CHOP-developed Drug for High-risk Tumors Advances to Clinical Trials in Children

Garrett Brodeur, MD, with patient Ellie and genetic counselor Sarah Baldino. Dr. Brodeur, Director of CHOP's Cancer Predisposition Program, is the researcher behind PEEL-224, a new cancer therapy.

Following a decade of research, a pioneering therapy developed by scientists at Children's Hospital of Philadelphia will be tested in children with solid tumors that have relapsed or have not responded to previous treatment.

PEEL-224 destroys tumors by inhibiting the enzyme topoisomerase-1 (Topo-1). The novel drug's unique chemical optimization and nanocarrier assembly dramatically increases drug delivery while simultaneously reducing the toxic effects of treatment compared to conventional chemotherapy.

The therapy has showed potential in pre-clinical studies and in adult patients. Now, CHOP will serve as a Phase 1/2 trial site to test PEEL-224 in children and adolescents who have some of the most aggressive solid tumors, including neuroblastoma, Ewing sarcoma, and rhabdomyosarcoma.

Garrett Brodeur, MD, director of the Cancer Predisposition Program at CHOP — together with research scientists Michael Chorny, PhD, and Ivan Alferiev, PhD — developed the prototype for PEEL-224 and led the studies that have advanced the therapy to clinical trials.

"We have come a long way in improving the survival rate for children with cancer, from around 20% when I started my career, to over 80% now," Dr. Brodeur said. "However, we have plateaued in recent years. We are going to need new approaches for the 20% who we are not curing, and to lower the toxicity of treatment in the children who we are curing."

A Less Toxic Way to Target Tumors

Nanotechnology was not on Dr. Brodeur's radar when he attended a talk by Robert Levy, MD, at CHOP in 2008. Dr. Levy, now director of Cardiology Research, explained during his presentation that nanoparticles — therapeutic agents between 10 and 100 nanometers in diameter — could be used to target metal stents in coronary arteries and reduce restenosis in patients with cardiovascular disease.

"He mentioned that nanoparticles could be used to treat cancer because of the enhanced permeability and retention effect," Dr. Brodeur said.

In normal tissues, blood vessels have tightly joined endothelial cells, whereas tumor blood vessels develop more rapidly, haphazardly, and tend to be leaky.

"By designing nanoparticles large enough to pass by most normal tissues but small enough to pass through leaky tumor vessels," Dr. Brodeur said, "drugs could be selectively delivered to tumors — which seemed like a wicked cool idea if achievable."

The design could solve a significant disadvantage in current cancer drug delivery methods: Traditional chemotherapy delivers only a small fraction of the drug to the tumor — less than 1%. That means that a drug such as irinotecan (SN-38) — that is commonly used to treat solid tumors — is limited in its effectiveness, is susceptible to drug resistance mechanisms in tumors, and can lead to severe side effects, like diarrhea and bone marrow suppression.

To overcome these challenges, Dr. Brodeur teamed up with Dr. Chorny and Dr. Alferiev in the Division of Cardiology at CHOP. The team sought to create a unique, more sustainable Topo-1 inhibitor and deliver it as a nanomedicine.

Together, they identified a new drug, called SN-22, which has pharmacological advantages compared to irinotecan (SN-38). Due to a modification in the drug's molecular structure, SN-22 withstands inactivation and rapid removal, allowing it to reach and sustain its markedly higher levels in the tumor. Additionally, unlike irinotecan, it also overcomes a mechanism of drug resistance that allows the most drug-resistant cancer cells to survive through therapy and give rise to recurrent tumors.

"This ability to hit the super-refractory cancer stem cells that are protected by this defense mechanism makes a day-and-night difference in the management of high-risk disease,"

Dr. Chorny said. "It also dramatically improves the chances to fully eradicate it, compared to standard therapies."

To further improve the therapy's effectiveness, the researchers assembled SN-22 to a nanoparticle, in which four molecules of the agent are attached to a four-arm polyethylene glycol scaffold. This design, known as a nanoparticle "prodrug," is inactive when infused, but converts to an active therapeutic by slowly releasing the Topo-1 inhibitor inside the tumor.

While smaller drugs like irinotecan easily cross from the blood into tissues all over the body, exposing patients to toxic side effects, the newly designed therapeutic is much larger than the active molecules in conventional chemotherapies. Its large size allows it to primarily accumulate in the tumor, and then it slowly releases SN-22 over hours and days — a "low and slow" drug delivery approach.

"With nanomedicines, a single injection can last a long time, so we get much more drug in the tumor," Dr. Brodeur said. "And because it stays in circulation while attached to the carrier, there is much less exposure to the patient, making this therapy both more effective and less toxic."

From the Bench to Children's Bedsides

In pre-clinical studies, SN-22 was highly effective — even against drug-resistant tumors. The therapy also did not lead to significant adverse effects, unlike irinotecan, which caused elevated liver enzymes and altered blood counts in animal models.

In 2019, Joshua Schiffman, MD, CEO and co-Founder of Peel Therapeutics, visited the Brodeur Lab to discuss the possibility of licensing the new therapy, now called PEEL-224. The company launched a successful clinical trial in 2022 to test PEEL-224 in adults with advanced, recurrent solid tumors.

"Preliminary data from the adult trials shows that even patients whose tumors were resistant to irinotecan responded to PEEL-224," Dr. Brodeur said. "And the therapy was dramatically less toxic."

Now, CHOP researchers will evaluate the therapy in children between 1 and 18 years old with a refractory, progressive, or relapsed solid tumor. The trial will be led by pediatric oncologists Jacquelyn Crane, MD, and Theodore Laetsch, MD.

For Dr. Brodeur, the clinical trial is only the first step in the growing potential of nanotechnology to develop more effective, less toxic cancer therapies — he and his colleagues have additional "second-generation" agents in the pipeline.

"There is so much optimization and variation that we can take advantage of in terms of using nanoparticles as a primary mode of drug delivery," Dr. Brodeur said.