Cell mechanism discovery could lead to ‘fundamental’ change in leukaemia treatment

Researchers have identified a new cell mechanism that could lead to a fundamental change in the diagnosis and treatment of leukaemia.

A team in the University of Kent’s pharmacy school conducted a study that discovered that leukaemia cells release a protein, known as galctin-9, that prevents a patient’s own immune system from killing cancerous blood cells.

Acute Myeloid Leukaemia (AML) — a type of blood cancer that affects over 250,000 people every year worldwide — progresses rapidly because its cells are capable of avoiding the patient’s immune surveillance. It does this by inactivating the body’s immune cells, cytotoxic T lymphocytes and natural killer (NK) cells.

Existing treatment strategies consist of aggressive chemotherapy and stem cell transplantation, which often do not result in effective remission of the disease. This is because of a lack of understanding of the molecular mechanisms that allow malignant cells to escape attack by the body’s immune cells.

Now the researchers at the Medway School of Pharmacy, led by Dr Vadim Sumbayev, Dr Bernhard Gibbs and Professor Yuri Ushkaryov, have found that leukaemia cells — but not healthy blood cells — express a receptor called latrophilin 1 (LPHN1). Stimulation of this receptor causes these cancer cells to release galectin-9, which then prevents the patient’s immune system from fighting the cancer cells.

The discovery of this cell mechanism paves the way for new ‘biomarkers’ for AML diagnosis, as well as potential targets for AML immune therapy, say the researchers.

‘Targeting this pathway will crucially enhance patients own immune defences, helping them to eliminate leukaemia cells’, said Dr Sumbayev. He added that the discovery has the potential to also be beneficial in the treatment of other cancers.

Demand for Diagnostic for Early Detection of Brain Injury After Surprising Study On NFL Players Brains And CTE

Chronic Traumatic Encephalopathy (CTE) is a slowly developing neurodegenerative condition typical of athletes involved in contact sports. This was evidenced in a recent study in which nearly every former NFL player whose brain was investigated had suffered from CTE.  The findings released this week were part of a study conducted by two leading medical institutions devoted to CTE research — the VA Boston Healthcare System and Boston University School of Medicine — and the results concluded that of 111 NFL players’ brains that were donated to science after the players’ deaths, 110 (99%) were found to have CTE. The disease currently can only be diagnosed post-mortem.

The study, published in the Journal of the American Medical Association, researchers looked at the brains of 202 deceased people who had played football at various levels, from high school to the NFL. (The brains had been donated to a brain bank at Boston University for further study.) The researchers analyzed the brains for signs of CTE and spoke to family members about the players’ histories.

Dr. Jesse Mez, an assistant professor of neurology at Boston University School of Medicine, one of the co-authors of the study, said that “the goal of doctors and scientists is to eventually be able to diagnose CTE among the living”. Dr. Mez said that the goal of doctors and scientists is to eventually diagnose CTE among the living, so that research and development of treatment methods can be expedited. “One of the important points is to develop bio-markers and figure out ways of differentiating this disease (CTE) from other neurodegenerative diseases, most certainly Alzheimer’s.” he adds.

Today, the analysis is made post-mortem (after death) from individuals who engaged to donate their brain for research. Medicortex Finland Oy, a biotechnology company in Finland, is developing a diagnostic tool for rapid sideline detection of brain injury.

This is exactly what Medicortex Finland Oy is aiming at. Medicortex is working towards the identification of a Traumatic Brain Injury (TBI) biomarker in body fluids and incorporating it into a quick and reliable diagnostic kit that can be easily used by sideline paramedics, first responders and healthcare professionals, and also by people with no medical profession. A rapid TBI test will furthermore help prioritize evacuation order in mass casualties and reframe from administration of contraindicated medications.

Recently Medicortex completed analyzing the results from the first clinical trial. The trial consisted of patients that were hospitalized due to a head injury. The clinical results confirmed the presence of a unique biomarker that will be further developed into a new diagnostic tool. Medicortex’s test utilizes easily accessible, non-invasive samples of body fluids. It is easy to understand the result of the test which enables straightforward confirmation or ruling-out of TBI without a need of a medical professional. Suspected athletes can be tested for TBI after a prominent hit to the head at sport arenas. The test can be performed by the coach of the team or by a First Aid group in charge.

Dr. Adrian Harel, Chief Executive Officer of Medicortex Finland, says that “Brain injury is a devastating condition leading to mortality if not diagnosed. We have the opportunity to develop the first portable non-invasive kit for head injury and concussion to help the patients and families that so desperately need it is remarkable.”

Medicortex Finland Oy (http://www.medicortex.fi) is an early clinical stage company dedicated to improving the diagnostics and treatment of Traumatic Brain Injury (TBI). Medicortex is currently developing biomarker diagnostics for rapid detection of TBI. The second goal will be to develop an innovative drug to halt the progression of brain injury. Medicortex was founded by and it is headed by a neurobiologist and entrepreneur Adrian Harel (PhD, MBA). The company operates in Turku, Finland.

New Therapeutic Approach for Difficult-to-Treat Subtype of Ovarian Cancer Identified

Scientists from The Wistar Institute demonstrate how a mutation in ovarian clear cell carcinoma can be exploited to design a targeted treatment.

A potential new therapeutic strategy for a difficult-to-treat form of ovarian cancer has been discovered by Wistar scientists. The findings were published online in Nature Cell Biology.

Ovarian clear cell carcinoma accounts for approximately 5 to 10 percent of American ovarian cancer cases and about 20 percent of cases in Asia, ranking second as the cause of death from ovarian cancer. People with the clear cell subtype typically do not respond well to platinum-based chemotherapy, leaving limited therapeutic options for these patients.

Previous studies, including those conducted at The Wistar Institute, have revealed the role of ARID1A, a chromatin remodeling protein, in this ovarian cancer subtype. When functioning normally, ARID1A regulates expression of certain genes by altering the structure of chromatin – the complex of DNA and proteins in which DNA is packaged in our cells. This process dictates some of our cells’ behaviors and prevents them from becoming cancerous.

“Conventional chemotherapy treatments have proven an ineffective means of treating this group of ovarian cancer patients, meaning that alternative strategies based on a person’s genetic makeup must be explored,” said Rugang Zhang, Ph.D., professor and co-program leader in Wistar’s Gene Expression and Regulation Program and corresponding author of the study. “Therapeutic approaches based on the ARID1A mutation have the potential to revolutionize the way we treat these patients.”

Recent studies have shown that ARID1A is mutated in more than 50 percent of cases of ovarian clear cell carcinoma. Mutations of ARID1A and the tumor suppressor gene TP53 are mutually exclusive, meaning that patients with a mutation of ARID1A do not also carry a mutation of TP53. Despite this, the function of TP53, which protects the integrity of our genome and promotes programmed cell death, is clearly impaired as patients with the disease still have a poor prognosis.

In this study, Zhang and colleagues studied the connection between ARID1A and histone deacetylases (HDACs), a group of enzymes involved in key biological functions. They found that HDAC6 activity is essential in ARID1A-mutated ovarian cancers. They were able to show that HDAC6 is typically inhibited by ARID1A, whereas in the presence of mutated ARID1A, HDAC6 levels increase. Because HDAC6 suppresses the activity of TP53, therefore inhibiting its tumor suppressive functions, higher level of HDAC6 allow the tumor to grow and spread.

Using a small molecule drug called rocilinostat that selectively inhibits HDAC6, the Zhang lab found that by blocking the activity of the enzyme in ARID1A-mutated cancers, they were able to increase apoptosis, or programmed cell death, in only those tumor cells containing the ARID1A mutation. This correlated with a significant reduction in tumor growth, suppression of peritoneal dissemination and extension of survival of animal models carrying ARID1A-mutated ovarian tumors.

“We demonstrated that targeting HDAC6 activity using a selective inhibitor like rocilinostat represents a possible therapeutic strategy for treating ovarian clear cell carcinoma and other tumors impacted by mutated ARID1A,” said Shuai Wu, Ph.D., a postdoctoral fellow in the Zhang lab and co-first author of the study. “Inhibitors like the one we used in this study have been well-tolerated in clinical trials, so our findings may have far-reaching applications.”

UC research examines lung cell turnover as risk factor & target for treatment of influenza pneumonia

Influenza is a recurring global health threat that, according to the World Health Organization, is responsible for as many as 500,000 deaths every year, most due to influenza pneumonia, or viral pneumonia. Infection with influenza most typically results in lung manifestations limited to dry cough and fever, and understanding how the transition to pneumonia occurs could shed light on interventions that reduce mortality. Research led by University of Cincinnati (UC) scientists takes a different approach to investigating how influenza spreads through the lungs by focusing on how resistant or susceptible cells lining the airway are to viral infection.

The work published today in the Proceedings of the National Academy of Sciences (PNAS) shows how stimuli that induce cell division in the lung promote spread of influenza from the airway to the gas exchanging units of the lung, known as the alveoli. The UC study also demonstrates that interventions that prevent alveolar cells from dividing reduce influenza mortality in animal models, suggesting a potential prophylactic and/or therapeutic strategy for influenza pneumonia.

“Almost all research into susceptibility or resistance to influenza focuses on host immune responses,” says Nikolaos Nikolaidis, PhD, research scientist in the Division of Pulmonary, Critical Care and Sleep Medicine in the Department of Internal Medicine at the UC College of Medicine and lead author on the paper. “Our approach was to examine factors that influence the vulnerability of alveolar cells to influenza infection, separate from how the immune system is dealing with the virus.”

“Less than 1 percent of alveolar cells are actively dividing at any given time in the healthy lung, rendering it naturally resistant to influenza infection,” says Frank McCormack, MD, Gordon and Helen Hughes Taylor Professor of Internal Medicine and director of the Division of Pulmonary, Critical Care and Sleep Medicine and senior author on the paper. “Recovery from lung injury due to supplemental oxygen therapy, cigarette smoke or scarring lung diseases is associated with expression of growth factors that result in multiplication of lung cells. Our work demonstrated that these mitogenically stimulated cells are rich targets for influenza infection while they are dividing.”

The researchers found that when sirolimus, which is FDA-approved for use as an anti-growth agent for the rare lung disease, lymphangioleiomyomatosis (LAM), was given to influenza-infected animal models, it prevented alveolar cells from dividing, and as a result, protected the mice from viral pneumonia and death.

“Although sirolimus also has off target immunosuppressive properties that could potentially pose added risks of side effects in virus-infected patients, trials of inhaled sirolimus could lead to approaches that do not entail systemic exposure,” says McCormack.

The McCormack lab expressed optimism that this observation has the potential to ultimately inform understanding of other unexplained risk factors for influenza, including very young age and pregnancy, and perhaps even to change medical management, such as more judicious use of supplemental oxygen in patients admitted with suspected viral pneumonia. Further, the team has hopes that the research could lead to a paradigm shift in the approach to therapy.

Nikolaidis says the next step in this research is to further explore why the multiplying alveolar epithelial cell is a better target for influenza. “Is it because the virus gets into the dividing cell more easily, because multiplying stimuli expand the pool of cellular machinery used by the virus to replicate, or because proliferation is associated with a reduction in innate cellular defenses? We are anxious to explore these and other potential mechanisms of viral susceptibility,” he adds.

Consortium Focused on Hemophilia A Patients, Announces Significant Progress in Development of ‘First in World’ Regenerative Medicine Therapy

Sernova Corp, an Ontario-based clinical stage regenerative medicine company, reported significant scientific progress achieved in the development of a ‘first in world’ personalized regenerative medicine therapy for the treatment of Hemophilia A patients by the HemAcure Consortium and confirmation of the second phase of funding of the Consortium by the European Commission.

The therapy being developed by international scientific Consortium members consisting of three European academic institutions, an enterprise for quality management and Sernova Corp is to treat severe Hemophilia A, a serious genetic bleeding disorder caused by missing or defective clotting factor VIII in the blood stream. This therapy consists of Sernova’s implanted Cell Pouch(TM) device transplanted with therapeutic cells, corrected to produce Factor VIII at a level sufficient to significantly reduce the side effects of the disease and improve patient quality of life.

HemAcure is the name of the consortium developing a product for hemophilia A. This project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No 667421. The consortium members include the University Hospital Wuerzburg (Coordinating Institute), Germany, IMS – Integrierte Management, Heppenheim, Germany, Università del Piemonte Orientale “Amedeo Avogadro,” Novara, Italy, Loughborough University, Loughborough, United Kingdom, ARTTIC International Management Services, Munich, Germany and Sernova Corp., London, Ontario, Canada.

The main objective of the HemAcure project is to develop and refine the tools and technologies for a novel ex vivo prepared cell based therapy within Sernova’s prevascularized Cell Pouch to treat this bleeding disorder that should ultimately lead to improved quality of life of the patients.

“We are thrilled with the approval by the European Union of the next stage of funding for the HemAcure program based on our quality interim report. This is a strong validation of the Consortium’s dedication and teamwork and the importance of this regenerative medicine approach,” said Dr. Joris Braspenning, HemAcure Program Coordinator.

 “The international HemAcure Consortium team members are pleased with the ground breaking scientific advances achieved at this point and are on track for this regenerative medicine solution to advance into human clinical evaluation,” remarked Dr. Philip Toleikis, Sernova President and CEO.  Toleikis added, “Sernova’s Cell Pouch platform technologies are achieving important world first milestones in both diabetes and now hemophilia, two significant clinical indications which are being disrupted by its regenerative medicine approach aimed at significantly improving patient quality of life.”

In summary, the following ground-breaking developments have been achieved by the Consortium:

  • A reliable procedure has been implemented to isolate and maintain required endothelial cells from a sample of the patient’s blood.
  • Using a novel gene correction process, the cells have been corrected and tuned to reliably produce the required Factor VIII to treat Hemophilia A.
  • The cells have been successfully scaled up to achieve the required therapeutic number, and cryopreserved for shipping and future transplant into the implanted Cell Pouch.
  • A preliminary study confirmed survival of the Factor VIII corrected human cells injected into the hemophilia model, achieving sustained therapeutic Factor VIII levels. This preliminary work is being used to aid in dosing of these cells in the Cell Pouch.
  • Safe Cell Pouch surgical implant and cell transplant procedures have been developed in the hemophilia A model in preparation for use in hemophilia patients.
  • Development of Cell Pouch vascularized tissue chambers suitable for Factor VIII producing cell transplant has been demonstrated in the hemophilia A model, expected to mimic the predicted findings in human patients.
  • In combination, this work is in preparation for safety and efficacy studies of the human hemophilia corrected Factor VIII producing cells in the Cell Pouch in a preclinical model of hemophilia.

This combination of advances by the HemAcure team represents a ‘first in world’ achievement towards developing a regenerative medicine therapy for the treatment of severe hemophilia A patients. “In this regard, these fundamental advancements have set the stage for further optimization and implementation of cell production processes under controlled GMP conditions,” stated Martin Zierau, IMS member consortium team leader responsible for coordination of GMP processes. With Factor VIII corrected cells, studies are ongoing to optimize cell dosing within the Cell Pouch and for study of safety and efficacy of hemophilia corrected Factor VIII cells in the hemophilia model. These studies are in support of the current extensive regulatory package already assembled for the Cell Pouch in anticipation of human clinical evaluation of the Cell Pouch with hemophilia corrected Factor VIII producing cells.

Sernova has developed its proprietary highly innovative Cell Pouch technologies for the placement and long-term survival and function of immune protected therapeutic cells. It has proven to be safe and efficacious in multiple small and large animal preclinical models and has demonstrated safety alone and with therapeutic cells in a clinical trial in humans for another therapeutic indication. We believe the Cell Pouch platform is the first such patented technology proven to become incorporated with blood vessel enriched tissue-forming tissue chambers without fibrosis for the placement and long-term survival and function of immune protected therapeutic cells.

People with Hemophilia have prolonged abnormal bleeding as a result of trauma. Hemophilia A, also called factor VIII (FVIII) deficiency is the most common form of Hemophilia and is a genetic disorder caused by missing or defective FVIII, a blood clotting protein. Severe hemophilia occurs in about 60% of cases where the deficiency of FVIII is less than 1% of normal blood concentration. While it is passed down from parents to children, about 1/3 of cases are caused by a spontaneous change in the gene. According to the US Centers for Disease Control and Prevention hemophilia occurs in about 1 in 5,000 births. If the prolonged bleeding occurs in the brain of a person with hemophilia, it can be fatal. Prolonged bleeding in joints can cause inflammatory responses and permanent joint damage. Approximately 20,000 people in the United States and 10,000 in Europe have the moderate or severe form of hemophilia A, as well as approximately 2,500 in Canada. All races and ethnic groups are equally affected by hemophilia A. Though there is no cure for the disease, it can be controlled with regular infusions of recombinant clotting FVIII. Annual costs for the treatment of the disease for each patient may range from $60,000 to $260,000 US for a total cost of between $2-5B per year in North America and Europe.

Horizon 2020 is the biggest EU Research and Innovation program ever with nearly €80 billion of funding available over seven years (2014 to 2020). It promises more breakthroughs, discoveries and world-firsts by taking great ideas from the lab to the market. The project is funded as part of societal challenges “personalizing health and care” in a specific call about innovative treatments and technologies. New therapies, such as gene or cell therapies, often require technological innovation in the form of development of specific component tools and techniques such as isolation and multiplication of a cell or development of a scaffold, delivery of the therapy to the patient and for following-up the effect of the therapy in the patient. In particular, achieving therapeutic scale production and GMP standards at reasonable cost is often underestimated. The European Union aims to improve the development of advanced methods and devices for targeted and controlled delivery, and to bring these innovative treatments to the patient.

Concurrent Chemotherapy, Proton Therapy Improves Survival in Patients with Advanced Lung Cancer

For patients with advanced, inoperable stage 3 lung cancer, concurrent chemotherapy and the specialized radiation treatment, proton therapy, offers improved survival compared to historical data for standard of care, according to a new study from The University of Texas MD Anderson Cancer Center.

The research, published in JAMA Oncology, reported an overall survival (OS) of 26.5 months. In contrast, the historical OS rate with standard of care concurrent chemotherapy and traditional radiation was 16 months at the time when the study was designed.

The findings are the final results of the single institution, Phase II study and represent the longest follow-up to date of stage 3 lung cancer patients who have received proton therapy, said Joe Y. Chang, M.D., professor, Radiation Oncology and the study’s corresponding author.

Lung cancer is the leading cause of cancer death in both men and women in the U.S. According to the American Cancer Society, more than 222,500 people will be diagnosed and 155,870 will die from the disease in 2017, with the majority of patients still being diagnosed when the disease is in an advanced stage.

“Advanced lung cancer patients with inoperable disease traditionally have been treated with concurrent chemotherapy and conventional photon radiation therapy. However, the therapy can be very difficult for patients due to associated toxicities and because many patients are also dealing with comorbidities,” explained Chang.

Proton therapy is an advanced type of radiation treatment that uses a beam of protons to deliver radiation directly to the tumor, destroying cancer cells while sparing healthy tissues. Protons enter the body with a low radiation dose and stop at the tumor, matching its shape and volume or depth. They deposit the bulk of their cancer-fighting energy right at the tumor, thereby reducing the dose to cardiopulmonary structures, which impacts the toxicity, functional status, quality of life and even survival for patients, explained Chang.

“With our study, we hypothesized that proton therapy would offer a survival benefit to patients and reduce treatment-associated toxicities, which can be very serious,” he said.

The study opened at MD Anderson in 2006; in this research, Chang and his colleague report on the study’s five-year results.

For the prospective Phase II trial, 64 patients with inoperable, Stage III non-small-cell lung cancer were enrolled. The study’s primary endpoint was OS. The researchers hypothesized that the median OS would increase from historical data of 16 months on standard therapy to 24 months. Secondary endpoints included distant metastasis and local and regional recurrence rates. Toxic effects of treatment in both the acute and late settings also were analyzed.

Median follow up was 27.3 months for all patients, and 79.6 months for alive patients. At five years, the median OS was 26.5 months, and the corresponding five-year OS was 29 percent. Median progression-free survival was 12.9 months, with a five-year progression-free survival of 22 percent.

In sum, 39 patients experienced a relapse, with distant sites representing 62 percent of all recurrences. Local and regional recurrence rates were low, 16 percent and 14 percent, respectively.

Among the acute and late toxic effects diagnosed in patients were: esophagitis, pneumonitis and cardiac arrhythmia. Of note, said Chang, no patients developed the most severe, or grade five, toxicities, as seen in patients who receive standard of care.

Chang noted his study is not without limitations. Of greatest significance: the study was designed more than a decade ago. While the study’s survival, recurrence rates and toxic effects are still favorable when compared to rates associated with the most advanced traditional photon radiation therapy, intensity modulated radiation therapy (IMRT), technology to diagnose and stage the disease, as well all treatment modalities have significantly improved.

“When the study opened, PET imaging had just been approved for lung cancer staging. The image quality was poor and didn’t include a CT component in most facilities across the country,” said Chang. “Obviously, the technology has improved dramatically over the last decade and has made a significant impact on diagnosis and staging. Also, delivery of both the conventional intensity-modulated radiation therapy (IMRT) and proton therapy (IMPT), have improved, thereby reducing side effects for both treatment modalities.”

For example, MD Anderson proton therapy patients with advanced lung cancer now can receive IMPT. The technique uses an intricate network of magnets to aim a narrow proton beam at a tumor and “paint” the radiation dose onto it layer by layer. Healthy tissue surrounding the tumor is spared, and side effects are even more reduced than earlier proton delivery, said Chang. A Phase II trial studying IMPT and concurrent chemotherapy is underway. Chang also noted the advancements in cancer biology and immunotherapy and that both are important areas of research focus in combination with proton therapy.

New combination of anti-obesity drugs may have beneficial effects

Research conducted in the Perelman School of Medicine at the University of Pennsylvania has revealed that a unique combination of hormone-based drugs can produce enhanced weight loss in laboratory tests with obese animals. The research is to be presented this week at the Annual Meeting of the Society for the Study of Ingestive Behavior (SSIB), the foremost society for research into all aspects of eating and drinking behavior.

“Imagine a drug regimen where an obese person would cycle between different drug therapies over the course of a month to achieve a greater degree of body weight loss compared to the effects achieved with either a single drug or the continuous combination of drugs,” said senior author Dr. Matthew Hayes. His team studied the combination of two different drug classes that target different hormones: amylin and glucagon-like peptide-1 (GLP-1). They found that combined treatments acted synergistically to suppress feeding and body weight. They also discovered that the weight loss effects of chronic amylin- and GLP-1-based combination therapies could be enhanced when obese lab animals are cycled through their drug treatments. “The idea of drug-cycling is nothing new,” says lead author Kieran Koch-Laskowski. “Millions of women on birth control pills, for example, already take daily pills that cycle between drug and placebo throughout the month,” she goes on to say.

Perhaps the most exciting finding of the current data coming out of Penn is the fact that the research finds these enhanced weight loss effects with a combination of drugs that are either already FDA approved or in clinical trials for metabolic diseases, “making the translational impact of our work extremely timely and highly clinically relevant!” says Hayes. The authors are now finalizing their research to demonstrate mechanically how these two hormonal systems interact to achieve greater weight loss in the hopes of fast-tracking their findings to new clinical treatments for obesity.

Identification of PTPRZ as a drug target for cancer stem cells in glioblastoma

Glioblastoma is the most malignant brain tumor with high mortality. Cancer stem cells are thought to be crucial for tumor initiation and its recurrence after standard therapy with radiation and temozolomide (TMZ) chemotherapy. Protein tyrosine phosphatase receptor type Z (PTPRZ) is an enzyme that is highly expressed in glioblastoma, especially in cancer stem cells.

The research group of Professor Masaharu Noda and Researcher Akihiro Fujikawa of the National Institute for Basic Biology (NIBB) showed that the enzymatic activity of PTPRZ is requisite for the maintenance of stem cell properties and tumorigenicity in glioblastoma cells. PTPRZ knockdown strongly inhibited tumor growth of C6 glioblastoma cells in a mouse xenograft model. In addition, the research team discovered NAZ2329, an allosteric inhibitor of PTPRZ, in collaboration with ASUBIO Pharma Co. Ltd.. NAZ2329 efficiently suppressed stem cell-like properties of glioblastoma cells in culture, and tumor growth in C6 glioblastoma xenografts. These results indicate that pharmacological inhibition of PTPRZ is a promising strategy for the treatment of malignant gliomas.

CAR T-Cell Therapy for Leukemia Leads to Remissions in Clinical Trial

In an early-phase clinical trial of an experimental immunotherapy, researchers achieved durable molecular remissions in patients with chronic lymphocytic leukemia who had failed other treatments

Researchers at Fred Hutchinson Cancer Research Center showed about 70 percent of patients with the most common adult leukemia had their tumors shrink or disappear following an experimental chimeric antigen receptor (CAR) T-cell immunotherapy.

The researchers also found that measuring genetic traces of cancer cells taken from bone marrow biopsies might be a better indicator of prognosis than the standard lymph node scan.

The Journal of Clinical Oncology published the results online July 17 of the Phase 1/2 clinical trial, which included 24 patients with chronic lymphocytic leukemia (CLL) who had failed other treatments. Most of the patients had seen their cancer progress despite treatment with ibrutinib, a targeted cancer drug approved in 2014 for CLL by the U.S. Food and Drug Administration.

This history placed them in a high-risk group that was found in previous studies to have short survival with standard therapies.

“It was not known whether CAR T-cells could be used to treat these high risk CLL patients,” said lead author Dr. Cameron Turtle, an immunotherapy researcher at Fred Hutch. “Our study shows that CD19 CAR T-cells are a highly promising treatment for CLL patients who have failed ibrutinib.”

CD19 CAR T-cells are a type of immunotherapy in which a patient’s T cells are extracted from their blood and modified in a lab to recognize CD19, a target on the surface of leukemia cells. The engineered T cells are then infused back into the patient where they multiply and hunt down and kill cancer cells.

In CLL, bone marrow makes too many abnormal lymphocytes, which are a type of white blood cell. The American Cancer Society estimates that in the U.S., there will be about 20,000 new cases and 4,600 deaths from CLL in 2017. Tests of blood, bone marrow and lymph nodes—where lymphocytes congregate to fight infection—reveal the disease.

The 24 patients participating in the study ranged in age from 40 to 73 years, with a median age of 61. They had received a median of five other therapies with as few as three and as many as nine.

Researchers found that 17 out of 24 (71 percent) of patients saw their tumors shrink or disappear following CAR T-cell therapy using the standard measure of lymph node size by CT scans four weeks after treatment.

Of side effects of CAR-T cell therapy, 20 of the 24 patients—83 percent—experienced cytokine release syndrome (grade 1-2, 18 patients; grade 4, one patient; grade 5, one patient) and 8 patients (33 percent) developed neurotoxicity (grade 3, five patients; grade 5, one patient). For the most part the side effects were reversible, but two patients had side effects severe enough to require being admitted to the intensive care unit and one of those patients died.

 (An earlier report on trial results was presented by Turtle in December at the American Society of Hematology annual meeting.)

The new paper expands on the measures used to indicate whether the CAR T-cell treatment is working.

To take a closer look to see if any cancer cells remained after treatment, the research team analyzed samples taken from some of the patients’ bone marrow four weeks after the CAR T-cell infusion. The team used a genetic test called IGH deep sequencing, which is akin to a bar code and enables researchers to track cancer cells in the body.

Turtle and his collaborators did the sequencing analysis in 12 of the patients. Seven of the 12 patients had no malignant copies. All patients without malignant copies were alive and free of disease at a median follow-up of 6.6 months after CAR T-cell infusion.

Compared with the CT scans, having no malignant gene sequences in bone marrow following CAR T-cell therapy was a better predictor of the cancer staying at bay—known as “progression-free survival,” the researchers found.

The study is the first to suggest that deep sequencing might be a superior measure for predicting outcomes four weeks after CAR T-cell therapy for CLL.

The immunotherapy team at Fred Hutch is still enrolling eligible patients with CLL, acute lymphoblastic leukemia and non-Hodgkin lymphoma for treatment on CD19 CAR T-cell trials. The patients are seen at Seattle Cancer Care Alliance, the clinical care partner for Fred Hutch.

Fred Hutch co-authors of the paper are Kevin Hay, Laila-Aicha Hanafi, Shelly Heimfeld, Stanley R. Riddell and David G. Maloney. Other co-authors are Daniel Li, Juno Therapeutics; Sindhu Cherian, Xueyan Chen and Brent Wood, University of Washington; and Arletta Lozanski and John C. Byrd, The Ohio State University.

Funding for the project came from Juno Therapeutics, National Cancer Institute, National Institute of Diabetes and Digestive and Kidney Diseases, Life Science Discovery Fund, the Bezos family, and the University of British Columbia.

Turtle, Maloney and Riddell receive research funding from Juno Therapeutics and are named as inventors on one or more patents or patent applications related to this work. Riddell is a co-founder of Juno Therapeutics and has equity interest in Juno Therapeutics. Li is an employee of and has equity interests in Juno Therapeutics. Fred Hutch receives research funding from Juno Therapeutics.

Radiation Therapy Prior to Surgery Reduces the Risk of Secondary Tumors in Early-Stage Breast Cancer Patients

Breast cancer patients receiving neoadjuvant radiation therapy have improved cancer-free survival over adjuvant radiation

Moffitt Cancer Center researchers launched a first of its kind study comparing the long-term benefits of radiation therapy in women with breast cancer either before surgery (neoadjuvant) or after surgery (adjuvant). Their study, published in the June 30 issue of Breast Cancer Research, found that patients who have neoadjuvant radiation therapy have a significantly lower risk of developing a second primary tumor at any site.

The majority of patients who have early stage breast cancer have surgery to remove their tumor or a complete mastectomy. Surgery is commonly followed by radiation therapy, which has been shown to increase relapse-free survival. However, in some cases, patients may require neoadjuvant radiation therapy to decrease the size of the tumor before surgery.  Currently, there are no studies that have analyzed the long-term effects of neoadjuvant radiation therapy on breast cancer patients.

Moffitt researchers compared the overall survival and the time to diagnosis of a second tumor, if any, of 250,195 breast cancer patients who received either neoadjuvant or adjuvant radiation therapy. They analyzed patient outcomes from a National Cancer Institute (NCI) registry database of cancer incidence and survival rates in the United States.  They included female patients in the analysis who were diagnosed between 1973 and 2011 with early-stage breast cancer. The analysis included 2,554 women who received localized neoadjuvant breast radiation therapy before surgery and 247,641 women who received localized adjuvant breast radiation therapy after surgery.

The researchers discovered that among the breast cancer patients who tested positive for the estrogen receptor (ER) biomarker, patients who had neoadjuvant radiation therapy had a significantly lower risk of developing a second primary tumor than patients who had adjuvant radiation therapy. This was true for patients who underwent both partial and complete mastectomies.  The researchers found that delaying surgery due to neoadjuvant radiation therapy was not a detriment to survival.

A number of recent studies have suggested that radiation therapy may re-educate and stimulate the immune system to target cancer cells. “The observed benefit of neoadjuvant radiation therapy aligns with the growing body of literature of the immune activation effects of radiation, including shrinking of untreated metastases outside the radiation field,” explained Heiko Enderling, Ph.D., associate member of Moffitt’s Integrated Mathematical Oncology Department.

T-cells lacking HDAC11 enzyme perform more effectively in destroying cancer cells

Researchers at the George Washington University (GW) Cancer Center have discovered a new role for the enzyme, histone deacetylase 11 (HDAC11), in the regulation of T-cell function.

T-cells can infiltrate tumors with the purpose of attacking the cancer cells. However, prior studies have found that the T-cells group around the tumor, but do not perform the job that they are meant to.

“The goal of the T-cell is to destroy the cancer tumor cells,” Eduardo M. Sotomayor, MD, director of the GW Cancer Center and senior author of the study, explained. “We wanted to look at and understand the mechanisms that allowed crosstalk between the tumor and the T-cells that stopped the T-cells from doing their job.”

The recent research, published in the journal Blood, centered on the discovery of “epigenetic checkpoints” in T-cell function in an effort to explain how and why these cells are modified to behave differently. The study found that when HDAC11 was removed the T-cells, they were more primed to attack the tumor.

More importantly, this research highlights that HDAC11, which was the last of 11 HDAC to be discovered, should be treated as an immunotherapeutic target.

While the study focused on the T-cells around a lymphoma tumor, this research is pertinent to all types of cancer. The goal for the team was to find a way to activate the T-cells so that they could destroy the tumor. However, the process of cell activation does need to be refined and handled carefully.

“We don’t want T-cells to be easily activated, as they can cause harm to the host — the patient. So we want to look at possible methods and therapies to activate the T-cells when they need to work,” said Sotomayor.

“The next step is to perform preclinical studies with specific inhibitors of HDAC11 alone and in tandem with other existing immunotherapies, such as anti-PD1/anti-PDL1 antibodies, in order to find the most potent combination. Our goal is to make the T-cells better at destroying cancer tumors.”

This study represents a step forward in understanding the underlying mechanisms of T-cell function and epigenetic regulation of the HDAC11 enzyme.

Largest study of malaria gene function reveals many potential drug targets

The malaria parasite’s success is owed to the stripping down of its genome to the bare essential genes, scientists at the Wellcome Trust Sanger Institute and their collaborators have found. In the first ever large-scale study of malaria gene function, scientists analysed more than half of the genes in the parasite’s genome and found that two thirds of these genes were essential for survival — the largest proportion of essential genes found in any organism studied to date.

The results, published today (13 July) in Cell, identify many potential targets for new antimalarial drug development, which is an important finding for this poorly understood parasite where drug resistance is a significant problem.

Nearly half of the world’s population is at risk of malaria and more than 200 million people are infected each year. The disease caused the deaths of almost half a million people globally in 2015*.

The genetics of the parasite that causes malaria, Plasmodium, have been tricky to decipher. Plasmodium parasites are ancient organisms and around half their genes have no similar genes — homologs — in any other organism, making it difficult for scientists to find clues to their function. This study provides the first ever experimental evidence of function for most of the genes.

Scientists studied the genes in one species of malaria, Plasmodium berghei, which were expressed in a single blood stage of its complicated, multi-stage life cycle. In the study, scientists designed a new method to decipher the function of the malaria parasite’s genes. The team switched off, or knocked out, 2,578 genes — more than half of the genome — and gave each knockout a unique DNA barcode**.

The team then used next generation genome sequencing technology to count those barcodes, and hence measure the growth of each genetically modified malaria parasite. If the switched-off gene was not essential, the parasite numbers shot up, but if the knocked out gene was essential, the parasite disappeared.

Dr Oliver Billker, joint lead author from the Wellcome Trust Sanger Institute, said: “This work was made possible by a new method that enabled us to investigate more than 2,500 genes in a single study — more than the entire research community has studied over the past two decades. We believe that this method can be used to build a deep understanding of many unknown aspects of malaria biology, and radically speed up our understanding of gene function and prioritisation of drug targets.”

The team systematically showed that the malaria parasite can easily dispose of the genes which produce proteins that give away its presence to the host’s immune system. This poses problems for the development of malaria vaccines as the parasite can quickly alter its appearance to the human immune system, and as a result the parasite can build resistance to the vaccine.

Dr Julian Rayner, joint lead author from the Wellcome Trust Sanger Institute, said: “We knew from previous work that on its surface the malaria parasite has many dispensable parts. Our study found that below the surface the parasite is more of a Formula 1 race car than a clunky people carrier. The parasite is fine-tuned and retains the absolute essential genes needed for growth. This is both good and bad: the bad news is it can easily get rid of the genes behind the targets we are trying to design vaccines for, but the flip side is there are many more essential gene targets for new drugs than we previously thought.”

Dr Francisco Javier Gamo, Director of the Malaria Unit at GlaxoSmithKline, said: “This study of unprecedented scale has resulted in many more, unique drug targets for malaria. The Holy Grail would be to discover genes that are essential across all of the parasite lifecycle stages, and if we could target those with drugs it would leave malaria with nowhere to hide. The technology that the Sanger Institute has developed gives us the potential to ask those questions systematically for the first time.”

Genetically enhanced, cord-blood derived immune cells strike B-cell cancers

Immune cells with a general knack for recognizing and killing many types of infected or abnormal cells also can be engineered to hunt down cells with specific targets on them to treat cancer, researchers at The University of Texas MD Anderson Cancer Center report in the journal Leukemia.

The team’s preclinical research shows that natural killer cells derived from donated umbilical cords can be modified to seek and destroy some types of leukemia and lymphoma. Genetic engineering also boosts their persistence and embeds a suicide gene that allows the modified cells to be shut down if they cause a severe inflammatory response.

A first-in-human phase I/II clinical trial of these cord-blood-derived, chimeric antigen receptor-equipped natural killer cells opened at MD Anderson in June for patients with relapsed or resistant chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL), or non-Hodgkin lymphoma. All are cancers of the B cells, another white blood cell involved in immune response.

“Natural killer cells are the immune system’s most potent killers, but they are short-lived and cancers manage to evade a patient’s own NK cells to progress,” said Katy Rezvani, M.D., Ph.D., professor of Stem Cell Transplantation and Cellular Therapy.

“Our cord-blood derived NK cells, genetically equipped with a receptor that focuses them on B-cell malignancies and with interleukin-15 to help them persist longer — potentially for months instead of two or three weeks — are designed to address these challenges,” Rezvani said.

Moon Shots Program funds project

The clinical trial is funded by MD Anderson’s Moon Shots Program™, designed to more rapidly develop life-saving advances based on scientific discoveries.

The chimeric antigen receptor (CAR), so-called because it’s added to the cells, targets CD19, a surface protein found on B cells.

In cell lines and mouse models of lymphoma and CLL, CD19-targeted NK cells killed cancer cells and extended survival of animals compared to simply giving NK cells alone. Addition of IL-15 to the CD19 receptor was crucial for the longer persistence and enhanced activity of the NK cells against tumor cells.

NK cells are a different breed of killer from their more famous immune system cousins, the T cells. Both are white blood cells, but T cells are highly specialized hunters that look for invaders or abnormal cells that bear a specific antigen target, kill them and then remember the antigen target forever.

Natural killers have an array of inhibitory and activating receptors that work together to allow them to detect a wider variety of infected, stressed or abnormal cells.

“By adding the CD19 CAR, we’re also turning them into guided missiles,” said Elizabeth Shpall, M.D., professor of Stem Cell Transplantation and Cell Therapy.

Using a viral vector, the researchers transduce NK cells taken from cord blood with the CD19 CAR, the IL-15 gene, and an inducible caspase-9-based suicide gene.

Cell line tests found the engineered NK cells to be more efficient killers of lymphoma and CLL cells, compared to unmodified NK cells, indicating the engineered cells’ killing was not related to non-specific natural killer cell cytotoxicity.

Another experiment showed the engineered cord blood NK cells killed CLL cells much more efficiently than NK cells taken from CLL patients and engineered, highlighting the need to transplant CAR-engineered NK cells from healthy cord blood rather than use a patient’s own cells.

Suicide gene to counter cytokine release syndrome

Mouse model lymphoma experiments using a single infusion of low dose NK cells resulted in prolongation of survival. At a higher, double dose, none of the mice treated with the CD19/IL-15 NK cells died of lymphoma, with half surviving for 100 days and beyond. All mice treated with other types of NK cells died by day 41.

A proportion of mice treated with the higher dose of engineered NK cells died of cytokine release syndrome, a severe inflammatory response that also occurs in people treated with CAR T cells.

To counteract this toxicity, the researchers incorporated a suicide gene (iC9) that can be activated to kill the NK cells by treatment with a small-molecule dimerizer. This combination worked to swiftly reduce the engineered NK cells in the mouse model.

Subsequent safety experiments were conducted in preparation for the clinical trial. Rezvani, the principal investigator of the clinical trial, says the protocol calls for vigilance for signs of cytokine release syndrome, treatment with steroids and tocilizumab for low-grade CRS with AP1903 added to activate the suicide gene for grade 3 or 4 CRS.

NK CARs available off the shelf

T cells modified with chimeric antigen receptors against CD19 have shown efficacy in clinical trials. In these therapies, a patient’s own T cells are modified, expanded, and given back to the patient, a process that takes weeks. Finding a matched donor for T cells would be a challenge, but would be necessary because unmatched T cells could attack the recipient’s normal tissue – graft vs. host disease.

Rezvani and Shpall have given patients cord-blood derived NK cells in a variety of clinical trials and found that they do not cause graft vs. host disease, therefore don’t have to be matched. NK cells can be an off-the-shelf product, prepared in advance with the necessary receptor and given promptly to patients.

“CAR NK cells are scalable in a way that CAR T cells are not,” Rezvani noted.

A strength of T cells is the development of memory cells that persist and repeatedly attack cells bearing the specific antigen that return. NK cells do not seem to have a memory function, but Rezvani says the experience of the longer-lived mice, which are now more than a year old, raises the possibility that a prolonged NK cell attack will suffice.

Shpall, Rezvani and colleagues are developing cord blood NK CARs for other targets in a variety of blood cancers and solid tumors.

MD Anderson and the researchers have intellectual property related to the engineered NK cells, which is being managed in accordance with the institution’s conflict-of-interest rules.

Shpall founded and directs MD Anderson’s Cord Blood Bank, originally established to provide umbilical cord blood stem cells for patients who need them but cannot get a precise donor match. Donated by mothers who deliver babies at seven Houston hospitals and two others from California and Michigan, the bank now has 26,000 cords stored. MD Anderson researchers pioneered the extraction and expansion of NK cells from umbilical cords.

Tumor-Targeting Drug Shows Potential for Treating Bone Cancer Patients

Preclinical study shows BMTP-11 targets high-risk osteosarcoma

The treatment of osteosarcoma, the most common tumor of bone, is challenging. A study led by The University of Texas MD Anderson Cancer Center found a drug known as bone metastasis-targeting peptidomimetic (BMTP-11) has potential as a new therapeutic strategy for this devastating illness.

Results from the preclinical study, which looked at BMTP-11 alone and in combination with the chemotherapy agent gemcitabine, were published in the July 11, 2017, online issue of Proceedings of the National Academy of Sciences.

Although osteosarcoma is a relatively rare cancer, it is a leading disease-related cause of death in children and young adults ages 10 to 20. However, over the last 25 years, the five-year survival rate has remained unchanged, and the treatment options for these patients are few. In addition, the side effects of available treatment options often are significant and cumulative, and may cause other health problems and damage to major organs.

“What’s novel about this treatment is that BMTP -11 targets the tumor and spares other organs,” said Valerae O. Lewis, M.D., chair of Orthopaedic Oncology at MD Anderson. “We believe this study lays the groundwork for a clinical trial for the treatment of osteosarcoma without the cumulative and mortal side effects seen with the current treatment options.”

The study results identified IL-11Rα as an osteosarcoma cell surface receptor that correlated with tumor progression and poor prognosis in osteosarcoma patients. The team, which included co-authors Renata Pasqualini, Ph.D., and Wadih Arap, M.D., Ph.D., both of whom worked on the study while at MD Anderson and are now professors at the University of New Mexico Health Sciences Center (UNMSC) School of Medicine, also illustrated that IL-11Rα and IL-11 are up-regulated in human metastatic osteosarcoma cell lines, and this correlated with the development of lung metastases in mouse models of the disease. The metastatic potential of the osteosarcoma cell lines could be modulated by targeting IL-11Rα expression. Death from respiratory failure linked to metastasis to the lungs remains a significant problem among osteosarcoma patients.

“We were able to document anti-tumor activity against osteosarcoma models,” said Pasqualini. “Given that a first-in-human trial of BMTP-11 has recently been reported, one would hope that this proof-of-concept study might lead to early translational clinical trials in human osteosarcoma as a logical next step in the context of an unmet medical oncology need.”

Arap added that “this work provides a preclinical foundation for the potential design and development of a second line combination therapy regimen composed of conventional chemotherapeutics plus the targeted candidate drug BMTP-11 for application in unfortunate patients with recalcitrant osteosarcoma.”

Blood Test for Early Detection of Pancreatic Cancer Headed to Clinic

A newly identified biomarker panel could pave the way to earlier detection and better treatment for pancreatic cancer, according to new research from the Perelman School of Medicine at University of Pennsylvania. Currently over 53,000 people in the United States are diagnosed with pancreatic cancer — the fourth leading cause of cancer death — every year. The blood biomarkers, detailed today in Science Translational Medicine, correctly detected pancreatic cancer in blood samples from patients at different stages of their disease.

The majority of pancreatic cancer patients are not diagnosed until an advanced stage, beyond the point at which their tumors can be surgically removed.

A team led by Ken Zaret, PhD, director of the Penn Institute for Regenerative Medicine and the Joseph Leidy Professor of Cell and Developmental Biology, and Gloria Petersen, PhD, from the Mayo Clinic, identified a pair of biomarkers that physicians could soon use to discover the disease earlier.

“Starting with our cell model that mimics human pancreatic cancer progression, we identified released proteins, then tested and validated a subset of these proteins as potential plasma biomarkers of this cancer,” Zaret said. The authors anticipate that health care providers will use the early-detection biomarkers to test for their presence and levels in blood from pancreatic cancer patients and blood drawn from individuals with a high risk of developing pancreatic cancer, including those who have a first-degree relative with pancreatic cancer, are genetically predisposed to the disease, or who had a sudden onset of diabetes after the age of 50.

“Early detection of cancer has had a critical influence on lessening the impact of many types of cancer, including breast, colon, and cervical cancer. A long standing concern has been that patients with pancreatic cancer are often not diagnosed until it is too late for the best chance at effective treatment,” said Robert Vonderheide, MD, DPhil, director of the Abramson Cancer Center (ACC) at the University of Pennsylvania. “Having a biomarker test for this disease could dramatically alter the outlook for these patients.”

The biomarker panel, enabled by discovery work of first author Jungsun Kim, PhD, a postdoctoral fellow in Zaret’s lab, builds on a first-of-its-kind human-cell model of pancreatic cancer progression the lab described in 2013. They used stem-cell technology to create a cell line from a patient with advanced pancreatic ductal adenocarcinoma. Genetically reprogramming late-stage human cancer cells to a stem-cell state enabled them to force the reprogrammed cells to progress to an early cancerous state, revealing secreted blood biomarkers of early-stage disease along the way.

The best candidate biomarker, plasma thrombospondin-2 (THBS2), was screened against 746 cancer and control plasma samples using an inexpensive, commercially available protein-detection assay. The team found that blood levels of THBS2, combined with levels of a known later-stage biomarker called CA19-9, was reliable at detecting the presence of pancreatic cancer in patients.

The team refined the assay with independent investigations of plasma samples from patients with different stages of cancer, from individuals with benign pancreatic disease, and from healthy controls, all obtained from Petersen, who directs the biospecimen resource program for pancreas research at the Mayo Clinic.

“Positive results for THBS2 or CA19-9 concentrations in the blood consistently and correctly identified all stages of the cancer,” Zaret said. “Notably, THBS2 concentrations combined with CA19-9 identified early stages better than any other known method.” The combination panel also improved the ability to distinguish cases of cancer from pancreatitis. The panel will next be validated in a set of samples from pancreatic cancer patients who provided a research blood sample prior to their diagnosis.

Breathing in a New Gene Therapy to Treat Pulmonary Hypertension

Mount Sinai has partnered with Theragene Pharmaceuticals, Inc. to advance a novel airway-delivered gene therapy for treating pulmonary hypertension (PH), a form of high blood pressure in blood vessels in the lungs that is linked to heart failure. If the therapy succeeds in human clinical trials, it will provide patients for the first time with a way to reverse the damage caused by PH.

This gene therapy technique comes from the research of Roger J. Hajjar, MD, Professor of Medicine and Director of the Cardiovascular Research Center at the Icahn School of Medicine at Mount Sinai, and has been proven effective in rodent and pig animal models. PH is a deadly disease that disproportionately affects young adults and women; 58 percent of cases are found in young adults and 72 percent are women. There is currently no effective cure for PH, and about 50 percent of people who are diagnosed will die from the disease within five years.

PH is a rare (15-50 cases per million people), rapidly progressing disease that occurs when blood pressure is too high in vessels leading from the heart to the lungs. The high pressure is caused by abnormal remodeling of the lung blood vessels, characterized by a proliferation of smooth muscle cells and a thickening and narrowing of these vessels, and can lead to failure of the right ventricle of the heart and premature death. Abnormalities in calcium cycling within the vascular cells play a key role in the pathophysiology of pulmonary hypertension, along with deficiencies in the sarcoplasmic reticulum calcium ATPase pump (SERCA2a) protein which regulates intracellular calcium within these vascular cells and prevents them from proliferating within the vessel wall. Downregulation of SERCA2a leads to the proliferative remodeling of the vasculature. This gene therapy, delivered via an inhaled aerosolized spray, aims to increase the expression of SERCA2a protein, and has been shown in rodents and pigs to improve heart and lung function, as well as reduce and even reverse cellular changes caused by PH.

Targeting ‘broken’ metabolism in immune cells reduces inflammatory disease

The team, led by researchers at Imperial College London, Queen Mary University of London and Ergon Pharmaceuticals, believes the approach could offer new hope in the treatment of inflammatory conditions like arthritis, autoimmune diseases and sepsis.

In a study published this week in the journal Nature Communications, they explain how blocking a single enzyme enabled them to reprogram macrophages – the immune cells which are activated in inflammatory conditions – to calm their activity and reduce inflammation in rats and mice with human-like disease.

At the heart of the research is the Krebs cycle, a complex loop of reactions which cells use to feed on sugar and generate molecules of ATP, the universal energy currency for cells.

In recent years, research has shown that the usual pathway is interrupted in immune cells such as macrophages, leading to a broken Krebs cycle.

“In immune cells that have to fight invaders, the metabolism is diverted from its usual cycle to make compounds that fight microbes,” explained Dr Jacques Behmoaras, from the Department of Medicine at Imperial, who led the research.

Dr Behmoaras added: “What we have found is that there’s an enzyme involved in this diversion of the usual cycle, which make immune cells produce these bacteria-killing compounds. If you block that enzyme, you block that specific branch of their metabolism, and make the cells cause less damage during inflammation.”

Using human macrophages, the researchers found that an enzyme called BCAT1 was pivotal in reprogramming macrophages. When the cells were activated – by exposing them to molecules found on the surface of bacteria – BCAT1 interfered with their usual metabolic pathways, and regulated another enzyme, responsible for producing bacteria-killing chemicals.

They used an experimental compound called ERG240, developed by Ergon Pharmaceuticals, a small biotech company based in the US. ERG240 resembles the amino acid leucine, one of the building blocks of proteins, which is linked together by BCAT1. By flooding the cells with ERG240 they were able to jam up BCAT1 and block its action, so stopping the metabolism being diverted and ‘fixing’ the broken Krebs cycle. What’s more, the compound was shown to work in animal models of inflammation, without toxic side effects.

The team found that when ERG240 was given to mice with symptoms of rheumatoid arthritis, it reduced the inflammation in their joints by more than half while protecting the integrity of their joints. Similarly, in a rat model of severe kidney inflammation, they found that ERG240 improved kidney function by reducing the number of macrophages flooding into the affected tissue to cause inflammation.

Dr Behmoaras states that although the research is still at an early stage, there is potential for treating inflammatory conditions in patients by targeting the metabolic activity in immune cells. The team believes that BCAT1 works together with other key enzymes of the Krebs cycle, which could themselves provide targets for therapy.

However, one of the key challenges in developing a therapy would be in finding the balancing point: calming the immune cells enough such that they reduce inflammation, but enabling them to react to microbial invaders.

“I think this ability to regulate metabolism in cells could have an effect on many human diseases,” said Dr Behmoaras. “Manipulating cell activity in inflammatory diseases where macrophages have a role, could have important therapeutic benefits.

“Our next step is to understand how other enzymes in the cycle are involved, to see if there is any possibility to block them and have similar effects. Understanding the complex metabolic circuits of these immune cells is a huge task. We will need to tackle this before we can manipulate cell activity and influence disease.

“This is a growing field of research with exciting discoveries ahead.”

How dragon blood could save your life (video)

Chemists have found potential drugs and other really useful compounds in some truly bizarre places in nature. For example, a natural immune defense in the blood of komodo dragons, a sponge armed with resistance to bacterial infection or a 400-million-year-old medical workhorse just might save your life someday.

The American Chemical Society, the world’s largest scientific society, is a not-for-profit organization chartered by the U.S. Congress. ACS is a global leader in providing access to chemistry-related information and research through its multiple databases, peer-reviewed journals and scientific conferences. ACS does not conduct research, but publishes and publicizes peer-reviewed scientific studies. Its main offices are in Washington, D.C., and Columbus, Ohio.

Childhood obesity major link to hip diseases

New research from the University of Liverpool, published in the Archives of Disease in Childhood journal, shows a strong link between childhood obesity and hip diseases in childhood.

Significant hip deformities affect around 1 in 500 children. Slipped Capital Femoral Epiphysis (SCFE) is the most common hip disease of adolescence. The condition always requires surgery, can cause significant pain, and often leads to a hip replacement in adolescence or early adulthood.

Children with a SCFE experience a decrease in their range of motion, and are often unable to complete hip flexion or fully rotate the hip inward. Unfortunately many cases of SCFE are misdiagnosed or overlooked, because the first symptom is knee pain, referred from the hip. The knee is often investigated and found to be normal. Early recognition of SCFE is important as the deformity may worsen if the slip remains untreated.

Factors explored

In an effort to identify children at higher risk of this condition researchers from the University’s Institute of Translational Medicine, led by National Institute of Health Research (NIHR) Clinician Scientist and Senior Lecturer in Orthopaedic Surgery Daniel Perry, examined hospital and community based records to explore factors associated with SCFE, and explanations for diagnostic delays.

All of the records examined were of individuals under 16-years-of-age with a diagnosis of SCFE and whose electronic medical record was held by one of 650 primary care practices in the UK between 1990 and 2013.

Using the height and weight of children recorded in the notes at some point before the disease was diagnosed the researchers were able to identify that obese children appear at highest risk of this condition.

The study was funded by the Academy of Medical Sciences.

Best evidence

Daniel Perry, who is also an Honorary Consultant Orthopaedic Surgeon at Alder Hey Children’s Hospital, said: “This is the best evidence available linking this disease to childhood obesity – which makes this condition to be one of the only obesity-related disease that can cause life-long morbidity starting in childhood.

“A significant proportion of patients with SCFE are initially misdiagnosed and those presenting with knee pain are particularly at risk.

“Ultimately this study helps us to better understand one of the main diseases affecting the hip in childhood. Whilst we confirm a strong association with obesity, we are still unable to say that obesity causes this disease.”

Researchers Studying Debilitating Lung Disease that Targets Puerto Ricans

Loyola Medicine is enrolling patients in the first major study of a rare, debilitating lung disease that disproportionately affects people from Puerto Rico.

The hereditary disease is called Hermansky-Pudlak syndrome (HPS). It can cause bleeding problems, low vision, albinism and in some patients, a debilitating and often fatal lung disease called pulmonary fibrosis, said Loyola Medicine pulmonologist Daniel Dilling, MD.

HPS affects fewer than 1 in 500,000 people worldwide. But it is more common in certain geographic pockets, especially Puerto Rico, where it affects 1 in 1,800 people.

Loyola is the only center in Illinois participating in a multicenter study of how HPS develops in patients over time. The first Loyola HPS patient to enroll is Jonathan Colon, 44, of Chicago, whose parents are from Puerto Rico. Puerto Ricans who have HPS are believed to have descended from a single founding patient.

Mr. Colon has pulmonary fibrosis, characterized by a buildup of scar tissue in the lungs. Pulmonary fibrosis makes breathing increasingly difficult, and in later stages patients need supplemental oxygen around the clock. Small exertions such as walking across a room can leave a patient gasping for breath. Without a lung transplant, the condition can be fatal.

The course of the disease varies among patients. Mr. Colon was diagnosed relatively early in the disease, and is taking a new drug that has slowed the progression of his pulmonary fibrosis. Dr. Dilling said Mr. Colon eventually may need a lung transplant. The operation would be challenging, because in HPS patients, blood does not coagulate normally, increasing the risk of bleeding.

Dr. Dilling said people of Puerto Rican descent who have albinism (abnormally light coloring) should be screened for HPS to ensure early treatment. Many Puerto Ricans with albinism do not know they are at risk for HPS, Dr. Dilling said.

The study is called “A Longitudinal Study of Hermansky-Pudlak Syndrome Pulmonary Fibrosis.” Its purpose is to identify the earliest evidence of pulmonary disease in individuals who are at risk for HPS pulmonary fibrosis. Researchers also hope to identify biomarkers that will help them understand the cause of HPS pulmonary fibrosis and facilitate future clinical trials. (A  biomarker is a substance in the body that predicts the incidence or outcome of a disease.)

The study is funded by the National Heart, Lung and Blood Institute of the National Institutes of Health. Principal investigator of the overall study is Lisa Young, MD, of Vanderbilt University.

For 29 years, Loyola has operated the largest and most successful lung transplant program in Illinois. More than 900 lung transplants—by far the most of any center in Illinois—have been performed and Loyola’s 40 lung transplants in 2016 were more than all other programs in Illinois combined.

Loyola’s lung transplant program regularly evaluates and successfully performs transplants in patients who have been turned down by other centers in Chicago and surrounding states and consistently records outstanding outcomes.

Loyola also is the only center in Illinois to join the recently launched Rare Lung Diseases Consortium, which is spearheading cutting-edge research on HPS and other rare lung diseases.The consortium is a unique collaboration among patient groups, researchers and the National Institutes of Health. Its mission is to conduct research into new diagnostic tests and treatments, provide clinical research training and focused clinical care and educate patients, physicians, researchers and the public about rare lung diseases.

The study will enroll about 150 patients aged 12 and older who have been diagnosed with HPS. For more information about enrolling at the Loyola site, contact Josie Corral, RN, at 708-216-5744 or at  jcorral@luc.edu.