US Pharm. 2021;46(5):38-40.

Novel Immunotherapy Approach to Fight Melanoma

In a study led by Yale Cancer Center, researchers have advanced a tumor-targeting and cell-penetrating antibody that can deliver payloads to stimulate an immune response to help treat melanoma. The study was presented at the American Association of Cancer Research virtual annual meeting.

“Most approaches rely on direct injection into tumors of ribonucleic acids (RNAs) or other molecules to boost the immune response, but this is not practical in the clinic, especially for patients with advanced cancer,” said Peter M. Glazer, MD, PhD, chair of the Department of Therapeutic Radiology at Yale, Chief of Radiation Oncology at Smilow Cancer Hospital, and senior author of the study. “In this study, we can deliver immune stimulatory RNA to tumors in vivo following systemic administration.”

RNA is a nucleic acid present in all living cells. Its principal role is to act as a messenger to carry instructions from DNA to control the synthesis of proteins, although in some viruses RNA rather than DNA carry the genetic information. In this study, using mice with melanoma tumors, members of the Glazer laboratory at Yale achieved almost complete tumor suppression upon IV injection of antibody/RNA complexes.

“These results are very encouraging,” added Dr. Glazer. “They highlight a novel approach for the systemic delivery of immunostimulatory RNAs in a targeted manner that may one day offer therapeutic advantages for difficult-to-treat cancers like melanoma, over current approaches.”

“Sweat Sticker” Diagnoses Cystic Fibrosis in Real Time

A Northwestern University–led research team has developed a novel skin-mounted sticker that absorbs sweat and then changes color to provide an accurate, easy-to-read diagnosis of cystic fibrosis within minutes.

While measuring chloride levels in sweat to diagnose cystic fibrosis is standard, the soft, flexible, skin-like “sweat sticker” offers a stark contrast to current diagnostic technologies, which require a rigid, bulky, wrist-strapped device to collect sweat.

After developing the sweat sticker at Northwestern, the researchers validated it in clinical pilot studies involving cystic fibrosis patients and healthy volunteers at the Cystic Fibrosis Center at the Ann & Robert H. Lurie Children’s Hospital of Chicago. The sticker showed enhanced performance in collected sweat volume and equivalent accuracy to traditional platforms.

The research and study findings were published on March 31 as the cover feature article in the journal Science Translational Medicine.

By softly adhering to the body, the millimeter-thick sticker makes direct but gentle contact with the skin without harsh adhesives. Not only does this make the sticker more comfortable and imperceptible to the wearer, but it also enables the sticker to collect 33% more sweat than current clinical methods. The high collection rate ensures that one test will consistently collect a large enough sample to provide an accurate result.

The sticker also has built-in colorimetric sensors that detect, measure, and analyze chloride concentration in real time using a smartphone camera—bypassing the need for expensive laboratory equipment and excruciating wait times. This opens possibilities for testing outside of hospitals in the home setting, which could provide relief to parents in rural or low-resource areas without access to clinical centers with specialized diagnostic tools.

Biointegrated electronics pioneer John A. Rogers, the Louis Simpson and Kimberly Querrey Professor of Materials Science and Engineering, Biomedical Engineering and Neurological Surgery in the McCormick School of Engineering and Feinberg School of Medicine and director of the Querrey Simpson Institute for Bioelectronics (QSIB), led the device development. Tyler Ray, who was a postdoctoral researcher in the Rogers laboratory at the time of the research, is the paper’s first author. He is now an assistant professor of mechanical engineering at the University of Hawaii at Manoa.

The most-common life-shortening genetic disease, cystic fibrosis affects one in every 3,300 births in the United States and 70,000 people worldwide. Promising outcomes wholly depend upon early diagnosis. Because the disease attacks the digestive system, patients can become severely malnourished if they do not receive treatment soon after birth.

All newborns are screened for cystic fibrosis within the first few days of life through a heel prick. If that screen is abnormal, then pediatricians order a sweat test to confirm the diagnosis. During the sweat test, the baby must wear the hard, wrist-strapped device for up to 30 minutes. Sometimes smaller babies have trouble producing enough sweat for the test. Other times, the loose, ill-fitting sweat-collection device is unable to collect a large enough sample. In these instances, the baby must repeat the test later, inducing anxiety and delaying treatment.

“Some parents bring their baby in for testing and are sent home without a confirmed result because the device was unable to collect enough sweat,” said study coauthor Dr. Susanna McColley, a cystic fibrosis expert and pediatric pulmonologist at Lurie Children’s Hospital and Northwestern Medicine. “They go home, without knowing if their baby has a serious disease or not, and their baby cannot yet start treatment. It can be agonizing.”

As former director of the clinical chemistry laboratory at Lurie Children’s, Shannon Haymond has witnessed this scenario too many times. Because of the poor fit and seal of the rigid collection devices on small infants’ arms, many families have experienced delayed results and diagnoses.

In fall 2016, the Rogers laboratory introduced a flexible sensor for the skin that could collect and analyze sweat in real time for health monitoring. After reading the paper, Dr. Haymond instantly saw the new device’s potential for cystic fibrosis.

“Many labs encountered problems caused by the current collection methods, making this a frequent focus of quality improvement efforts,” said Dr. Haymond, coauthor of the study and vice chair for computational biology and director of mass spectrometry at Lurie Children’s. “I thought the flexible skin sensors could simplify the process and improve collection results. And because the sweat stickers are disposable and designed for single use, they have an added advantage of preventing infection.”

By building sensing capabilities into the sticker, the Northwestern team offers potential for a speedier diagnosis. Users can simply snap a photo of the sweat-filled sticker and wirelessly transmit it to a clinic for quick analysis, alleviating diagnostic delays and allowing patients to start treatment as soon as possible.

“The device uses a network of microfluidic channels to collect sweat directly from the skin and route it to chambers to react with chemical reagents,” Ray said. “Those reagents cause a change in color that correlates to the chloride concentration level. By collecting and analyzing sweat at the point of collection, we can enable an earlier diagnosis. This is crucial for preventing severe complications and improving long-term patient outcomes.”

Next, the team believes its sweat sticker could be used to routinely track cystic fibrosis patients’ long-term health and gauge how they respond to treatment. If the sticker detects a change in chloride levels, for example, that could inform a physician’s treatment plan.

B-Cell Factor Possible Key to Hemophilia Immune Tolerance

A group of scientists recently made a key discovery that could prevent and eradicate immune responses that lead to treatment failure in about one-third of people with severe hemophilia A.

Hemophilia is the most common severe inherited bleeding disorder in men. The disease affects one in 10,000 males worldwide and results from deficiency of blood clotting factor VIII (FVIII). Both children and adults with hemophilia A (80% of all hemophilia patients) receive treatment that involves infusing FVIII protein into the bloodstream. However, about 30% of them develop an immune response in the form of antibodies to FVIII (inhibitors), rendering treatment ineffective and increasing risk of mortality.

For inhibitor-positive patients, immune tolerance induction (ITI) options are scarce, costly, and invasive. Investigators at Indiana University School of Medicine, Children’s Hospital of Philadelphia, and the University of Pennsylvania joined efforts to explore immune responses to FVIII under a National Institutes of Health–funded U54 initiative.

The study, led by IU School of Medicine’s Moanaro Biswas, PhD, and Valder R. Arruda, MD, PhD, from Children’s Hospital of Philadelphia and the University of Pennsylvania, is titled “B cell activating factor [BAFF] modulates the factor VIII immune response in hemophilia” and was published in the Journal of Clinical Investigation in March. Bhavya Doshi, MD, from Children’s Hospital of Philadelphia, is the first author.

For the study, the group used plasma samples from pediatric and adult hemophilia A patients and animal models to determine whether BAFF plays a role in the generation and maintenance of FVIII inhibitors.

They also looked at combining antibody to BAFF in an ITI approach with a CD20 antibody (rituximab). Rituximab alone has shown mixed results in eradicating inhibitors when used alone in previous studies for hemophilia A. Next, the group will perform in-depth mechanistic studies to identify additional BAFF modifiers, which may provide additional insight into the pathways that lead to BAFF elevation and inhibitor formation.

These data also have important translational potential for inhibitor in hemophilia A, since there is an FDA-approved anti-BAFF antibody currently used as part of immunosuppressive regimens for autoimmune diseases.

Researchers Look for Drugs That Keep HIV Latent

When HIV infects cells, it can either exploit the cells to start making more copies of itself or remain dormant—a phenomenon called latency. Keeping these reservoirs latent is a challenge. A new paper, published in the Proceedings of the National Academy of Sciences, explains a way to look for chemicals that can keep the virus suppressed into its dormant state.

“The current drug treatments block healthy cells from becoming infected by the virus,” said Yiyang Lu, a PhD student in the Dar laboratory at the University of Illinois Urbana-Champaign. “The latent reservoir poses a bigger problem because it can start producing the virus at any time. Consequently, patients have to remain on antiretroviral therapy all their lives to prevent a viral rebound.”

So far, there are two types of drug treatment strategies: shock-and-kill, where reactivated cells are killed due to HIV, and a second drug cocktail prevents other cells from being infected, or block-and-lock, which forces the virus into a deep latent state so that it does not reactivate again. The problem with the first approach is that there are always some leftover reservoirs that do not become activated. The problem with the second approach, which the researchers are trying to solve, is that there are not many drugs that have been discovered.

Since the transition from latency occurs randomly, measuring the fluctuations in gene expression can provide more coverage than the average gene expression. “Commercial drug screens usually look at mean gene expression. Instead, we used a drug screen that looks at fluctuations in gene expression. Our screen allowed us to therefore find more compounds that could have been overlooked,” Lu said.

“We implemented a time-series drug-screening approach that is less commonly used in other labs,” said Roy Dar, an assistant professor of bioengineering at Illinois and faculty member of the Carl R. Woese Institute for Genomic Biology. The researchers used a T- cell population, which is a reservoir for HIV, that had been infected by the virus. They imaged the cells in 15-minute intervals for 48 hours and tested over 1,800 compounds. They looked at noise maps to identify which drugs can modulate the gene expression.

Using the screen, they were able to find five new latency-promoting chemicals, raising the possibility that similar screens can be successfully adapted to study other systems that exhibit variability in gene expression, such as cancer. They are currently working on understanding how the five novel drugs suppress viral reactivation. “We want to test if these drugs have off-target effects in terms of how many other genes they affect in the host cells,” Dr. Dar said. “We also want to test these drugs in patient samples to see whether these drugs suppress HIV in them.”

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