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Brain Tumor

Boosting Pancreatic Cancer Treatment with Immunotherapy and KRAS Targeted Therapy

Adding immunotherapy to new KRAS inhibitors boosted responses in preclinical models, setting the stage for future trials of the combination strategy.

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The treatment of pancreatic cancer has long been a challenging endeavor, with limited options available for patients diagnosed with this aggressive form of cancer. However, researchers from the Perelman School of Medicine at the University of Pennsylvania and Penn Medicine’s Abramson Cancer Center have made significant progress in developing a new approach that combines immunotherapy with KRAS targeted therapy.

The study, published in Cancer Discovery, found that adding immunotherapy to a type of inhibitor that targets multiple forms of the cancer-causing gene mutation KRAS kept pancreatic cancer at bay in preclinical models for significantly longer than the same targeted therapy alone. This breakthrough prime the combination strategy for future clinical trials.

Patients with pancreatic cancer have an overall poor prognosis, and nearly 90 percent of these cases are driven by KRAS mutations, which researchers long considered “undruggable.” However, recent studies have shown that newer RAS inhibition tools may have an immune stimulatory effect, making them ideal to pair with immunotherapy for longer and better treatment response.

In this study, the researchers used RAS(ON) multi-selective inhibitors, investigational agents that target the active or ON-state of multiple forms of RAS mutations. These inhibitors use a different mechanism of action than most other KRAS inhibitors to inhibit the active state of multiple forms of RAS mutations.

The research team found that not only was RAS(ON) multi-selective inhibition effective in preclinical pancreatic cancer models, but it was even more effective when combined with immunotherapy. Using the combination approach, all mouse models had tumor shrinkage and half had a complete response, meaning the tumor was eliminated.

The researchers used a Penn-developed immunocompetent model that allows the tumor to spontaneously evolve after implantation, making it possible to discern the drug’s impact on the surrounding tumor microenvironment. The research team found that RAS(ON) multi-selective inhibition reshaped the tumor microenvironment by bringing in more T cells and other immune cells, making the tumor particularly receptive to immunotherapy.

The study was supported by Revolution Medicines, the National Institutes of Health, and several other organizations. A clinical trial testing RAS(ON) inhibitors with other anticancer agents is now open at several sites across the country, including Penn Medicine.

“We’re hopeful that we’re starting to crack the code on immunotherapy and RAS therapy for pancreatic cancer,” said Robert Vonderheide, MD, DPhil, director of the Abramson Cancer Center. “After decades of limited progress, it’s encouraging to see new treatment approaches making their way into the clinic for patients.”

Brain Tumor

Sleep Apnea Linked to Brain Changes and Cognitive Decline in Older Adults

Obstructive sleep apnea, a condition that causes lower oxygen levels during sleep, is linked to degeneration of brain regions associated with memory through damage to the brain’s small blood vessels, according to a new study. The study found the brain changes were strongly associated with the severity of drops in oxygen levels during rapid eye movement (REM) sleep. The study does not prove that sleep apnea causes this degeneration; it only shows an association.

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Sleep apnea, a condition that causes repeated disruptions to breathing during sleep, has been linked to cognitive decline and memory-related brain changes in older adults. A study published online in Neurology found that the severity of drops in oxygen levels during rapid eye movement (REM) sleep was strongly associated with degeneration of brain regions associated with memory.

Obstructive sleep apnea occurs when throat muscles relax during sleep, blocking the airway and causing a person to wake up repeatedly to breathe. This disrupted sleep pattern can lower oxygen levels, which in turn can damage small blood vessels in the brain.

The study included 37 people with an average age of 73 who did not have cognitive impairment. Researchers measured their oxygen levels throughout the night during all stages of sleep, including REM sleep. Participants also had brain scans to measure brain structure and took a memory test before and after sleep.

The results showed that lower oxygen levels during REM sleep were associated with higher levels of white matter hyperintensities in the brain, which can be caused by injury to small blood vessels. Having a blood oxygen level of 90% or lower is cause for concern. The study also found that having more white matter hyperintensities was linked to decreased volume and reduced thickness in areas associated with memory.

“This study may partially explain how obstructive sleep apnea contributes to cognitive decline associated with aging and Alzheimer’s disease,” said study author Bryce A. Mander, PhD. “It highlights the importance of addressing sleep disorders as a potential risk factor for cognitive decline.”

The study has some limitations, including that participants were primarily white and Asian people, so results may not be the same for other populations.

Overall, the findings suggest that sleep apnea is associated with cognitive decline and memory-related brain changes in older adults. Addressing sleep disorders and maintaining good sleep hygiene can help mitigate these risks.

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Brain Tumor

“Revolutionizing Lymphoma Treatment: Enhanced CAR T Cell Therapy Shows Promise in Small Study”

A phase I study of a next-generation CAR T cell therapy showed a 52 percent complete remission rate for patients with relapsed/refractory lymphoma.

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The article describes a groundbreaking study that has shown promising results in treating lymphoma patients who have resisted multiple rounds of other cancer treatments, including commercially available CAR T cell therapies. The new enhanced CAR T cell therapy, dubbed huCART19-IL18, was found to be highly effective in 81% of patients and resulted in complete remission in 52%. This is a significant improvement over traditional CAR T cell therapies, which have been shown to result in long-term remission in only around 50% of patients.

The study, led by researchers at the University of Pennsylvania, used a new process that shortens the manufacturing time for the CAR T cells to just three days. This means that patients with aggressive, fast-growing cancers can begin CAR T cell therapy quicker than is currently possible with standard manufacturing times of nine to 14 days.

The addition of interleukin 18 (IL18) to the CAR T cells enhanced their ability to attack cancer cells and protected them from immune suppression and T cell exhaustion. The researchers also found that the type of CAR T cell therapy patients previously received may impact the efficacy of huCART19-IL18.

This study represents a significant development in the ongoing evolution of CAR T cell therapy, as it is the first time a cytokine-enhanced CAR T has been tested in patients with blood cancer. The researchers believe that incorporating cytokine secretion into CAR T cell design will have broad implications for enhancing cellular therapies, even beyond blood cancers.

The study has already led to several other clinical trials being planned, including studies for acute lymphocytic leukemia (ALL) and chronic lymphocytic leukemia (CLL). Another trial for non-Hodgkin’s lymphoma using a similar IL18-armored CAR T cell product is currently enrolling patients. On the manufacturing side, the team is partnering with a Penn spinout company to improve the process for how these CAR T cells are created and expanded in the laboratory before being reinfused into the patient.

Overall, this study has shown promise in treating lymphoma patients who have resisted multiple rounds of other cancer treatments, and further research is needed to fully understand its potential.

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Biochemistry

A Breakthrough in Brain Research: The Iontronic Pipette Revolutionizes Neurological Studies

Researchers have developed a new type of pipette that can deliver ions to individual neurons without affecting the sensitive extracellular milieu. Controlling the concentration of different ions can provide important insights into how individual brain cells are affected, and how cells work together. The pipette could also be used for treatments.

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The development of an iontronic pipette at Linköping University has opened up new avenues for neurological research. This innovative tool allows researchers to deliver ions directly to individual neurons without affecting the surrounding extracellular milieu. By controlling the concentration of various ions, scientists can gain valuable insights into how brain cells respond to different stimuli and interact with each other.

The human brain consists of approximately 85-100 billion neurons, supported by a similar number of glial cells that provide essential functions such as nutrition, oxygenation, and healing. The extracellular milieu, a fluid-filled space between the cells, plays a crucial role in maintaining cell function. Changes in ion concentration within this environment can activate or inhibit neuronal activity, making it essential to study how local changes affect individual brain cells.

Previous attempts to manipulate the extracellular environment involved pumping liquid into the area, disrupting the delicate biochemical balance and making it difficult to determine whether the substances themselves or the changed pressure were responsible for the observed effects. To overcome this challenge, researchers at the Laboratory of Organic Electronics developed an iontronic micropipette measuring only 2 micrometers in diameter.

This tiny pipette can deliver ions such as potassium and sodium directly into the extracellular milieu, allowing scientists to study how individual neurons respond to these changes. Glial cell activity is also monitored, providing a more comprehensive understanding of brain function.

Theresia Arbring Sjöström, an assistant professor at LOE, highlighted that glial cells are critical components of the brain’s chemical environment and can be precisely activated using this technology. In experiments conducted on mouse hippocampus tissue slices, it was observed that neurons responded dynamically to changes in ion concentration only after glial cell activity had saturated.

This research has significant implications for neurological disease treatment. The iontronic pipette could potentially be used to develop extremely precise treatments for conditions such as epilepsy, where brain function can be disrupted by localized imbalances in ion concentrations.

Researchers are now continuing their studies on chemical signaling in healthy and diseased brain tissue using the iontronic pipette. They also aim to adapt this technology to deliver medical drugs directly to affected areas of the brain, paving the way for more targeted treatments for neurological disorders.

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