduce the risk of allergic reactions to common foods and may provide protection from accidental exposure emergencies.

NIAID funds the ongoing trial with additional support from and collaboration with Genentech, a member of the Roche Group, and Novartis Pharmaceuticals Corporation. The two companies collaborate to develop and promote omalizumab, marketed as Xolair, and are supplying it for the trial. The National Center for Advancing Translational Sciences, also part of NIH, supports some of the staff, space and services used to conduct the trial.

An estimated 7.6% of children in the United State roughly 5.5 million kids have food allergies. On February 16, 2024, the Food and Drug Administration approved omalizumab for the reduction of allergic reactions, including anaphylaxis, that may occur with an accidental exposure to one or more foods in adults and children aged 1 year and older with food allergy. The FDA approval was based on data from a planned interim analysis of the Phase 3 NIAID trial. People taking omalizumab still need to avoid foods they are allergic to. Omalizumab is not approved for the emergency treatment of allergic reactions, including anaphylaxis.

Previously, the only available treatment for food allergy was oral immunotherapy, or OIT, which involves daily ingestion of a specific food allergen in gradually increasing doses up to a maintenance amount.

The multi-stage trial is called Omalizumab as Monotherapy and as Adjunct Therapy to Multi-Allergen OIT in Food Allergic Children and Adults, or OUtMATCH. The first stage of the study was designed to see if taking omalizumab increased the threshold for the amount of food that caused allergic reactions, thereby reducing the likelihood of reactions to small amounts of food allergens during accidental exposure.

Omalizumab works by binding to the allergy-causing antibody called immunoglobulin E in the blood and preventing it from arming key immune cells responsible for allergic reactions. This renders these cells much less sensitive to stimulation by any allergen.

The NIAID-funded Consortium for Food Allergy Research (CoFAR) is conducting OUtMATCH at 10 locations across the United States. The CoFAR has enrolled 177 children and adolescents ages 1 to 17 years and three adults ages 18 to 55 years, all with confirmed allergy to peanut and at least two other common foods among milk, egg, cashew, wheat, hazelnut or walnut.

In the first stage of the trial, people who reacted to small amounts of food allergens during oral food challenges were assigned at random to receive injections of either omalizumab or placebo. Neither the participants nor the investigators knew which food was used in a challenge nor who was in which group. After 16 to 20 weeks of injections, the participants were challenged again in a carefully controlled setting to see if they could tolerate a greater amount of food than they did at the outset. The goal was to find out if omalizumab injections led to a statistically significant increase in the proportion of participants who could consume roughly the equivalent of 2.5 peanuts without a moderate or severe allergic reaction, up from less than half a peanut at the outset, and similarly greater quantities of milk, egg or cashew among people allergic to those foods.

Investigators found that omalizumab was superior to placebo in increasing the reaction threshold for peanut, milk, egg and cashew as well as wheat, walnut and hazelnut to levels that likely would protect against allergic reactions upon accidental exposure. Seventy-nine of 118 omalizumab-treated children and adolescents, or 66.9%, could consume at least a single dose of 600 mg or more of peanut protein without a moderate or severe allergic reaction during the post-treatment challenge, in contrast with four out of 59 children and adolescents, or 6.8%, who received placebo. The researchers observed similar results for milk, egg, cashew, wheat, walnut and hazelnut at a threshold dose of 1,000 mg protein or more.

Many omalizumab-treated participants ate more than 600 mg of peanut protein without a moderate or severe allergic reaction. Sixty-seven percent consumed a cumulative dose of 1,044 mg of peanut protein, or about four peanuts, and 44% ate a cumulative dose of 6,044 mg of peanut protein, or about 25 peanuts. In addition, substantial proportions of treated participants consumed a cumulative dose of 1,044 mg of more than one food without a moderate or severe allergic reaction. Sixty-nine percent ate this amount of two foods, and 47%, three foods.

The first 60 participants who completed the first stage entered a 24-week open-label extension of omalizumab injections followed by additional oral food challenges. Most participants who had received omalizumab in the first stage maintained or increased the amount of food protein they could consume without an allergic reaction during the extension.

Robert Wood, M.D., and Sharon Chinthrajah, M.D. are leading the trial. Dr. Wood is the Julie and Neil Reinhard Professor of Pediatric Allergy and Immunology and director of the Pediatric Clinical Research Unit at the Johns Hopkins University School of Medicine. Dr. Chinthrajah is an associate professor of medicine and of pediatric allergy and clinical immunology at Stanford University School of Medicine.

Further information about the ongoing OUtMATCH trial is available at ClinicalTrials.gov under study identifier NCT03881696. The outcomes of later stages of the trial will be published in the future.

NIAID conducts and supports researchat NIH, throughout the United States, and worldwideto study the causes of infectious and immune-mediated diseases, and to develop better means of preventing, diagnosing and treating these illnesses. News releases, fact sheets and other NIAID-related materials are available on the NIAID website.

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.

NIHTurning Discovery Into Health

RA Wood, et al. Omalizumab for the treatment of multiple food allergy. The New England Journal of Medicine DOI: 10.1056/NEJMoa2312382. (2024).

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Antibody reduces allergic reactions to multiple foods in NIH clinical trial - National Institutes of Health (NIH) (.gov)

Immunology

Mestag Therapeutics Enlists Leading Cancer Biology and Immunology Advisors to Support Clinical Development of its … – GlobeNewswire

CAMBRIDGE, United Kingdom, Feb. 20, 2024 (GLOBE NEWSWIRE) -- Mestag Therapeutics (Mestag), a biotech company harnessing new insights into fibroblast-immune interactions to develop impactful treatments for patients, today announced the appointments of additional distinguished, world-leading advisors to guide the development of its lead program M300, a first-in-class antibody program designed to conditionally induce the formation of Tertiary Lymphoid Structures (TLS) in the tumor.

The new appointments expand Mestags advisors and comprise a unique group of investigators with extensive experience in the development of novel cancer therapies and specific expertise in the field of TLS biology in cancer. TLSs are aggregates of immune cells which provide a site of entry and education for immune cells in the tumor. The presence of TLS in tumors has recently become recognized as strongly predictive of improved patient outcomes and better response to therapy.1,2,3,4

Susan Hill, PhD, Chief Executive Officer of Mestag Therapeutics, said, Mestags M300 program opens up a new paradigm for the treatment of solid tumors. Advances in understanding TLS biology in cancer, and the associated benefit to patient outcomes, have enabled us to design a first-in-class program with the potential to benefit large numbers of patients with cancer. We are honored to work with such an eminent group of experts in this field to drive the program urgently into the clinic.

The newly appointed M300 advisors comprise Prof. Gabriele Bergers, group leader at the Flanders Institute for Biotechnology (VIB) Center for Cancer Biology and Professor of Oncology at the University of Leuven in Leuven, Belgium; Prof. Julie R. Brahmer, Director of the Thoracic Oncology Program, Professor of Oncology at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, as well as the Marilyn Meyerhoff Professor in Thoracic Oncology; Prof. Jeffrey L. Browning, Research Professor at the Boston University School of Medicine in the Departments of Virology, Immunology and Microbiology and Rheumatology; Prof. Wolf H. Fridman, Professor Emeritus of Immunology at Universit Paris-Cit, France; Prof. Catherine Sauts-Fridman, Professor Emeritus at Universit Paris-Cit; Prof. Elizabeth M. Jaffee, Professor of Oncology and Deputy Director at The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins; and Prof. Ignacio Melero, Professor of Immunology at the Academic Hospital of Navarra and at the Center for Applied Medical Research (CIMA) of the University of Navarra.

Ignacio Melero, MD, PhD, advisor to Mestag and Professor of Immunology at the Academic Hospital of Navarra and at the Center for Applied Medical Research (CIMA) of the University of Navarra, said, I look forward to collaborating with Mestag and to be a part of their world-class advisory team. I believe there is potential to develop transformative therapies for patients battling cancer. Mestags novel approach leverages known immunobiology, which for the first time, is being translationally harnessed to stimulate an anti-cancer immune environment within cancer tissue. Recent evidence supports the beneficial role of tertiary lymphoid structures in cancer, and the ability of a therapy to safely increase their presence could result in an efficacious intervention in patients with solid tumors.

Biographical information

Gabriele Bergers, PhD, is a Professor of Oncology at the University of Leuven and a group leader at the Vlaams Instituut voor Biotechnologie (VIB)-Center for Cancer Biology in Leuven since 2016.Before her move to the VIB, shewas a Professor in the Department of Neurological Surgery and a PI in the Brain Tumor Research Center (BTRC) at the Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco (UCSF), for 20 years. She has made seminal discoveries aboutperivasculartumor niches regarding the vasculature andtheimmune cell compartmentin regulating neovascularization, inflammation, and TLS formation in cancer and in revealing and understanding intrinsic and evasive resistance mechanisms of tumors to antiangiogenic immunotherapies. Dr. Bergers has received awards, including the Sidney Kimmel, the Sandler Opportunity, UCSF Breakthrough Biomedical Research, and the Judah Folkman. She hasacted as anexternal advisory board member fora number ofuniversities and pharmaceutical companies. Dr. Bergers wasthe Co-director of the Tumor Microenvironment Brain Tumor Center at UCSF and an advisor to the Max-Planck-Institute for Biomedicine in Muenster, Germany.She was a scientific co-founder of Oncurious.

Julie R. Brahmer, MD, is the Director of the Thoracic Oncology Program, Professor of Oncology at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, co-Leader of Cancer Immunology, as well as the Marilyn Meyerhoff Professor in Thoracic Oncology. She also directs the Kimmel Cancer Center on the Johns Hopkins Bayview campus and is co-principal investigator on Johns Hopkins' National Clinical Trials Network (NCTN) cooperative group grant. Dr. Brahmer is an active clinical leader in the treatment of lung cancer and mesothelioma. Dr. Brahmer's research and clinical practice focuses on the development of new therapies for the treatment of lung cancer and mesothelioma. She is a member of the American Society of Clinical Oncology, serves on the board of directors of the Society of Immunotherapy for Cancer, and is the Chair of the Eastern Cooperative Oncology Group (ECOG) Thoracic Committee. She is also on the medical advisory board of several lung cancer patient advocacy groups including LUNGevity, the Lung Cancer Research Fund, and Lung Cancer Research Foundation of America.

Jeffrey L. Browning, PhD, is a Research Professor at the Boston University School of Medicine in the Departments of Virology, Immunology and Microbiology and Rheumatology. He has a PhD in biochemistry from the University of Wisconsin. As a research scientist in the immunobiology discovery group at Biogen from 1984 to 2012, he centered on the tumor necrosis factor (TNF) family of regulatory molecules, including the discovery of the lymphotoxin, B-cell activating factor (BAFF) and TNF-like weak inducer of apoptosis (TWEAK) systems, and translation of modulators of the lymphotoxin pathway to the clinic in indications ranging from autoimmune disease and inflammatory bowel disease to oncology. He joined Boston University School of Medicine in 2013, with a current focus on altered vascular and stromal states in the perivascular compartment in the skin of systemic sclerosis and lupus patients and the impact on the pathology. Early in his career, he undertook postdoctoral work in the biophysics department of the University of Basel, Switzerland, using nuclear magnetic resonance to study membrane structure; and in the neurobiology department at the University of California, San Francisco researching the neuromuscular junction.

Wolf H. Fridman, MD, is Professor Emeritus of Immunology at Universit Paris-Cit. He is an expert in analysis of the tumor microenvironment, demonstrating that context, including functionality, location and density of the immune infiltrate in colorectal tumors, is the major prognostic factor for human cancers. He is involved in developing bioinformatic tools to quantify tumor microenvironment cells used to predict prognosis and immunotherapeutic responses in renal cell and colorectal cancers and sarcomas. His immune classification of soft tissue sarcoma tumors helped demonstrate that TLS and B cell signatures predict favorable clinical outcomes and therapeutic responses to anti-PD-1 therapy better than T cells, findings recently extended to other cancers treated with immune checkpoint blockers. These showed plasma cells generated inside TLS produce anti-tumor antibodies associated with a patients response to immunotherapy, opening the way for novel immune-based tools for efficient prognosis and therapy.

Catherine Sauts-Fridman, PhD, is Professor Emeritus at Universit Paris-Cit. She is the former Director of the Cancer, Immunology and Immunopathology department and Director of the Immunotherapy and Cancer team at Centre de Recherche des Cordeliers. Her research focuses on the heterogeneity of the immune and inflammatory components of the tumor microenvironment to identify new prognostic and theranostic markers. She carried out work in several fields: histocompatibility antigens, demonstration of the association of human leukocyte antigens (HLAs) with beta2-microglobulin and description of the 3rd histocompatibility locus in mice, H-2L and HLA-C in man, receptors for immunoglobulin G antibodies (biological activity and 3D structure), immuno-oncology (role of interleukin-17, TIME profiles of patients at risk of disease progression in localized kidney cancers, role of Tertiary Lymphoid Structures). She is the former President of the French Society of Immunology and European Federation of Immunological Societies. She founded the EFIS-EJI Ita Askonas Award to acknowledge female group leaders in immunology, and she founded the first European Congress of Immunology. She is Editor-in-Chief of La Revue Immunit et Cancer.

Elizabeth M. Jaffee, MD, is an internationally recognized expert in cancer immunology and pancreatic cancer. She is Deputy Director of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Co-Director of the Skip Viragh Pancreatic Cancer Center, and Associate Director of the Bloomberg Kimmel Institute for Cancer Immunotherapy. Her research focus is on developing novel immunotherapies for the treatment and prevention of pancreatic cancer. Prof. Jaffee is a past President of AACR and has served on several committees at the National Cancer Institute. She is Chief Medical Advisor to the Lustgarten Foundation for Pancreatic Cancer Research, and the Inaugural Director of the Convergence Institute for Integrating Technologies and Computational Sciences at Johns Hopkins. She is Chair of President Bidens Cancer Panel.

Ignacio Melero, MD, PhD, is Professor of Immunology at the Academic Hospital of Navarra and at the Center for Applied Medical Research (CIMA) of the University of Navarra. He leads a group working in translational tumor immunotherapy with an emphasis on cell therapy, cytokine gene therapy, and immune-stimulatory monoclonal antibodies. Earlier in his career, Dr. Melero contributed to seminal discoveries in the function of Natural Killer cells, and T-cell co-stimulation via CD137 (4-1BB). Dr. Melero has been awarded the BIAL Prize of Medicine, the Conde de Cartagena Award from the Royal Academy of Medicine, Doctor Durantez LAIR Foundation Award and a CRI research award. He has served on advisory boards of Bristol Myers-Squibb, Roche-Genentech, AstraZeneca, Merck Serono and Boehringer Ingelheim, and holds research grants by Pfizer, Bristol Myers Squibb, and Alligator.

About Mestags M300 Program

M300 is a first-in-class antibody program designed to conditionally induce the formation of Tertiary Lymphoid Structures (TLS) in the tumor. TLSs are aggregates of immune cells that form in tumor tissue as part of our bodies natural anti-cancer mechanisms, and drive powerful immune responses by recruiting, educating, and activating new anti-tumor T and B-cells. Fibroblast populations play a key role in the induction and maintenance of TLSs. TLSs in tumors are strongly predictive of both improved patient outcomes across solid tumor types and better response to therapy.1,2,3,4

About Mestag Therapeutics

Mestag harnesses new insights into fibroblast-immune interactions to develop impactful treatments for patients. We are progressing a pipeline of sophisticated first-in-class antibodies designed to improve the lives of patients with cancer and inflammatory disease. Together with our collaboration partner Janssen Biotech, Inc., a Johnson & Johnson company, we are also identifying novel targets for future therapies.

Our founding investigators comprise global experts in inflammatory disease, cancer, computational biology and fibroblast biology from the University of Oxford, Brigham & Womens Hospital, Harvard Medical School and Cold Spring Harbor Laboratory. We are supported by leading life science investors SV Health Investors, Johnson & Johnson Innovation JJDC, Inc., Forbion, GV (formerly Google Ventures) and Northpond Ventures.

Mestag is headquartered in Cambridge, UK, and in 2021 was recognized on the Fierce 15 list of innovative biotechnology companies.

For further information please visit our website http://www.mestagtherapeutics.com

For enquiries, please contact:

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Mestag Therapeutics Enlists Leading Cancer Biology and Immunology Advisors to Support Clinical Development of its ... - GlobeNewswire

Immunology

Smoking has long-term effects on the immune system – Institut Pasteur

Like other factors such as age, sex and genetics, smoking has a major impact on immune responses. This is the finding recently made by a team of scientists at the Institut Pasteur using the Milieu Intrieur cohort of 1,000 healthy volunteers, established to understand variability in immune responses. In addition to its short-term impact on immunity, smoking also has long-term consequences. For many years after they have quit the habit, smokers are left with effects on some of their bodies' defense mechanisms acquired while smoking. These findings, which for the first time reveal a long-term memory of the effects of smoking on immunity, were published in the journal Nature on February 14, 2024.

Individuals' immune systems vary significantly in terms of how effectively they respond to microbial attacks. But how can this variability be explained? What factors cause these differences? "To answer this key question, we set up the Milieu Intrieur cohort comprising 1,000 healthy individuals aged 20 to 70 in 2011," comments Darragh Duffy, Head of the Translational Immunology Unit at the Institut Pasteur and last author of the study. While certain factors such as age, sex and genetics are known to have a significant impact on the immune system, the aim of this new study was to identify which other factors had the most influence."

The scientists exposed blood samples taken from individuals in the Milieu Intrieur cohort to a wide variety of microbes (viruses, bacteria, etc.) and observed their immune response by measuring levels of secreted cytokines(1). Using the large quantities of data gathered for individuals in the cohort, the team then determined which of the 136 investigated variables (body mass index, smoking, number of hours' sleep, exercise, childhood illnesses, vaccinations, living environment, etc.) had the most influence on the immune responses studied. Three variables stood out: smoking, latent cytomegalovirus infection(2) and body mass index. "The influence of these three factors on certain immune responses could be equal to that of age, sex or genetics," points out Darragh Duffy.

As regards smoking, an analysis of the data showed that the inflammatory response, which is immediately triggered by infection with a pathogen, was heightened in smokers, and moreover, the activity of certain cells involved in immune memory was impaired. In other words, this study shows that smoking disrupts not only innate immune mechanisms, but also some adaptive immune mechanisms.

A comparison of immune responses in smokers and ex-smokers revealed that the inflammatory response returned to normal levels quickly after smoking cessation, while the impact on adaptive immunity persisted for 10 to 15 years. This is the first time it has been possible to demonstrate the long-term influence of smoking on immune responses.

Darragh DuffyHead of the Translational Immunology Unit at the Institut Pasteur and last author of the study

Basically, the immune system appears to have something resembling a long-term memory of the effects of smoking. But how? "When we realized that the profiles of smokers and ex-smokers were similar, we immediately suspected that epigenetic processes were at play(3)," says Violaine Saint-Andr, a bioinformatician in the Institut Pasteur's Translational Immunology Unit and first author of the study. "We demonstrated that the long-term effects of smoking on immune responses were linked to differences in DNA methylation(4) with the potential to modify the expression of genes involved in immune cell metabolism between smokers, ex-smokers and non-smokers." It therefore appears that smoking can induce persistent changes to the immune system through epigenetic mechanisms.

This is a major discovery elucidating the impact of smoking on healthy individuals' immunity and also, by comparison, on the immunity of individuals suffering from various diseases.

Violaine Saint-AndrBioinformatician in the Institut Pasteur's Translational Immunology Unit and first author of the study

(1) proteins secreted by a large number of immune cells to communicate among themselves and participate in immune defense.

(2) a virus in the herpes family that is often asymptomatic though dangerous to fetuses.

(3) changes in DNA that affect how genes are expressed, i.e. how they are used by cells.

(4) methylation is a type of chemical modification. Methyl groups position themselves on DNA, changing the way in which the genome is read in the cell.

Smoking changes adaptive immunity with persistent effects, Nature, February 14, 2024

Violaine Saint-Andr1,2*, Bruno Charbit3, Anne Biton2, Vincent Rouilly4, Cline Possm1, Anthony Bertrand1,5, Maxime Rotival6, Jacob Bergstedt6,7,8, Etienne Patin6, Matthew L. Albert9, Lluis Quintana-Murci6,10, Darragh Duffy1,3*, and the Milieu Interieur Consortium

1Translational Immunology Unit, Department of Immunology, Institut Pasteur, Universit Paris Cit, Paris 75015, France. 2Bioinformatics and Biostatistics HUB, Department of Computational Biology, InstitutPasteur, Universit Paris Cit, Paris 75015, France. 3Cytometry and Biomarkers UTechS, Center for Translational Research, Institut Pasteur, Universit Paris Cit, Paris 75015, France. 4DATACTIX, Paris, France. 5Frontiers of Innovation in Research and Education PhD Program, LPI Doctoral School, Universit Paris Cit, Paris, France. 6Institut Pasteur, Universit Paris Cit, CNRS UMR2000, Human Evolutionary Genetics Unit, Paris 75015, France. 7Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden. 8Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. 9HIBIO, San Francisco, California, USA. 10Chair Human Genomics and Evolution, Collge de France, Paris 75005, France. *Corresponding author

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Smoking has long-term effects on the immune system - Institut Pasteur

Immunology

Spring Allergies Attack More Than Just Your Nose – ACAAI Public Website – American College of Allergy Asthma and Immunology

February 15, 2024

Your nose, eyes, respiratory system and skin can all be involved when spring allergies hit

ARLINGTON HEIGHTS, Ill. (February 15, 2024) If you suffer from spring allergies, you already know that you tend to feel miserable once pollen season descends. But did you know that allergies can affect many different systems within your body and that theyre all interconnected?

Spring allergens such as pollen, mold spores and other airborne particles not only trigger nasal allergies, but also can have a profound effect on a variety of allergic conditions including asthma and eczema, says allergist Gailen Marshall, MD, PhD, president of the American College of Allergy, Asthma and Immunology (ACAAI). Understanding how all the allergic responses are interconnected is crucial for effectively managing and improving the overall quality of life for people who are affected.

How will you feel the effects?

Nasal allergies: The image that pops to mind when you hear spring allergies is someone sneezing and blowing their nose. Inhaled pollen can trigger an allergic reaction in susceptible people, leading to symptoms like sneezing, itching and nasal congestion. Nasal allergies are commonly referred to as hay fever although there is no connection to either hay or fever. The impact of these allergies isnt limited to the respiratory tract.

Asthma flares: For people with asthma, exposure to spring allergens can make their symptoms much worse. Pollen and other airborne allergens can irritate the airways, leading to a rapid tightening of the airways and increased inflammation over time. This aggravation can result in wheezing, coughing, and/or difficulty breathing. The link between nasal allergies and asthma, sometimes known as the allergic march, shows the progression in some individuals.

Eczema: Beyond the respiratory system, spring allergens and warmer temperatures can also impact the skin. Eczema, a chronic inflammatory skin condition, may worsen during the spring months. Pollen and other environmental allergens can trigger flare-ups in individuals with sensitive skin. The connection between environmental allergies and skin conditions emphasizes the need for a comprehensive approach to managing allergic diseases.

Eye allergies: Seasonal allergic conjunctivitis (SAC) is by far the most common type of eye allergy. Patients can experience symptoms in spring, summer and/or fall, depending on the type of plantpollensin the air. Typical symptoms include itching, redness, burning and clear, watery discharge. People with SAC may have chronic dark circles (known as allergic shiners) under their eyes. The eyelids may be puffy, and bright lights may be bothersome. SAC symptoms often accompany the runny nose, sneezing and nasal congestion associated with hay fever and other seasonal allergies.

Whats an allergic person to do?

Get the right medications: Although people react differently to different allergens, often the symptoms look very similar. If you find yourself reacting in the same way at the same time every year, you might have allergies and the right medication can help. Medications such as antihistamines, nasal corticosteroids, and bronchodilators play a crucial role in alleviating symptoms associated with spring allergies. These therapies can help manage both respiratory and skin flares, along with stuffiness, sneezing and itchy eyes.

Avoid your allergens: Once you know what you have an allergic reaction to, you can work to avoid that substance. Measures such as keeping windows shut to keep out pollen, taking a shower at night, and washing your clothes after being outside around pollen, can all help ease symptoms. If you have eczema, moisturizing often is key to reducing itching, and avoid fabrics that irritate your skin. For eye allergies, artificial tears can temporarily wash allergens from the eyes and moisten them.

See an allergist: A board-certified allergist can work with you to identify your personal allergen sensitivity profile and get your symptoms under control. Allergists can do testing to determine what is causing your symptoms, and develop a plan tailored to your needs. Your allergist may suggest allergen immunotherapy, either in shot or tablet form. Immunotherapy can be a long-term solution that can modify your immune systems response to specific allergens.

Although symptoms may not always be severe, allergies andasthmaare diseases and should be treated that way. Many people with allergies, asthma or eczema simply dont realize how much better they can feel. To locate an allergist in your area, visit AllergyAndAsthmaRelief.org.

About ACAAI ACAAI is a professional medical organization of more than 6,000 allergists-immunologists and allied health professionals, headquartered in Arlington Heights, Ill. The College fosters a culture of collaboration and congeniality in which its members work together and with others toward the common goals of patient care, education, advocacy, and research. ACAAI allergists are board-certified physicians trained to diagnose allergies and asthma, administer immunotherapy, and provide patients with the best treatment outcomes. For more information and to find relief, visit AllergyandAsthmaRelief.org. Join us on Facebook, Pinterest, Instagram, and Twitter/X.

Allergy, Allergy Symptoms, Allergy Treatment

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Spring Allergies Attack More Than Just Your Nose - ACAAI Public Website - American College of Allergy Asthma and Immunology

Immunology

Theratechnologies Announces Publication in Frontiers in Immunology that Deepens Understanding of Sudocetaxel … – GlobeNewswire

MONTREAL, Feb. 20, 2024 (GLOBE NEWSWIRE) -- Theratechnologies Inc. (Theratechnologies or the Company) (TSX: TH) (NASDAQ: THTX), a biopharmaceutical company focused on the development and commercialization of innovative therapies, today announced the publication of a peer-reviewed article in Frontiers in Immunology that enhances understanding of the molecular mechanism of action of sudocetaxel zendusortide (also known as TH1902) as a potential anticancer treatment. Sudocetaxel zendusortide is an investigational, first-in-class peptide-drug conjugate (PDC) that targets the sortilin receptor (SORT1) and expedites the internalization and delivery of the cytotoxic payload (docetaxel) directly into cancer cells.

The article, Sudocetaxel Zendusortide (TH1902) triggers the cGAS/STING pathway and potentiates anti-PD-L1 immune-mediated tumor cell killing appears in the Cancer Immunity and Immunotherapy section of the February (Volume 15) issue of the journal. It reports on preclinical research in which sudocetaxel zendusortide induced complete and prolonged tumor regression in a triple-negative breast cancer (TNBC)-derived xenograft tumor model and demonstrated tumor regression associated with growth inhibition and immune cell infiltration in a cold murine (syngeneic) tumor model. Additionally, combining sudocetaxel zendusortide with an anti-PD-L1 checkpoint inhibitor led to increases in tumor growth inhibition and median animal survival.

The results published in Frontiers in Immunology demonstrate that sudocetaxel zendusortide exerts its antitumor activity, in part, through modulation of the immune tumor microenvironment, said Christian Marsolais, Ph.D., Senior Vice President and Chief Medical Officer at Theratechnologies, and one of the papers co-authors. Our findings reinforce that combining this novel peptide-drug conjugate with anti-PD-L1 checkpoint inhibitor therapy may yield improved clinical outcomes, with potentially profound implications for patients across various cancer types.

An important aspect of our research is the activation of an antitumor immunity process through involvement of the cGAS/STING pathway, a key regulator in the cancer-immunity cycle, commented Prof. Borhane Annabi, Chair in Cancer Prevention and Treatment in the Chemistry Department at the Universit du Qubec Montral, and a co-author of the Frontiers in Immunology paper. Although the animal tumor model we worked with is considered a non-immunogenetic, or cold tumor model, we observed a net increase in leukocyte infiltration within sudocetaxel zendusortide-treated tumors, especially for tumor-infiltrating lymphocytes and tumor-associated macrophages. This realization supports the rationale for further exploration of the combination of sudocetaxel zendusortide with immunotherapy.

The article can be accessed online here.

About Immunotherapy in Cold and Hot Tumors

Immunotherapies have significantly improved the treatment of cancer. Researchers continue to explore the power of the immune system to find and destroy cancer cells. Hot tumors show signs of inflammation, meaning the tumor has already been infiltrated by immune cells rushing to fight the cancerous cells. Only a few types of cancers are considered to be hot. Cold tumors have not yet been infiltrated with T cells. This signals that the immune response is not working, making it difficult to provoke an immune response with immunotherapies. Most cancers of breast, ovary, prostate, pancreas, and brain (e.g., glioblastoma [GBM]) are cold tumors, and are largely treated with traditional therapies like radiation and chemotherapy. As a result, researchers have sought to understand how to turn cold tumors hot by reversing the suppressive microenvironment surrounding cold tumors and by attracting more of the right anti-tumor lymphocytes.

About Sudocetaxel Zendusortide (TH1902) and SORT1+ Technology

Sudocetaxel zendusortide is a first-of-its-kind sortilin receptor (SORT1)-targeting PDC, and the first compound to emerge from the Companys broader licensed oncology platform. As a new chemical entity, sudocetaxel zendusortide employs a cleavable linker to conjugate (attach) a proprietary peptide to docetaxel, a well-established cytotoxic chemotherapeutic agent used to treat many cancers. The FDA granted Fast Track designation to sudocetaxel zendusortide as a single agent for the treatment of all sortilin-positive recurrent advanced solid tumors that are refractory to standard therapy. Sudocetaxel zendusortide is currently being evaluated in a Phase 1 clinical trial in individuals with advanced ovarian cancer.

Theratechnologies has established the SORT1+ TechnologyTMplatform as an engine for the development of PDCs that target SORT1, which is expressed in multiple tumor types. SORT1 is a scavenger receptor that plays a significant role in protein internalization, sorting, and trafficking. Expression of SORT1 is associated with aggressive disease, poor prognosis, and decreased survival. It is estimated that SORT1 is expressed in 40% to 90% of endometrial, ovarian, colorectal, triple-negative breast (TNBC), and pancreatic cancers, making this receptor an attractive target for anticancer drug development.

About Theratechnologies

Theratechnologies (TSX: TH) (NASDAQ: THTX) is a biopharmaceutical company focused on the development and commercialization of innovative therapies addressing unmet medical needs. Further information about Theratechnologies is available on the Company's website at http://www.theratech.com, on SEDAR+ at http://www.sedarplus.caand on EDGAR at http://www.sec.gov. Follow Theratechnologies on Linkedinand X (formerly Twitter).

Forward-Looking Information

This press release contains forward-looking statements and forward-looking information (collectively, the Forward-Looking Statements) within the meaning of applicable securities laws, that are based on managements beliefs and assumptions and on information currently available to it. You can identify forward-looking statements by terms such as may, will, should, could, promising, would, outlook, believe, plan, envisage, anticipate, expect and estimate, or the negatives of these terms, or variations of them. The Forward-Looking Statements contained in this press release include, but are not limited to, statements regarding the combination of sudocetaxel zendusortide with anti-PD-L1 checkpoint inhibitor therapy which may yield improved clinical outcomes, the potential treatment of various types of cancer with sudocetaxel zendusortide, the development of PDCs resulting from the SORT1+ TechnologyTMplatform and our estimates regarding the expression of SORT1 in various types of cancer. Although the Forward-Looking Statements contained in this press release are based upon what the Company believes are reasonable assumptions in light of the information currently available, investors are cautioned against placing undue reliance on these statements since actual results may vary from the Forward-Looking Statements contained in this press release. These assumptions include, without limitation, that the results observed in pre-clinical testing will be replicated into humans, sudocetaxel zendusortide will be able to treat various types of cancer, the Company will be successful in developping addtional PDCs from the SORT1+ TechnologyTMplatform and positive safety and efficacy results will be observed from the current Phase 1 clinical trial studying sudocetaxel zendusortide. Forward-Looking Statements assumptions are subject to a number of risks and uncertainties, many of which are beyond the Companys control, that could cause actual results to differ materially from those that are disclosed in or implied by such Forward-Looking Statements. These risks and uncertainties include, but are not limited to, the inability of sudocetaxel zendusortide to demonstrate efficacy results when used in human subjects, limitations in the types of cancer for which sudocetaxel zendusortide could be used and limitations in the capacity of the Company to develop new PDCs. We refer current and potential investors to the Risk Factors section of our Annual Information Form dated February 27, 2023, available on SEDAR+ atwww.sedarplus.caand on EDGAR atwww.sec.govas an exhibit to our report on Form 40-F dated February 28, 2023, under Theratechnologies public filings. The reader is cautioned to consider these and other risks and uncertainties carefully and not to put undue reliance on forward-looking statements. Forward-Looking Statements reflect current expectations regarding future events and speak only as of the date of this press release and represent our expectations as of that date.

We undertake no obligation to update or revise the information contained in this press release, whether as a result of new information, future events or circumstances or otherwise, except as may be required by applicable law.

Contacts:

Media inquiries: Julie Schneiderman Senior Director, Communications & Corporate Affairs communications@theratech.com 1-514-336-7800

Investor inquiries: Philippe Dubuc Senior Vice President and Chief Financial Officer pdubuc@theratech.com 1-438-315-6608

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Theratechnologies Announces Publication in Frontiers in Immunology that Deepens Understanding of Sudocetaxel ... - GlobeNewswire

Immunology

Shikhar Mehrotra named co-leader of Cancer Biology and Immunology research program at MUSC Hollings – The Cancer Letter

Shikhar Mehrotra, professor of surgery and Cecilia and Vincent Peng Endowed Chair in melanoma and cutaneous oncology, will take on the role of co-leader of the Cancer Biology and Immunology Research Program at MUSC Hollings Cancer Center, alongside Philip Howe, professor and chair of the Department of Biochemistry & Molecular Biology, and Sophie Paczesny, professor in the Department of Microbiology & Immunology.

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Shikhar Mehrotra named co-leader of Cancer Biology and Immunology research program at MUSC Hollings - The Cancer Letter

Immunology

Gut Microbiome Benefits of Breast Milk Revealed in Mouse Study – Technology Networks

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An immune component of breast milk known as the complement system shapes the gut environment of infant mice in ways that make them less susceptible to certain disease-causing bacteria, according to a study led by researchers at the Johns Hopkins Bloomberg School of Public Health.

The researchers found that mouse pups that nursed from lactating mice whose breast milk lacked a key complement protein had different gut microbe populations than pups that nursed on standard mouse breast milk, making them highly vulnerable toCitrobacter rodentium,a bacterium that infects the guts of mice.Citrobacter rodentiumis similar to certain types of diarrhea-causingE. colithat can infect humans but not mice.

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The researchers experiments suggest that mouse breast milks complement components boost mouse infant health by directly eliminating some types of gut-dwelling bacteria. This reshaping of the gut microbiota leaves the infant mice far less susceptible toCitrobacter rodentiuminfection, thus protecting the young from certain infectious threats. The reshaping activity is not dependent on antibodies, in contrast to the way complement components are thought to typically work.

The researchers also confirmed in separate in vitro analyses that human breast milk contains these complement components, which demonstrated similar activity in targeting specific bacteria.

Taken together, these findings shed light on the mechanisms of how breast milk functions to provide protection from certain bacterial infections.

Thestudywas published online January 18 in the journalCell.

These findings reveal a critical role for breast milk complement proteins in shaping offsprings gut microbecompositions and protecting against bacterial infection in the gutin early life, says study senior author Fengyi Wan, PhD, a professor in theBloomberg SchoolsDepartment of Biochemistry and Molecular Biology. This represents an important expansion of our understanding of breast milks protective mechanisms.

The studys first author is Dongqing Xu, PhD, an assistant scientist in Wans research group.

Breastfeeding has many known and suspected benefits. It provides excellent nutrition to infants and appears to protect against some short-term or long-term illnesses. Breast milk is also known to help protect against common infections by sharing antibodies and white blood cells from the mother.

Breast milk also contains complement proteins that can work with, or complement, antibodies in attacking bacteria. While complement proteins that circulate in the blood have been the focus of much research, complement proteins in breast milk have been far less studied, and until now their role has been unclear.

In the new study, Wan and his team used engineered mice that lacked critical complement genes. They found that milk from female mice of this type left several-weeks-old mouse pupseven those with normal complement geneshighly susceptible to colitis, often lethal, fromCitrobacter rodentiuminfections.By contrast, pups feeding on normal, complement-containing milk showed only minor and transient signs of gut infection.

The team discovered that this protective effect of breast milk complement proteins depends on their capacity in shaping infant gut microbiota. The complement proteins kill certain gut bacterial species, and this culling of microbes creates an overall gut environment in which harmful inflammation is much less likely in the presence ofCitrobacter rodentium.

Gut microbiota is of great importance to health, says Wan. Breast milk complement proteins contribute crucially to the establishment of a protective gut microbiota during the early stages of development, promoting infant health and defending against pathogens.

The study also appears to mark an advance in basic immunology. Complement proteins in blood, although known to be capable of causing direct damage to bacterial cells, have been thought to typically work in partnership with antibodies in a specific immune response. However, Wan and his team showed that this breast milk complement activity against bacteria does not require antibodies and is a nonspecific immune response.

This opens the door to a lot of new investigations, for example, elucidating the specific complement biology in breast milk and comparing that to complement biology in the blood, andassessingthe role of complement beyond the antibody-dependent specific immune system, Wan says.

Reference:Xu D, Zhou S, Liu Y, Scott AL, Yang J, Wan F. Complement in breast milk modifies offspring gut microbiota to promote infant health. Cell. 2024:S0092867423013843. doi:10.1016/j.cell.2023.12.019

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Gut Microbiome Benefits of Breast Milk Revealed in Mouse Study - Technology Networks