Immunotherapies called chimeric antigen receptor (CAR) T cells use genetically engineered versions of a patient's own immune cells to fight cancer. These treatments have energized cancer care, especially for people with certain types of blood cancers. Now, scientists at Memorial Sloan Kettering Cancer Center's Sloan Kettering Institute (SKI) have developed new CAR T cells that can do something their predecessors cannot: Make drugs.
Standard-issue CAR T cells are designed in the lab to recognize specific markers on cancer cells. When these CAR T cells are given back to a patient, they proliferate and go on the attack, acting as a kind of "living drug."
Despite their usefulness for treating blood cancers, there are several limitations of current CAR T models. One is that the CAR T cells can only kill cancer cells that contain the marker they are designed to recognize. But it is not uncommon for cancer cells to stop making this marker and thus to "escape" from the therapy.
Researchers have developed an optical biopsy system that can distinguish between cancerous and healthy liver tissue. The new technology could make it easier to diagnose liver cancer, which is the sixth most common cancer globally.
"The instrument is designed to be compatible with the needles currently used for liver biopsies," said Evgenii Zherebtsov, a member of the research team from Orel State University in Russia. "It could thus one day help surgeons more precisely navigate the biopsy instrument to decrease the number of errors in taking tissue samples that are used for diagnosis."
In the Optica Publishing Group journal Biomedical Optics Express, the researchers report that the optical biopsy system can reliably distinguish between cancerous and healthy cells in mouse models. The system also showed promise in preliminary tests conducted in people with suspected liver cancer.
"Optical biopsy methods like the one we developed make it possible to differentiate healthy and tumor tissues with a high degree of accuracy," said Elena V. Potapova, who was co-first author of the paper with Zherebtsov. "Although our system was specifically designed for use in abdominal surgery, our results show that similar technologies could be useful for other medical applications."
An experimental immunotherapy can temporarily reprogram patients' immune cells to attack a specific target via only a single injection of messenger RNA (mRNA), similar to the mRNA-based COVID-19 vaccines, according to a new study from researchers in the Perelman School of Medicine at the University of Pennsylvania.
The researchers, whose work is published today in Science, demonstrated the new approach with an mRNA preparation that reprograms T cells—a powerful type of immune cell—to attack heart fibroblast cells. Heart failure is often driven in part by these fibroblast cells, which respond to heart injury and inflammation by chronically overproducing fibrous material that stiffens the heart muscle, impairing heart function—a condition called fibrosis. In experiments in mice that model heart failure, the reduction in cardiac fibroblasts caused by the reprogrammed T cells led to a dramatic reversal of fibrosis.
"Fibrosis underlies many serious disorders, including heart failure, liver disease, and kidney failure, and this technology could turn out to be a scalable and affordable way to address an enormous medical burden," said senior author Jonathan A. Epstein, MD, chief scientific officer for Penn Medicine and executive vice dean and the William Wikoff Smith Professor of Cardiovascular Research in the Perelman School of Medicine. "But the most notable advancement is the ability to engineer T cells for a specific clinical application without having to take them out of the patient's body."
Severe and persistent disability often undermines the life-saving benefits of cancer treatment. Pain and fatigue—together with sensory, motor, and cognitive disorders—are chief among the constellation of side effects that occur with the platinum-based agents used widely in chemotherapy treatments worldwide.
A new study by Georgia Tech researchers in the lab of Timothy C. Cope has found a novel pathway for understanding why these debilitating conditions happen for cancer patients and why scientists should focus on all of the possible neural processes that deliver sensory or motor problems to a patient's brain—including the central nervous system—and not just the "peripheral degeneration of sensory neurons" that occurs away from the center of the body.
The new findings "Neural circuit mechanisms of sensorimotor disability in cancer treatment" are published in the Proceedings of the National Academy of Sciences (PNAS) and could impact development of effective treatments that are not yet available for restoring a patient's normal abilities to receive and process sensory input as part of post cancer treatment, in particular.
A blood test, combined with a risk model based on an individual's history, more accurately determines who is likely to benefit from lung cancer screening than the current U.S. recommendation, according to a study published today in the Journal of Clinical Oncology led by researchers from The University of Texas MD Anderson Cancer Center.
A personalized lung cancer risk assessment, combining a blood test based on a four-marker protein panel developed at MD Anderson and an independent model (PLCOm2012) that accounts for smoking history, was more sensitive and specific than the 2021 and 2013 U.S. Preventive Services Task Force (USPSTF) criteria. The study included participants from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial with at least a 10 pack-year smoking history. If implemented, the blood test plus model would have identified 9.2% more lung cancer cases for screening and reduced referral to screening among non-cases by 13.7% compared to the 2021 USPSTF criteria.
"We recognize that a small percentage of people who are eligible for lung cancer screening through an annual low-dose CT scan are actually getting screening. Moreover, CT screening is not readily available in most countries. So, our goal, for many years, has been to develop a simple blood test that can be used first to determine need for screening and make screening for lung cancer that much more effective," said Sam Hanash, M.D., Ph.D., professor of Clinical Cancer Prevention and leader of the McCombs Institute for the Early Detection and Treatment of Cancer. "Our study shows for the first time that a blood test could be useful to determine who may benefit from lung cancer screening."
A team of Vanderbilt researchers has revealed some of the mechanisms by which polyps develop into colorectal cancer, setting the framework for improved surveillance for the cancer utilizing precision medicine.
Their study, published Dec. 14 in Cell, describes findings from a single-cell transcriptomic and imaging atlas of the two most common colorectal polyps found in humans: conventional adenomas and serrated polyps. They determined that adenomas arise from expansion of stem cells that are driven by activation of WNT signaling, which contributes to the development of cancer, while serrated polyps derive into cancer through a different process called gastric metaplasia. The finding about metaplasia, an abnormal change of cells into cells that are non-native to the tissue, was surprising, the researchers said.
"Cellular plasticity through metaplasia is now recognized as a key pathway in cancer initiation, and there were pioneering contributions to this area by investigators here at Vanderbilt," said Ken Lau, PhD, associate professor of Cell and Developmental Biology, one of the study's corresponding authors. "We now have provided evidence of this process and its downstream consequences in one of the largest single-cell transcriptomic studies of human participants from a single center to date."
Interleukin-12 (IL-12), a potent inducer of cell-mediated immunity, can stimulate the anti-tumor effector functions of the activated T and NK cells for solid tumors rejection. However, clinical administration of IL-12 has been limited because of its short half-life, low efficacy, and dose-limiting systemic toxicity.
In a study published in Science Immunology, Prof. Peng Hua at the Institute of Biophysics of the Chinese Academy of Sciences and Prof. Fu Yangxin at the University of Texas Southwestern Medical Center, and collaborators, developed a new generation IL-12, the pro-IL-12, with low toxicity, tumor restriction, and high anti-tumor efficiency.
The researchers first constructed an IL-12-Fc fusion protein to extend the in vivo half-life of IL-12 and further engineered a pro-IL-12 with the functional site blocked by an MMP-cleavable peptide-linked IL-12 natural extracellular receptor-binding domains. Pro-IL-12 could be reactivated when the linker was cleaved by tumor-enriched MMP14. Systemic treatment with pro-IL-12 resulted in effective tumor control and prolonged mouse survival.
An international research group at the RIKEN Cluster for Pioneering Research (CPR) has successfully treated cancer in mice using metal catalysts that assemble anticancer drugs together inside the body. Published in the scientific journal Nature Communications, the study is the first report of therapeutic in vivo synthetic chemistry being used to make anticancer substances where they are needed simply by injecting their ingredients through a vein. Because this technique avoids indiscriminate tissue damage, it is expected to have a significant impact on cancer treatment.
Aside from effectiveness at killing cancer cells, a major challenge to cancer chemotherapy is how to mitigate the toxic side effects on the body. Drugs that can damage cancer cells can damage non-cancerous cells as well, and the negative side effects of chemotherapy can cause permanent and debilitating damage. Current methods for reducing these side effects include selective delivery of anticancer drugs to cancer tissue (drug delivery) and conversion of non-toxic compounds (prodrugs) into toxic compounds nearby the cancerous tissue.
(EurekAlert) In a study conducted at the University of São Paulo’s Human Genome and Stem Cell Research Center (HUG-CELL) in Brazil, serial systemic injections of zika virus into mice with brain tumors destroyed the cancer without causing neurological damage or injuring other organs, and increased the animals’ survival rate.
The scientists also injected zika into cerebral organoids, brain-like organs created in vitro using stem cells. The virus not only prevented progression of the tumors but actually reduced their size.
In both the mice and the organoids, cytokines (proteins that regulate the immune response) suppressed tumor growth after treatment, and defense cells migrated to the brain region affected by the tumor, alerting the immune system to its existence.
These results, reported in an article published in a special issue of the journal Viruses, confirm the efficacy and safety of treatment with zika in both models, opening up prospects for the use of virotherapy to treat central nervous system tumors.
Jonsson Comprehensive Cancer Center Researchers Identify Signaling Mechanisms in Pancreatic Cancer Cells that Could Provide Treatment Targets
January 11, 2022
(EurekAlert) Research led by scientists at the Jonsson Comprehensive Cancer Center (JCCC) at UCLA provides new insights into molecular “crosstalk” in pancreas cancer cells, identifying vulnerabilities that could provide a target for therapeutic drugs already being studied in several cancers. This interdisciplinary research was led by a team of JCCC investigators, Dr. Caius Radu, an expert in cancer cell metabolism, and Dr. Timothy Donahue, a pancreas cancer surgeon and an expert in pancreas cancer biology.
“Pancreatic ductal adenocarcinoma, which is highly resistant to current therapies, is expected to become the second most common cause of cancer-related deaths in the United States within this decade,” said senior author Caius Radu, MD, a researcher at Jonsson Comprehensive Cancer Center at UCLA and Professor in the Department of Molecular and Medical Pharmacology at UCLA. “Results of this study increase our understanding of the inflammatory microenvironment within these tumors and suggest targeted pharmacological strategies that could be employed to leverage this hallmark feature of pancreas cancer by current treatments.”
The preclinical research, using tumor cells from patients and cell line-derived xenograft tumors, was published online at Cell Reports on Jan. 11. It centers on STING-driven type I interferon, an immune system signaling molecule that impairs cancer cell proliferation in lab studies but tends to have the opposite effect in clinical practice, where tumor cells adapt to them and often become resistant to treatment with radiation, chemotherapy and immune checkpoint blockade. Interferons are produced in immune and other cells, including some types of cancer cells.
“We determined that a subset of PDAC tumors exhibit an intrinsic interferon response that has not been modeled by standard cell culture conditions. Using several advanced techniques, we found that interferon signaling causes the tumor cells to rely on a specific signaling pathway for survival. However, if we inhibit a protein called ATR, which plays an important role in this signaling pathway, we can cause catastrophic damage to the cancer cells’ DNA and induce programmed cell death,” said Evan Abt, a postdoctoral researcher in Dr. Radu’s lab and co-first author of the article with Thuc Le, adjunct assistant professor in Molecular and Medical Pharmacology, and Amanda Dann, MD, a resident in surgery at the UCLA David Geffen School of Medicine.
Results suggest that new small molecule drugs that inhibit ATR and are being studied for treatment of several cancers, including PDAC, could be used in combination with interferon “amplification” to thwart the tumor cells’ ability to escape.
A team led by University of California, Irvine researchers has developed a new biopsy technology that can profile multiple tumor microenvironment biomarkers simultaneously, revealing cellular spatial organization and interactions that will help advance personalized disease diagnosis and treatment. Current single-biomarker biopsies lack the ability to analyze many different markers and often fail to predict patient outcomes.
Called the multi-omic, single-scan assay with integrated combinatorial analysis, the fluorescence imaging-based technology can spatially profile a large number of mRNA and protein markers in cells and tissues, including clinical tumor tissues. A study published today in Nature Communications shows that MOSAICA enables direct, highly multiplexed biomarker profiling in a 3D spatial context using a single round of staining and imaging instead of the repeated processing steps typically needed in conventional methods.
Clinicians and scientists will now have a holistic view of the different immune and cancer cell types in tumor tissues, providing greater insight for determining patient prognosis and treatment.
"Spatial biology is a new science frontier and mapping out each cell and its function in the body at both the molecular and tissue level is fundamental to understanding disease and developing precision diagnostics and therapeutics," said Weian Zhao, Ph.D., UCI professor of pharmaceutical sciences and study co-corresponding author. "Many cancer immunotherapeutics, including immune checkpoint inhibitors, don't work and scientists realized that was because of the spatial organization of all the tumor tissue cell types, which dictates drug efficacy. The MOSAICA can characterize the spatial cellular compositions and interactions in the tumor immune microenvironment in biopsies to inform personalized diagnosis and treatment."
New treatment target identified for radiation-resistant cervical cancer https://phys.org/news/2022-01-treatment ... ancer.html
by Julia Evangelou Strait, Washington University in St. Louis Beatty / Washington University School of Medicine
Understanding how cells die is key to developing new treatments for many diseases, whether the goal is to make cancer cells die or keep healthy cells alive in the face of other illnesses, such as massive infections or strokes. Two new studies from Washington University School of Medicine in St. Louis have identified a previously unrecognized pathway of cell death—named lysoptosis—and demonstrate how it could lead to new therapies for cervical cancer.
Both studies, which together analyzed data in roundworms, mice and human cells, appear Jan. 12 in the Nature journal Communications Biology.
The blood of patients with cervical cancer and other tumor types is dotted with a protein called SERPINB3. According to the new research, when the gene that manufactures SERPINB3 is absent in cervical cancer cells, the tumor cells die more easily when exposed to the stress of radiation. Similarly, microscopic roundworms called C. elegans that are missing the equivalent gene die more easily when exposed to stresses in their environments.
"It's been known for a long time that high levels of this protein in the blood are a marker of cervical cancer and other squamous cell cancers—the higher the protein levels in the blood, the worse the prognosis," said Stephanie Markovina, MD, Ph.D., assistant professor of radiation oncology.
Researchers at Karolinska Institutet in Sweden have together with international collaborators completed a comprehensive international validation of artificial intelligence (AI) for diagnosing and grading prostate cancer. The study, published in Nature Medicine, shows that AI systems can identify and grade prostate cancer in tissue samples from different countries equally well as pathologists. The results suggest AI systems are ready to be responsibly introduced as a complementary tool in prostate cancer care, researchers say.
The international validation was performed via a competition called PANDA. The competition lasted for three months and challenged more than 1000 AI experts to develop systems for accurately grading prostate cancer.
Despite high remission rates for patients treated with T cells that are supercharged in laboratories into elite cancer warriors, there is still a considerable population of patients who eventually relapse, their cancers invariably coming back.
It is estimated that CAR T cell therapy—a breakthrough form of cancer immunotherapy—has a 30 percent to 40 percent rate of success for durable remission. That means a significant number of patients aren't quite as lucky. To improve the odds, medical scientists in laboratories worldwide are searching for ways to make CAR T cell cancer therapy work more effectively.
CAR T cells—chimeric antigen receptor T cells—start out as the patients' own T cells isolated from a blood sample, but the cells are primed in a laboratory using a genetic modification process that causes T cells to express a cancer-seeking-and-destroying receptor on their surface.
That special receptor is known as the chimeric antigen receptor, or CAR, engineered to bind to a specific target— the cancer's antigen—a molecular complex known as CD19. Cancer cell destruction can be swift—indeed, so much so that the therapy has been known to quickly force some cancers into remission. CAR T cell therapy is used in the treatment of certain cancers of the blood, primarily acute lymphoblastic leukemia, B-cell lymphoma, follicular lymphoma and multiple myeloma.
CAR T cells' population is expanded into a formidable army before being transfused into the patient. A lab grows millions of altered T cells before shipping them back to the patient's hospital. Once returned, the modified T cells are stronger, bolder and cancer-seeking. Bearing the chimeric antigen receptor allows these T cells to hunt down and destroy cancer cells. Because they seek and destroy malignant cells around the clock, some doctors have referred to CAR T cell therapy as "a living drug."
Computer engineers and radiologists at Duke University have developed an artificial intelligence platform to analyze potentially cancerous lesions in mammography scans to determine if a patient should receive an invasive biopsy. But unlike its many predecessors, this algorithm is interpretable, meaning it shows physicians exactly how it came to its conclusions.
The researchers trained the AI to locate and evaluate lesions just like an actual radiologist would be trained, rather than allowing it to freely develop its own procedures, giving it several advantages over its "black box" counterparts. It could make for a useful training platform to teach students how to read mammography images. It could also help physicians in sparsely populated regions around the world who do not regularly read mammography scans make better health care decisions.
The results appeared online December 15 in the journal Nature Machine Intelligence.
"If a computer is going to help make important medical decisions, physicians need to trust that the AI is basing its conclusions on something that makes sense," said Joseph Lo, professor of radiology at Duke. "We need algorithms that not only work, but explain themselves and show examples of what they're basing their conclusions on. That way, whether a physician agrees with the outcome or not, the AI is helping to make better decisions."
Engineering AI that reads medical images is a huge industry. Thousands of independent algorithms already exist, and the FDA has approved more than 100 of them for clinical use. Whether reading MRI, CT or mammogram scans, however, very few of them use validation datasets with more than 1000 images or contain demographic information. This dearth of information, coupled with the recent failures of several notable examples, has led many physicians to question the use of AI in high-stakes medical decisions.
A combination of two drugs that open the floodgates to an immune system attack on cancer curtailed tumor growth in some patients with non-small cell lung cancer (NSCLC) that was resistant to a single immunotherapy agent, results from a recent clinical trial show. The addition of radiation therapy to the two-drug regimen did not improve outcomes, however, researchers at Dana-Farber Brigham Cancer Center and other centers report in a new study.
The paper, published online today by The Lancet Oncology, is part of a broad-based effort to extend the benefits of drugs known as immune checkpoint inhibitors by combining them with other treatments and with one another. The new trial is one of the first to test radiation therapy in combination with immune therapy in patients with cancer. The fact that radiation therapy didn't enhance the effect of the two-drug therapy suggests that future studies should explore different combinations, the study authors say.
"Patients with NSCLC that doesn't respond to checkpoint inhibitors known as PD(L)-1 inhibitors have few treatment options. In this trial, we tested a PDL-1 inhibitor in combination with a drug that targets a different immune checkpoint protein, CTLA-4—an approach that has shown promise in laboratory research but hasn't been extensively tested in patients whose NSCLC is resistant to PD(L)-1 inhibitors," says study lead author Jonathan Schoenfeld, MD, MPH, of Dana-Farber Brigham Cancer Center.
"We not only found that the combination brought the cancer under control in some patients, but our laboratory work suggests a way of determining which patients are likely to have this benefit," he remarked.
Researchers from Indiana University School of Medicine are discovering new ways to find out how effective a drug might be against cancer. Their findings are detailed in a new paper published by Science Advances.
"This paper completely changes the way we need to collect tumor tissues and test for drug sensitivity," said Harikrishna Nakshatri, Ph.D., a senior author of the paper. Nakshatri is the Marian J. Morrison professor of breast cancer research at IU School of Medicine and a researcher with the Vera Bradley Foundation Center for Breast Cancer Research at the Indiana University Melvin and Bren Simon Comprehensive Cancer Center. Hal Broxmeyer, Ph.D., a distinguished professor at IU School of Medicine who passed away in December 2021, also contributed to this study.
Typically, tumors are collected and exposed to room oxygen, which is about 21 percent. However, different organs in the body have different oxygen levels. For example, the brain has 4.4 percent oxygen, blood 5.3 percent, and liver 5.4 percent. When cancer drugs are used on tumors in the clinical setting, they're still in a patient's body and are not exposed to ambient air.
"The oxygen level in our different parts of the body is almost half of what we find in ambient air," Nakshatri said. "Oxygen can have a different effect on the function of different proteins in the tumors. They may get activated, lose their activity level, get degraded or get stabilized. We wanted to test the tumors in a way that more closely resembles how they are in the body, so we know more about what drugs to use."
Researchers at the University of Sussex are one step further to developing a blood test capable of diagnosing the most aggressive form of brain tumor.
Professor Georgios Giamas and his team, in collaboration with Mr Giles Critchley, Consultant Neurosurgeon and Spinal Surgeon at University Hospitals Sussex, have identified distinctive biomarkers within patient blood samples, which could signal the presence of glioblastoma. The biomarkers (biological signatures for a disease) were identified within extracellular vesicles—small particles which all cells secrete which carry different information, such as DNA or proteins.
The ability to identify these biomarkers within the extracellular vesicles suggests that a liquid biopsy approach could be a viable option for glioblastoma diagnosis, providing both a quicker and less invasive alternative to current diagnostic methods.
More than 11,000 people are diagnosed with a primary brain tumor in the UK each year. Glioblastoma is the most common high grade primary brain tumor in adults, which means it can grow and spread exceptionally quickly. As a result, it's important for diagnosis to be quick, so patients can access treatment as soon as possible.
(The University of Texas MD Anderson Cancer Center and Eisbach Bio GmbH via EurekAlert) HOUSTON and MUNICH ― The University of Texas MD Anderson Cancer Center and Eisbach Bio GmbH today announced a strategic research collaboration to jointly discover and develop precision oncology drugs that target synthetic lethal engines key to tumor genome evolution.
The agreement aligns the drug discovery and development expertise of MD Anderson’s Therapeutics Discovery division with the innovative discovery platform and allosteric assay technology of Eisbach to generate medicines that selectively disrupt genome replication and DNA repair in cancers harboring defined genetic alterations.
“Modern genomics has revealed synthetic lethal targets in certain cancers with tumor suppressor gene mutations, and Eisbach has developed tools to pinpoint precisely where these targets are vulnerable at the molecular level,” said Adrian Schomburg, Ph.D., chief executive officer of Eisbach. “We are excited to collaborate with MD Anderson to develop innovative targeted therapies that exploit these unique vulnerabilities.”
Synthetic lethality is a phenomenon in which cancer cells with mutations in certain pathways are hypersensitive to drugs targeting related pathways. Notably, defects in certain DNA damage repair pathways – common to many cancer types – render cancer cells dependent on processes that reorganize the cancer genome.
“Cancers harboring mutations in tumor suppressor genes have been notoriously difficult to treat in the past,” said Timothy A. Yap, M.B.B.S., Ph.D., associate professor of Investigational Cancer Therapeutics and medical director of the Institute for Applied Cancer Science (IACS) at MD Anderson. “However, growing clinical evidence with PARP inhibitors demonstrates that targeting synthetic lethality is a promising strategy in certain cancer types, and we look forward to continued progress in this space.”
