Study shows promise of combined immunotherapy-radiation treatment

A study in mice implanted with breast and melanoma cancers adds to a growing body of evidence that highly focused radiation – long thought to suppress immunity – can actually help boost the immune system’s fight against cancer when combined with a new kind of immune-enhancing drug.

The study, led by Johns Hopkins Kimmel Cancer Center researchers, shows how in principle, radiation may specifically activate immune system cells responsible for attacking cancer cells, leading immune cells to “remember” how to fight cancer long after the cancer is gone.

Andrew Sharabi, M.D., Ph.D., a resident in the Department of Radiation Oncology and Molecular Radiation Science at Johns Hopkins, was expected to present details of the study at the 2014 annual meeting of the American Society of Radiation Oncology (ASTRO) in San Francisco September 15.

The study made use of a relatively new class of anticancer agent that interferes with a tumor’s ability to dampen the immune system’s cancer recognition process. With the U.S.

Food and Drug Administration’s recent approval of one such “checkpoint inhibitor” (pembrolizumab) and more in the pipeline, Sharabi says, tumors once hidden from the immune system may now be found and destroyed. But scientists, he added, have only begun to explore how standard therapies like radiation could be combined with the new immunotherapies.

“The immune system has powerful brakes, and removing those brakes with checkpoint inhibitors may be key to unleashing the full potential of the immune system against cancer,” says Sharabi. “Adding radiation therapy to this mix may provide an additional boost by increasing tumor cell death and releasing targets for the immune system.” “We found that focused radiation therapy, once thought to suppress the immune system, actually increases specific, antitumor responses from the immune system,” says Sharabi.

Clinical trial evaluates safety of stem cell transplantation in spine

Researchers at the University of California, San Diego School of Medicine have launched a clinical trial to investigate the safety of neural stem cell transplantation in patients with chronic spinal cord injuries.

“The goal of this study is to evaluate the safety of transplanting neural stem cells into the spine for what one day could be a treatment for spinal cord injuries,” said Joseph Ciacci, MD, principal investigator and neurosurgeon at UC San Diego Health System. “The study’s immediate goal, however, is to determine whether injecting these neural stem cells into the spine of patients with spinal cord injury is safe.” Related goals of the clinical trial include evaluating the stem cell graft’s survival and the effectiveness of immuno-suppression drugs to prevent rejection.

The researchers will also look for possible therapeutic benefits such as changes in motor and sensory function, bowel and bladder function, and pain levels. Patients who are accepted for the study will have spinal cord injury to the T7-T12 level of the spine’s vertebrae and will have incurred their injury between one and two years ago.

All participants will receive the stem cell injection. The scientists will use a line of human stem cells approved by the U.S. FDA for human trials in patients with chronic traumatic spinal injuries.

These cells were previously tested for safety in patients with amyotrophic lateral sclerosis (ALS). Since stem cell transplantation for spinal cord injury is just beginning clinical tests, unforeseen risks, complications or unpredictable outcomes are possible. Careful clinical testing is essential to ensure that this type of therapy is developed responsibly with appropriate management of the risks that all medical therapies may present.

Pre-clinical studies of these cells by Ciacci and Martin Marsala, MD, at the UC San Diego School of Medicine, showed that these grafted neural stem cells improved motor function in spinal cord injured rats with minimal side effects indicating that human clinical trials are now warranted. This clinical trial at UC San Diego Health System is funded by Neuralstem, Inc. and was launched and supported by the UC San Diego Sanford Stem Cell Clinical Center.

The Center was recently created to advance leading-edge stem cell medicine and science, protect and counsel patients, and accelerate innovative stem cell research into patient diagnostics and therapy.

Researchers find new way to combat antibiotic resistance

In recent years, new strains of bacteria have emerged that resist even the most powerful antibiotics. Each year, these superbugs, including drug-resistant forms of tuberculosis and staphylococcus, infect more than 2 million people nationwide, and kill at least 23,000.

Despite the urgent need for new treatments, scientists have discovered very few new classes of antibiotics in the past decade. MIT engineers have now turned a powerful new weapon on these superbugs.

Using a gene-editing system that can disable any target gene, they have shown that they can selectively kill bacteria carrying harmful genes that confer antibiotic resistance or cause disease. Led by Timothy Lu, an associate professor of biological engineering and electrical engineering and computer science, the researchers described their findings in the September 21, 2014 issue of Nature Biotechnology.

In August 2014, Lu’s lab reported a different approach to combating resistant bacteria by identifying combinations of genes that work together to make bacteria more susceptible to antibiotics. Lu hopes that both technologies will lead to new drugs to help fight the growing crisis posed by drug-resistant bacteria.

“This is a pretty crucial moment when there are fewer and fewer new antibiotics available, but more and more antibiotic resistance evolving,” he says. “We’ve been interested in finding new ways to combat antibiotic resistance, and these papers offer two different strategies for doing that.” Most antibiotics work by interfering with crucial functions such as cell division or protein synthesis.

However, some bacteria, including the formidable MRSA (methicillin-resistant Staphylococcus aureus) and CRE (carbapenem-resistant Enterobacteriaceae) organisms, have evolved to become virtually untreatable with existing drugs. In the new Nature Biotechnology study, graduate students Robert Citorik and Mark Mimee worked with Lu to target specific genes that allow bacteria to survive antibiotic treatment.

The CRISPR genome-editing system presented the perfect strategy to go after those genes. CRISPR, originally discovered by biologists studying the bacterial immune system, involves a set of proteins that bacteria use to defend themselves against bacteriophages (viruses that infect bacteria).

One of these proteins, a DNA-cutting enzyme called Cas9, binds to short RNA guide strands that target specific sequences, telling Cas9 where to make its cuts. Lu and colleagues decided to turn bacteria’s own weapons against them. They designed their RNA guide strands to target genes for antibiotic resistance, including the enzyme NDM-1, which allows bacteria to resist a broad range of beta-lactam antibiotics, including carbapenems.

The genes encoding NDM-1 and other antibiotic resistance factors are usually carried on plasmids – circular strands of DNA separate from the bacterial genome – making it easier for them to spread through populations.

When the researchers turned the CRISPR system against NDM-1, they were able to specifically kill more than 99% of NDM-1-carrying bacteria, while antibiotics to which the bacteria were resistant did not induce any significant killing. They also successfully targeted another antibiotic resistance gene encoding SHV-18, a mutation in the bacterial chromosome providing resistance to quinolone antibiotics, and a virulence factor in enterohemorrhagic E. coli.

In addition, the researchers showed that the CRISPR system could be used to selectively remove specific bacteria from diverse bacterial communities based on their genetic signatures, thus opening up the potential for “microbiome editing” beyond antimicrobial applications. To get the CRISPR components into bacteria, the researchers created two delivery vehicles – engineered bacteria that carry CRISPR genes on plasmids, and bacteriophage particles that bind to the bacteria and inject the genes.

Both of these carriers successfully spread the CRISPR genes through the population of drug-resistant bacteria. Delivery of the CRISPR system into waxworm larvae infected with a harmful form of E. coli resulted in increased survival of the larvae.

The researchers are now testing this approach in mice, and they envision that eventually the technology could be adapted to deliver the CRISPR components to treat infections or remove other unwanted bacteria in human patients.

Phase 1 human clinical trial to assess the safety and efficacy of a new monoclonal antibody for CLL patients

Researchers at the University of California, San Diego School of Medicine have launched a phase 1 human clinical trial to assess the safety and efficacy of a new monoclonal antibody for patients with chronic lymphocytic leukemia (CLL), the most common form of blood cancer in adults.

The new antibody targets ROR1, a protein used by embryonic cells during early development and exploited by cancer cells to promote tumour growth and metastasis, the latter responsible for 90 percent of all cancer-related deaths. Because ROR1 is not expressed by normal adult cells, scientists believe it is a biomarker of cancer cells in general and cancer stem cells in particular.

Because it appears to drive tumour growth and disease spread, they believe it also presents an excellent target for anti-cancer therapy. Developed at UC San Diego Moores Cancer Center by Thomas Kipps, MD, PhD, who holds the Evelyn and Edwin Tasch Chair in Cancer Research, and colleagues, the antibody is called cirmtuzumab (also known as UC-961).

In previous animal studies, Kipps’ team reported that ROR1 is singularly expressed on CLL and also on a variety of different cancers, including cancers of the breast, pancreas, colon, lung and ovary. In mouse models of CLL, ROR1 acts as an accelerant when combined with another oncogene to produce a faster-growing, more aggressive cancer.

Cirmtuzumab was developed under the auspices of the California Institute for Regenerative Medicine’s HALT leukemia grant awarded to Dennis Carson, MD, principal investigator, and Catriona Jamieson, MD, PhD, co-principal investigator to develop six distinct therapies against cancer stem cells. Kipps led one of the six projects and generated antibodies against ROR1, leading to the cirmtuzumab trial in patients with CLL.

“The primary goal of this phase I clinical trial is to evaluate whether cirmtuzumab is a safe and well-tolerated cancer stem cell-targeted agent in patients with CLL,” said Jamieson, chief of the Division of Regenerative Medicine, associate professor of medicine, director of stem cell research at UC San Diego Moores Cancer Center, deputy director of the Sanford Stem Cell Clinical Center and a principal investigator of the cirmtuzumab clinical trial.

Michael Choi, MD, assistant clinical professor of medicine and co-principal investigator of the clinical trial said: “The trial will involve patients with relapsed or refractory CLL, who will receive an intravenous infusion every 14 days at Moores, followed by regular monitoring and clinic visits to assess efficacy and identify and manage any adverse effects. Initial treatment is planned for two months.”

Plasma-based biomaterial reduces infections, speeds healing of bone fractures

Data presented in September at the South African Orthopaedic Association Congress in Cape Town from a recently completed clinical trial with the REPAIR Bone Putty show the blood plasma-based putty reduced infections, sped bone healing, and promoted more rapid wound closure of open tibia fractures.

Dr. David North, an orthopaedic surgeon associated with the University of Cape Town, presented the findings.

“We are very excited about the outcomes of this first clinical trial” The REPAIR Putty – developed by Carmell Therapeutics – incorporates a novel material made from blood plasma containing a concentration of natural healing factors that bathe the injured tissue as the material degrades. This first study was designed to assess the safety and performance of the Putty in augmenting the healing of fractures.

“We were very pleased and a bit surprised by the results,” said Dr. Brian Bernstein, Principal Investigator for the study, Director of the Orthopaedic Trauma Group in Cape Town and Chairman of the South African Orthopaedic Trauma Society.

“We are always concerned about infections with open bone fractures, and the idea of using a concentration of natural growth factors to augment healing and reduce infections is especially attractive, particularly if such a product can be offered at a reasonable cost.” Open fractures are problematic to treat as infections, delayed bone healing, and wound closure/sepsis are significant challenges. In this 30 patient trial, 70% of the patients enrolled had more severe type IIIA & IIIB injuries involving comminuted bone, high levels of contamination and severe soft tissue injuries.

Additionally, 67% were smokers, a factor known to retard healing, and 70% received external fixation that uses pins to penetrate the skin and stabilize the fracture, with an associated high rate of pin-tract infections. Patients agreeing to participate in the study were randomly placed into either a control or treatment group.

The REPAIR Putty was placed into the fracture site during fracture reduction of the treatment patients, and both groups were followed for one year. No adverse events associated with the use of the Putty were observed for the 20 treatment patients.

A statistically significant acceleration of bone healing occurred at 180 days with more rapid wound closure at 30 days approaching significance for the treatment patients compared to the controls. While the company anticipated that the putty would accelerate bone healing and wound closure, a big surprise was the reduction in infections.

Eighty percent of control patients experienced at least 1 infection during the study compared to only 22% of the putty treated injuries, a statistically significant difference. With the most severe type III injuries, the infection reduction was even more significantly reduced with 100% of controls vs. 25% of treatment patients experiencing at least 1 infection.

The relatively high rates of infection for the controls (80% & 100%) were due to the use of external fixation. When pin related infections were removed from the data, the control group had a 43% infection rate for the more severe injuries, which compares well with the reported literature; by contrast, the Putty group in this subset had only a 17% infection rate.

The researchers believe that the infection reduction is largely due to the blood plasma component of the Putty not only eluting natural regenerative factors but also recruiting the body’s immune system to the area of the injury over several weeks as it degrades, thereby leveraging the body’s own ability to fight off infections.

This result is most significant for trauma patients - high doses of antibiotics are typically given prophylactically to prevent infection, but the rise of antibiotic-resistant bacteria is raising new concerns about antibiotic overuse. The REPAIR Bone Putty may become a game changer in the way these fractures are treated.

Two-drug combination accelerates wound healing, reduces scar tissue

A combination of two drugs already approved by the U.S. Food and Drug Administration for different applications reduces wound healing time by one-quarter and significantly decreases scar tissue in mice and rats, Johns Hopkins researchers report.

If the findings, reported in the September issue of the Journal of Investigative Dermatology, hold true in future human studies, the dual treatment could speed skin healing in people with skin ulcers, extensive burns, surgical wounds and battlefield injuries. Zhaoli Sun, M.D., Ph.D., director of the Transplant Biology Research Center at the Johns Hopkins University School of Medicine, and his colleagues say the wound healing potential of the two drugs used in the animal study was discovered incidentally while looking for ways to prevent rejection of liver transplants.

One of the drugs, AMD3100, is generally used to move stem cells from bone marrow to the bloodstream so the cells can be harvested and stored for patients recovering from cancer chemotherapy. The other, tacrolimus, tamps down the immune response. Sun and his team noticed that in addition to successfully preventing liver graft rejection in their study, the drugs, when used together, seemed to improve wound healing in animals.

Focusing on just the wound healing “side effect” of the drug duo, Sun and his colleagues launched the rodent study to determine how well the combination worked and what the mechanism behind its therapeutic effects might be. The researchers first divided mice into four groups, each of which received four 5-millimeter circular cuts to remove skin and tissue from their backs.

Some of the mice received injections of just AMD3100. Others received injections of tacrolimus in doses just one-tenth of what is usually given to prevent organ and tissue rejection.

Another group received injections of both AMD3100 and low-dose tacrolimus. A fourth group, the control animals, received saline injections rather than the drugs. Animals that received only saline healed completely in 12 days, while those that received both drugs healed in nine days, a reduction of 25%.

Those that received either one of the two drugs had only a modest improvement in healing time, cutting it by a single day. The researchers had similar findings with groups of rats, where the drug combination working slightly better, reducing healing time by 28% compared to saline.

Additionally, they found that the wounds in animals that received the drug combination healed with less scar tissue and regrew skin’s hair follicles. “The findings mean that wound healing is not only accelerated, but also that real skin regeneration is occurring,” Sun says.

“These animals had more perfect skin repair in the wound area.” Further tests showed that the drugs work synergistically, with AMD3100 pushing stem cells from bone marrow into the bloodstream and tacrolimus stimulating cells in wound areas to give off molecules that attract the stem cells. Though the reported study tested the drug combination only on surgical excisions, Sun and his colleagues say the beneficial effects also apply to burn injuries and excisions in diabetic rats in studies that are currently underway.

Xenon gas protects the brain after head injury

Treatment with xenon gas after a head injury reduces the extent of brain damage, according to a study in mice.

Head injury is the leading cause of death and disability in people aged under 45 in developed countries, mostly resulting from falls and road accidents. The primary injury caused by the initial mechanical force is followed by a secondary injury which develops in the hours and days afterwards.

This secondary injury is largely responsible for patients’ mental and physical disabilities, but there are currently no drug treatments that can be given after the accident to stop it from occurring. Scientists at Imperial College London found that xenon, given within hours of the initial injury, limits brain damage and improves neurological outcomes in mice, both in the short term and long term.

The findings, published in the journal Critical Care Medicine, could lead to clinical trials of xenon as a treatment for head injury in humans. Although xenon is chemically inert, this does not mean it is biologically inactive.

Xenon has been known to have general anaesthetic properties since the 1950s. Previous studies at Imperial have found that xenon can protect brain cells from mechanical injury in the lab, but this new study is the first time such an effect has been shown in live animals, a vital step before any new treatments can be tested in humans.

Mice were anaesthetised before having a controlled mechanical force applied to the brain. Some were then treated with xenon at different concentrations and at different times after injury.

Mice treated with xenon performed better in tests assessing their neurological deficits, such as movement and balance problems, in the days after injury and after one month. They also had less brain damage, even if treatment was delayed up to three hours after the injury.

Dr Robert Dickinson from the Department of Surgery and Cancer at Imperial College London, who led the study, said: “After a blow to the head, most of the damage to the brain doesn’t occur immediately but in the hours and days afterwards. At present we have no specific drugs to limit the spread of the secondary injury, but we think that is the key to successful treatment.

“This study shows that xenon can prevent brain damage and disability in mice, and crucially it’s effective when given up to at least three hours after the injury. It’s feasible that someone who hits their head in an accident could be treated in the hospital or in an ambulance in this timeframe.

“These findings provide crucial evidence to support doing clinical trials in humans.” l doi: 10.1097/CCM. 0000000000000624

Foetal heart rate monitoring fails to detect brain injury – more precise tool required

Researchers at Johns Hopkins have added to evidence that continuous electronic foetal heart rate monitoring, widely used during maternal labour, has so many false positive readings that it is unable to reliably identify foetal brain injury caused by oxygen deficiency.

Results of the new study by a team at the Johns Hopkins University School of Medicine appeared in the September 2014 issue of Obstetrics & Gynecology. “Brain injuries caused by oxygen deprivation in newborns are rare, and our study shows that in most cases, irregularities detected by an electronic heart rate monitor are false alarms,” says Ernest Graham, M.D., associate professor of gynaecology and obstetrics at Johns Hopkins.

“During the last hour of labour prior to delivery, we see many abnormal patterns in the foetal heart rate, but the vast majority of the babies are born normal.” “Our current standard of care is to monitor the foetal heart rate during labour, but we need a more precise method to identify term babies that are born with hypoxic brain injury,” he says. For the study, the researchers analyzed medical records and monitor readouts for the last hour of labour before delivery of 39 babies with hypoxic-ischemic encephalopathy and 78 babies without such brain injuries at The Johns Hopkins Hospital and Johns Hopkins Bayview Medical Center between 2007 and 2013.

The investigators found some differences in the foetal heart rate tracings between the groups but report that those differences were not enough to distinguish damaged babies from normal ones. Previous studies have shown that continuous heart rate monitoring is not sensitive enough to definitively pick up specific kinds of brain damage, and the Johns Hopkins research adds further support for the need for more precise detection tools, Graham says.

Hypoxic-ischemic encephalopathy, characterized by restricted blood flow to the brain, is blamed for 23% of neonatal deaths globally, but it occurs at a rate of one to four cases in every 1,000 births. Treating the infant within six hours of birth with whole-body cooling reduces symptoms and mortality.

The monitoring aims to alert physicians if the foetal brain is deprived of oxygen during labour and delivery; data show that if the heartbeat slows, it may signal oxygen deprivation.

When that happens, the choice is often a rapid caesarean section to limit or prevent any damage from oxygen loss. Graham says, however, that his study affirms that electronic foetal monitoring appears not sensitive or specific enough to identify the rare cases of brain injury.

He hopes his study leads to the development of new technologies for intrapartum foetal monitoring. “We were looking for more subtle but definitive changes on the monitor tracings indicative of brain injury to incorporate into our training of young physicians, but we did not find them,” he says. “We need a more precise tool.”

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