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Cancer Cells Send Out “Drones" (Their Own Exosomes) to Battle Immune System from Afar—New Research “Presents Paradigm-Shifting Picture of How Cancers Take Systemic Approach to Suppressing Immune System”-- Findings Called “Truly Remarkable”

Cancer cells are more than a lump of cells growing out of control; they participate in active combat with the immune system for their own survival. Being able to evade the immune system is a hallmark of cancer. Cancer cells release biological "drones" to assist in that fight--small vesicles called exosomes circulating in the blood and armed with proteins called PD-L1 that cause T-cells to tire before they have a chance to reach the tumor and do battle, according to researchers from the University of Pennsylvania (Penn). The work, published online on August 8, 2018 in Nature, is a collaboration between Wei Guo, PhD, a Professor of Biology in the School of Arts and Sciences, and Xiaowei Xu, MD, PhD, a Professor of Pathology and Laboratory Medicine in the Perelman School of Medicine. While primarily focused on metastatic melanoma, the team found that breast and lung cancer also release the PD-L1-carrying exosomes. The article is titled “Exosomal PD-L1 Contributes to Immunosuppression and Is Associated with Anti-PD-1 Response.” The research offers a paradigm-shifting picture of how cancers take a systemic approach to suppressing the immune system. In addition, it also points to a new way to predict which cancer patients will respond to anti-PD1 therapy that disrupts immune suppression to fight tumors and a means of tracking the effectiveness of such therapies. "Immunotherapies are life-saving for many patients with metastatic melanoma, but about 70 percent of these patients don't respond," said Dr. Guo. "These treatments are costly and have toxic side effects so it would be very helpful to know which patients are going to respond.

Red Fox Genome Sequence Hints at Genetic Bases of Behavior

For nearly 60 years, the red fox has been teaching scientists about animal behavior. In a long-term experiment, foxes at the Russian Institute of Cytology and Genetics have been selected for tameness or aggression, recreating the process of domestication from wolves to modern dogs in real time. On August 6, 2018, with the first-ever publication of the fox genome, scientists will begin to understand the genetic basis of tame and aggressive behaviors, which could shed light on human behavior, as well. The open-access article was published in Nature Ecology & Evolution and is titled “Red Fox Genome Assembly Identifies Genomic Regions Associated with Tame and Aggressive Behaviors," "We've been waiting for this tool for a very, very long time," says Dr. Anna Kukekova, Assistant Professor in the Department of Animal Sciences at the University of Illinois and lead author of the paper. She has been studying the famous Russian foxes since 2002. "In our previous work, we tried to identify regions of the fox genome responsible for tame and aggressive behavior, but these studies required a reference genome and all we could use was the dog genome. For us, the fox genome provides a much better resource for genetic analysis of behavior." After sequencing and assembling the fox genome, the team turned to the famous Russian foxes to look for genetic regions differentiating the tame, aggressive, and conventional populations - farm-raised foxes ancestral to the tame and aggressive populations but not bred for any particular behavioral trait. The researchers sequenced the genomes of 10 individuals from each population, then compared them to the full fox genome and each other.

With a Little Help from Their Friends--Viral Innate Immunity Requires Coordination of Three Different Cell Types

(BY RACHEL DERITA, PhD Candidate,Thomas Jefferson University, Department of Cancer Biology) The innate immune system is highly orchestrated and involves many different signals between different cell types to function properly. It is also our first line of defense before the acquired immune system is activated. Therefore, understanding exactly how the innate immune system reacts to viral infections is extremely important for how we treat patients and discover mechanisms of immunity in the future. A recent study from the laboratory of Luis J. Sigal, PhD, Professor of Microbiology and Immunology at Thomas Jefferson University in Philadelphia, reveals a cascade of events between three different cell types in the lymph node. In this study, published in the July 3, 2018 issue of Cell Reports, the activity of the innate immune system after a mousepox infection in the skin of mice was analyzed. The open-access article is titled: “Migratory Dendritic Cells, Group 1 Innate Lymphoid Cells, and Inflammatory Monocytes Collaborate to Recruit NK Cells to the Virus-Infected Lymph Node.” First, it was shown that, after the infection, sentinel cells of the skin called dendritic cells become infected. These cells then rapidly migrate to the lymph node, carrying the virus with them. Once at the draining lymph node, the infected dendritic cells perform two tasks that involve recruiting two other innate immune cell types to the lymph node within the first 24 hours of infection. First, specific molecules called chemokines are released by the infected dendritic cells, which specifically attract inflammatory monocytes. Second, the infected dendritic cells stimulate the small number of natural killer (NK) cells present in the lymph node to produce an inflammatory molecule called interferon gamma.

Wilms Tumor Studies Offer New Insights

Connecting two previously unrelated insights about the formation of a pediatric kidney cancer (Wilms tumor), researchers at the University of Texas (UT) Southwestern Medical Center have uncovered the means by which the cancer continues to grow, providing potential targets for more effective treatments in the future. Wilms tumor is the most common cancer of the kidney in children. Typically, the disease is treated with surgery, radiation, and chemotherapy. This combination is effective for many patients but has numerous side effects, and a cure remains elusive for those with aggressive disease. This situation has driven investigators at UT Southwestern to look for more effective and less toxic ways to treat Wilms tumor. Previously, pediatric investigators from the nationally recognized Kidney Cancer Program at UT Southwestern's Harold C. Simmons Comprehensive Cancer Center identified a new molecular subset of Wilms tumors driven by recurrent mutations at "hot spot" residues in genes of the microRNA (miRNA) processing pathway (Rakheja et al., Nat Comm, 2014). A miRNA is a tiny RNA that influences the production of specific proteins in cells. Nevertheless, it was unclear exactly why impairment of miRNA function caused Wilms tumors. In follow-up studies, the researchers identified a previously unknown connection between the miRNA pathway and insulin-like growth factor 2 (IGF2), a secreted protein that drives organ growth and is known to play a critical role in Wilms tumor and other cancers. In related work, the UT Southwestern scientists also identified new, miRNA-independent mechanisms of IGF2 regulation in Wilms tumor. "Our previous discovery of miRNA processing mutations opened a window into this important class of Wilms tumors," said Dr. James Amatruda, Associate Professor of Pediatrics, Molecular Biology, and Internal Medicine.

PureTech Health Announces Collaboration with Roche to Advance Technology for Oral Administration of Antisense Oligonucleotides, Using PureTech’s Milk-Derived Exosome Platform

On July 20, 2018, PureTech Health plc (LSE: PRTC) (“PureTech Health”), a clinical-stage biopharmaceutical company developing novel medicines focused on the Brain-Immune-Gut (BIG) Axis, announced that it has entered into a multiyear collaboration with F. Hoffmann-La Roche Ltd and Hoffmann-La Roche Inc., to advance PureTech’s milk-derived exosome platform technology for the oral administration of Roche’s antisense oligonucleotide platform. Under the terms of the agreement, PureTech Health will receive up to $36 million, including upfront payments, research support, and early preclinical milestones. PureTech Health will be eligible to potentially receive development milestone payments of over $1 billion and additional sales milestones and royalties for an undisclosed number of products. PureTech’s milk exosome-based technology is uniquely designed to facilitate the oral administration of complex payloads such as nucleic acids, peptides, and small molecules. These exosomes are believed to traffic via lymphatic circulation and could potentially enable the targeting of immune cells in novel ways. Daphne Zohar, Co-founder and Chief Executive Officer of PureTech Health, said: “We are excited to accelerate the development of this promising technology from our internal lymphatic and immune cell trafficking programs. The expertise and resources that Roche is bringing to the collaboration will help us to potentially address one of the biggest challenges in oligonucleotide-based therapeutic development: oral administration of nucleic acids.” PureTech Health has been advancing internal research and development projects that focus on the Brain-Immune-Gut (BIG) Axis, with an emphasis on lymphatics and immune cell trafficking to modulate immunity in a tissue-specific manner.

CellMax Life Blood Testing Platform for Early Cancer Detection Granted Six U.S. Patents Covering Entirety of Sub-$200 Test and Platform, Which Isolates Rare CTCs) from One Tube of Blood

CellMax Life, enabling early cancer detection and management with affordable, non-invasive blood tests, announced on July 25, 2018 that six U.S. patents have been granted for the compny’s biomimetic platform CMx, which detects circulating tumor cells (CTCs). The patents cover the entire detection workflow, from the capture of very rare CTCs present at fewer than five cells per billion normal cells in early-stage cancer, to the processes ensuring their intact release and identification by means of advanced imaging techniques, allowing CellMax Life to detect CTCs in up to 90 percent of samples. In addition to these six U.S. patents, there are also 16 global patents issued and several additional patents pending in the company’s growing portfolio. “In the past, finding CTCs was not possible in pre-cancer and early-stage cancer, as the cells numbered too few to accurately identify in the bloodstream,” said Shai Friedland, MD, Chief of Gastroenterology & Hepatology, VA Palo Alto Health Care System from the Stanford University School of Medicine. “The CellMax CMx platform’s ability to achieve high sensitivity for pre-cancerous colorectal lesions, while remaining cost-effective and convenient is notable. The CMx platform positions CellMax Life’s CTC test to potentially become a standard option for the 100 million Americans over the age of 45 who are eligible for colorectal cancer screening.” The CellMax CMx platform, has its origins in research conducted on biomimetic smart materials and interfaces by Professor Ying Chih Chang at Stanford University (Professor & Research Fellow, Genomics Research Center, Academia Sinica, Taiwan, Adjunct Professor Stanford University).

Study Supports Blood Test to Help Diagnose Brain Injury

For the first time in the U.S., a blood test will be available to help doctors determine if people who've experienced a blow to the head could have a traumatic brain injury such as brain bleeding or bruising. Until this point, physicians have relied on subjective markers - mainly patient-reported symptoms such as headaches, nausea, or light sensitivity - to make an educated "guess" on which individuals have brain trauma and require a head CT scan. Particularly among athletes who may hide symptoms in order to keep playing, a subjective assessment is not always reliable. The new test provides an objective indicator of injury that can potentially be obtained quickly and easily in busy emergency departments. In February 2018, the U.S. Food and Drug Administration approved the test as part of a fast-track program to get breakthrough technologies to patients more quickly. Called the Banyan Brain Trauma Indicator®, the test aids in the evaluation of patients with a suspected traumatic brain injury or concussion, also known as a mild traumatic brain injury. On July 24, 2018, the major study that led to approval of the test was published in The Lancet Neurology. The clinical trial included close to 2,000 individuals presenting with a head injury to 22 emergency departments in the U.S. and Europe. Banyan Biomarkers, Inc., the company that developed the test, is working with its commercial partners to make the test available in hospitals and emergency departments. The article is titled “Serum GFAP and UCH-L1 for Prediction of Absence of Intracranial Injuries on Head CT (ALERT-TBI): A Multicentre Observational Study.” "Many concussion patients don't seek medical care for their injury, a decision due in part to the perception that emergency departments have nothing to offer in terms of diagnosis," said lead study author Jeffrey J.

A Molecular Key for Delaying Progression of Multiple Sclerosis Is Found

Multiple sclerosis is an autoimmune disease that attacks and destroys a structure known as the "myelin sheath,” whose integrity is indispensable for the brain and spinal cord to function properly. Current treatment of multiple sclerosis is based on modulating the activity of the immune system or preventing its cells from accessing the central nervous system and damaging it. These therapies are effective in the early phases of the disease, but they do not prevent its advance and the progressive functional deterioration. During the progressive phase of the disease, it is the microglial cells in the brain that are the main cause of the chronic inflammation responsible for the neurological deterioration. These microglial cells are the brain's sentries and react when faced with any damage or infection in it. This reaction, which is in principle beneficial, becomes harmful when it is prolonged over time, leading to chronic inflammation, and aggravates the disease and encourages its progression. In the new work published online on April 7, 2018 in EMBO Molecular Medicine, it was possible to identify a receptor known as P2X4 present in the microglial cells that increases their anti-inflammatory potential in order to reduce the damage in multiple sclerosis and, above all, encourage the body's own repair responses. This experimental development was conducted using animal models of this disease, thanks to which it was possible to discover that the drugs that activate this receptor improve the symptoms during the chronic phase of the disease when furthering the repair of the nervous tissue. The open-access article is titled “P2X4 Receptor Controls Microglia Activation and Favors Remyelination in Autoimmune Encephalitis.” As Dr.

Pre-Clinical Studies in Mice Show Strong Therapeutic Potential of CAR-T Cell Immunotherapy in Colorectal Cancer

(BY RACHEL DERITA, PhD Candidate,Thomas Jefferson University, Department of Cancer Biology) At Thomas Jefferson University in Philadelphia, researchers have recently shown that in mice, a CAR-T cell therapy successfully eliminated primary colorectal tumors and prevented metastatic growth. This is a breakthrough for the potential use of chimeric antigen receptor (CAR) - T cell therapy in the treatment of solid tumors. The University of Pennsylvania (UPenn) has previously made clinical advances recently with its use of CAR-T cell therapy in non-solid tumors, but there is still a great need for new therapeutic options involving the immune system in solid tumors. CAR-T cell therapy involves taking a patient’s own immune cells, then engineering them to target tumor cells specifically, and then infusing them back into the patient. In the current study, led by Dr. Adam Snook, PhD, Assistant Professor, T cells were engineered to target an antigen called GUCY2C. This protein had been previously identified as a biomarker and potential therapeutic target in colorectal cancer by the laboratory of Scott Waldman, PhD, MD, Chair of the Department of Pharmacology & Experimental Therapeutics at Jefferson. Dr. Snook also mentions that other high-mortality cancers such as esophageal and pancreatic cancer also express GUCY2C. This means that this pre-clinical study has implications for treating up to 25% of patients who would otherwise die from their cancer. In the Jefferson study, researchers used a “human-ready” mouse model of colorectal cancer to test CAR-T cell therapy targeted against GUCY2C. None of the mice experienced side effects and the therapy successfully fought the tumor over the duration of 75 days. The average survival time for the control group was only 30 days.

Sulfate Code That Allows Neurodegenerative Proteins into Cells

Researchers at the University of Texas (UT) Southwestern Medical Center, reporting in the July 6, 2018 issue of the Journal of Biological Chemistry, have uncovered details of how cells take in corrupted proteins that can turn normal proteins corrupt, leading to neurodegenerative diseases such as Alzheimer's and Parkinson's. The new article is titled “Specific Glycosaminoglycan Chain Length and Sulfation Patterns Are Required for Cell Uptake of Tau Versus Α-Synuclein and -Amyloid Aggregates.” Understanding the molecular details of how these proteins spread from cell to cell could lead to therapies to halt disease progression. Alzheimer's and Parkinson's are associated with particular proteins in the brain misfolding, aggregating, and inducing normal proteins to misfold and aggregate. Dr. Marc Diamond's group at UT Southwestern discovered in 2013 that to enter new cells and propagate misfolding, the disease-associated proteins tau, alpha-synuclein, and amyloid-beta must bind to a type of sugar-protein molecule called heparan sulfate proteoglycan (HSPG) on the cell's surface. This binding triggers the cell to bring the corrupted protein inside. In the new study, the group sought to understand more about how this process worked. "The question was, how specific is this (process)? Or is it not specific at all?" asked Dr. Barbara Stopschinski, the physician and researcher in Dr. Diamond's lab who oversaw the new work. What were the details of the chemical communication between HSPG and tau that triggered tau's entry into the cells? And was this process different for alpha-synuclein (associated with Parkinson's disease), amyloid-beta, and tau (both associated with Alzheimer's disease)?

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