In late March 2020, Pediatric oncologist Elias Sayour, M.D., Ph.D., at the University of Florida (UF) Health received a U.S. $ 2.5 million grant from the pediatric cancer foundation CureSearch for Children’s Cancer to start a first-in-human clinical trial to test a novel form of immunotherapy to treat the most aggressive forms of malignant brain tumors.
The study, approved by the U.S. Food and Drug Administration (FDA), is expected to start in the summer od 2020. The clinical study is the latest step in a yearslong translational-research pursuit to determine the efficacy of a new vaccine method developed in Sayour’s lab.
In simple terms, the method works like a flu vaccine, which takes pieces of the flu virus and activates the immune system against them. Sayour’s technique takes pieces of a tumor’s genetic material and activates the immune system to identify and destroy that tumor. If high-grade glioma, a hard-to-treat tumor type, is responsive to this immunotherapy, the treatment will likely translate to other pediatric and adult solid tumors as well.
The method has shown promise in preclinical research in mouse models and currently is being evaluated in a clinical trial involving five pet dog patients suffering from terminal brain cancer with no other treatment options, in collaboration with the UF College of Veterinary Medicine.
Under the two-year CureSearch Catapult Award, the clinical trial will open with an initial companion study in a cohort of four patients with glioblastoma to ensure safety. Following that, Phase I of the trial is planned to include up to 24 adult and pediatric patients.
Once an optimal and safe dose is confirmed, an estimated 25 children would participate in Phase II, said Sayour, an assistant professor in the Lillian S. Wells Department of Neurosurgery and the department of pediatrics in the UF College of Medicine, part of UF Health, and principal investigator of the RNA Engineering Laboratory within UF’s Preston A. Wells, Jr. Center for Brain Tumor Therapy.
A devastating diagnosis
High-grade gliomas, known as anaplastic astrocytoma and glioblastoma, are highly malignant tumors of the central nervous system (CNS). They are among the most devastating diagnoses, with only median survival, typically less than two years.
Overall, these cancers account for approximately 15% to 20 % of CNS tumors in children and adolescents and while children under three years of age are rarely affected, they can appear in all age groups.
The current standard of care of high-grade gliomas involves surgery, radiation and some combination of chemotherapy to relieve symptoms, eliminate or control the tumor. But to date, effective treatments have been elusive. As a result, many patients are encouraged to participate in a clinical trial, if possible.
Like other forms of immunotherapy, the method developed in Sayour’s lab attempts to “educate” the immune system that the tumor is foreign. His method does this in a new way: surgically removing the tumor to obtain a biopsy, extracting genetic material called RNA, and then encasing the RNA in biocompatible lipid nanoparticles.
“When reinjected into the patient, these nanoparticles make cancer look to the body as a dangerous virus, activating the immune system almost immediately against cancer,” Sayour said.
The technique uses lipids, or fats, because those are biocompatible, and it uses nanoparticles to “trick” the immune system by appearing like a viral infectious source when it hits the bloodstream.
“We’re actually taking the tumor of that child, their own individual tumor, and we’re wrapping it in a nanoscale particle to make that patient’s tumor look like a terrible infection to their immune system,” Sayour said.
“And we will try to determine if this immunotherapy works for these children in a way immunotherapy currently doesn’t,” he added.
This method is designed to prompt inflammatory responses within a few hours of administration, said Sayour, a member of the UF Health Cancer Center and the Evelyn F. and William L. McKnight Brain Institute of the University of Florida. In preclinical studies using a mouse model, the technique has prompted a robust anti-viral response and rejection of the tumor, he said.
“Sayour’s preclinical work is extraordinary, and if successful, the implication for treating all solid tumors is nothing short of groundbreaking,” noted Kay Koehler, CureSearch President & Chief Executive Officer.
“Unfortunately, this is the type of innovative project that often goes unfunded in the current research landscape. Our goal is to fill that funding gap and ensure that the most promising projects advance quickly to the clinic to help all children diagnosed with cancer,” Koehler added.
Co-principal investigator Sridharan Gururangan, FRCP, director of pediatric neuro-oncology at UF Health, will help lead the translational effort to bring the new approach from the lab to the clinic.
“We will try to determine if this new form of immunotherapy will work on its own and can also be combined successfully with standard-of-care treatments and other forms of immunotherapy,” Gururangan said.
Pet dogs with the devastating diagnosis of malignant glioma typically survive less than two months, Sayour said. Dogs offer a naturally occurring model for glioma because they are the only other species that develops spontaneous brain tumors with some frequency, with about 14 to 20 per 100,000 dogs acquiring brain tumors compared with an estimated 29.9 per 100,000 people, according to a new study by researchers at Virginia-Maryland College of Veterinary Medicine at Virginia Tech and Wake Forest University Comprehensive Cancer Center.
Sheila Carrera-Justiz, D.V.M., a veterinary neurologist at the UF College of Veterinary Medicine who is partnering with Sayour on the clinical trials, said gliomas in dogs are universally terminal. “There is no definitive treatment in canines,” Carrera-Justiz said. “There is no option for these dogs, and so any clinical trial is going to be really helpful and have the potential to extend their life with a good quality of life. We showed in dogs that this vaccine is safe and effective. It doesn’t hurt. It stimulates the immune system, and they lived longer than expected.”
, “While our canine trial is only a limited data set of five patients, all of our dogs treated thus far have lived longer than I would have expected, and we have one dog that’s a year out right now,” Sayour added.
For the new human pediatric clinical trial, Sayour’s lab will partner with a multi-institutional consortium, the Pacific Pediatric Neuro-Oncology Consortium, to send the immunotherapy treatment to children’s hospitals across the country. They will do this by receiving an individual patient’s tumor, manufacturing the personalized nanoparticle vaccine at UF and sending it back to the patient’s medical team, Sayour said.
“This trial is the culmination of many years of hard work that Sayour has devoted to the development and translation of this technology for the treatment of children and adults with brain tumors,” said Duane Mitchell, M.D., Ph.D., director of the UF Clinical and Translational Science Institute and co-director of the Preston A. Wells, Jr. Center for Brain Tumor Therapy.
“Approval by the FDA for this first-in-human clinical trial is a huge accomplishment in the translational research milestones for our brain tumor center,” Mitchell noted.
The trial will be the fifth first-in-human immunotherapy study undertaken at UF’s Wells Center in pursuit of new treatments or new combinations of treatments to turn deadly brain cancers into livable conditions.
“Sayour’s innovative trial of nanoparticle-delivered immunotherapy represents a huge advance toward finding those treatments,” said Brian Hoh, M.D., chair of UF’s Lillian S. Wells Department of Neurosurgery.
“We are extremely impressed by Dr. Sayour’s bench-to-bedside research, and the UF Health Cancer Center is proud to collaborate with the Preston A. Wells, Jr. Center for Brain Tumor Therapy to fund the preclinical studies for FDA approval to proceed with this trial with the support of CureSearch for Children’s Cancer as we enter this next phase,” said Jonathan Licht, M.D., director of the UF Health Cancer Center.
“These types of new therapies arising from the minds of UF Health researchers are part of the core mission of the UF Health Cancer Center, and we look forward to the successful conduct of this trial,” Licht concluded.
Adoptive Cellular Therapy in Pediatric Patients With High-grade Gliomas (ACTION) – NCT03334305
 Sayour EJ, De Leon G, Pham C, et al. Systemic activation of antigen-presenting cells via RNA-loaded nanoparticles. Oncoimmunology. 2016;6(1):e1256527. Published 2016 Nov 18. doi:10.1080/2162402X.2016.1256527