Life-changing and Practice-changing Novel Therapeutics Advance

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The U.S. Food and Drug Administration approved the first-ever treatment for peanut allergies, an oral immunotherapy that researchers in our Allergy Section have worked over a decade to help develop. While the medication is not a cure-all, Jonathan Spergel, MD, PhD, section chief of CHOP’s Food Allergy Center, said it may minimize severe reactions to accidental exposure for many children managing peanut allergies — of which there are 1.2 million children in the United States.

“For many patients, [this medication] opens up their lives tremendously,” Dr. Spergel said. “They’re able to go out to dinner, or go out to a ballgame, or travel with a lot less anxiety. It gives them some level of confidence, and for many patients, it’s really opened up the door to do many things restricted to them in the past. For patients who have done well, it’s been truly life changing.”

Children and young adults ages 4 to 17 are eligible for the drug, which pharmaceutical company Aimmune Therapeutics manufactures. Previously, no treatments for peanut allergies existed, save for avoiding peanuts altogether. And despite a parent or caregiver’s best attempts to monitor what their child consumes, reactions to peanut allergies still send one in four children to the emergency room every year.

Shifting Standard of Care

Curative therapy for pediatric acute myeloid leukemia (AML) involves high doses of anthracycline chemotherapy. Although this treatment is highly effective at killing cancer cells, it is also highly cardiotoxic. In a study of more than 1,000 pediatric patients with AML, researchers found that pre-treatment with dexrazoxane before each round of anthracycline chemotherapy helped mitigate cardiotoxicity often associated with the treatment.

Dexrazoxane also was linked to lower treatment-related mortality, and it did not increase other non-cardiac toxicities. The study appeared in the Journal of Clinical Oncology.

Richard Aplenc, MD, PhD, MSCE, led the Children’s Oncology Group (COG) study. Dr. Aplenc is assistant vice president and chief clinical research officer at CHOP, professor of Pediatrics at the Perelman School of Medicine at the University of Pennsylvania, and core faculty member of the Center for Pediatric Clinical Effectiveness (CPCE) at CHOP. First author Kelly D. Getz, PhD, MPH is also a core faculty member of the CPCE at CHOP, and assistant professor of Epidemiology at Penn.

“We demonstrated the benefit of dexrazoxane with respect to the cardioprotection and secondarily, the suggestion of a lower treatment-related mortality,” Dr. Getz said. “These findings are practice-changing: The upcoming COG Phase III clinical trial for AML will include a requirement to administer dexrazoxane for cardioprotection to patients receiving standard anthracycline chemotherapy.”

A team of researchers enhanced the body’s bacteria-capturing neutrophil extracellular traps (NETs) by adding a protein called platelet factor 4 that binds to the NETS and makes them better at catching and holding onto bacteria. This approach could transform the way clinicians treat sepsis in the future and could have implications for the treatment of other immune conditions in which NETs are involved. Sepsis is a deadly complication of infection and a leading cause for hospital death.

“These results indicate that our NET-stabilizing interventions enhance that ability of NETs to capture bacteria while preventing them from releasing antibacterial compounds that can cause organ damage, dramatically improving bacterial clearance as well as survival in a mouse model of sepsis,” said Kandace Gollomp, MD, physician researcher in the Division of Hematology and first author of the paper. “Given that the treatment was most effective when combined with antibiotics, it’s possible that these two treatments may act synergistically to lead to better outcomes.”

The findings appeared in the journal Blood, and the study team presented them as an abstract at the 61st American Society of Hematology annual meeting, where the work was one of the highest scoring abstracts among a group of more than 4,500 submissions. The researchers’ idea to make NETS even stickier to catch more bacteria also caught the attention of the National Institutes of Health Director Francis Collins, MD, PhD, who covered the study in his blog post “Building a Better Bacterial Trap for Sepsis.”

Investigator Michael Chorny, PhD, received support from the National Cancer Institute for a collaborative effort with Garrett Brodeur, MD, director of the Cancer Predisposition Program, and Ivan Alferiev, PhD, research associate professor of Pediatrics, to evaluate and optimize a novel prodrug-based delivery strategy for tumor-specific pharmacotherapy of neuroendocrine cancers.

A prodrug is a medication that is inert until it is converted by the body into a pharmacologically active drug. The prodrug design will be a tool for achieving high selectivity and potency of a chemotherapeutic, while protecting normal tissues from toxic drug exposure.

“The drug itself is chemically optimized to overcome drug elimination and drug resistance,” Dr. Chorny explained. “The end result is more drug to the tumor, and less to the patient.”

The researchers hope this project will facilitate the development, translation, and clinical implementation of targeted prodrugs for treating high-risk neuroblastoma and other aggressive solid tumors that currently lack effective treatment options.

In a related breakthrough study, the research team engineered a prodrug in their lab that led to long-term remissions in 80 percent to 100 percent of mice with drug-resistant or high-risk solid tumors. The findings, which could soon lead to clinical trials, appeared in Cancer Research, a journal of the American Association for Cancer Research.

Refining Gene-delivery

A team of CHOP-Penn investigators successfully delivered a gene therapy using a viral vector capable of crossing the blood-brain barrier and found evidence that the corrected gene had distributed to various parts of the brain, including the cerebral cortex, hippocampus, and mid-brain.

John Wolfe, VMD, PhD, a researcher at CHOP and the University of Pennsylvania’s School of Veterinary Medicine and the Perelman School of Medicine, worked with a large animal model of a type of lysosomal storage disease, alpha-mannosidosis. This inherited condition causes severe disease of the brain, naturally occurs in this animal model, and results from a mutated copy of the alpha-mannosidase gene.

“This is the first example of a large-brain mammal with a bona fide human genetic disease that has intellectual disability as part of the human syndrome where we’ve been able to correct the biochemistry and pathologic lesions in the whole brain,” said Dr. Wolfe in a Penn Today article. “It’s a big advance. Nobody has been able to treat the whole brain of a large-brained animal before. We’re hopeful that this will translate into clinical use in humans.”

The study findings appeared in Brain, a journal of neurology.

Ian Henrich, PhD, a postdoc researcher in the Department of Pathology and Laboratory Medicine at CHOP, is one of three recipients of the University Science Center’s QED Proof-of-Concept Program award. Dr. Henrich is collaborating with Margaret Chou, PhD, a cancer researcher, to investigate the effects of USP6, a protein that optimizes a patient’s immune response, on acute myeloid leukemia (AML), the second most common blood cancer.

At the end of the one-year QED period, Drs. Chou and Henrich aim to have a final phase product — a nanoparticle delivering USP6 that can be targeted to the AML cancer cell with verified activity in animal models that will lead to future clinical trials. The researchers are confident USP6-related therapy will have implications beyond AML. USP6 simultaneously targets multiple pathways, attacking cancer cells from various immunostimulatory angles, which helps prevent them from building resistance.

“Not only do we envision that the USP6 nanoparticle therapy could act as the standalone agent in combating cancer, we think it can greatly increase the number of patients who can respond to existing immunotherapies,” Dr. Chou said.