UF Health scientists make breakthrough in possible cancer treatment

The University of Florida has developed a preliminary vaccine that may give a patient's immune system the potential to fight treatment-resistant cancers.

In what a news release called a first-ever human clinical trial of this type, in which four adult patients participated, the vaccine "quickly reprogrammed the immune system to attack glioblastoma, the most aggressive and lethal brain tumor." The vaccine uses mRNA (messenger RNA) technology and lipid nanoparticles, which a news release said is similar to COVID-19 vaccines, but with two main differences: the use of a patient’s own tumor cells to create a personalized vaccine as well as a new delivery mechanism within the vaccine.

"This disease is so challenging," said Elias Sayour, UF Health pediatric oncologist and co-leader of the UF Health Cancer Center’s Immuno-Oncology and Microbiome research program, in an interview with The Sun. "Even though each glioblastoma is different from another patient's glioblastoma, within each patient's tumor, the tumor cells are often different from each other, and that makes it really challenging when you want to target these cancer cells if they're all a little different from each other. And on top of that, these tumors, these glioblastomas, they trick the immune system and the immune system is actually working on behalf of the tumor — not against it. So it's this, like, double whammy where not only is the immune system not fighting the cancer, it's actually helping it, and it even kills immune cells that you can try to generate against it. So, in many ways, we feel like if we can cure this disease, we honestly believe we can cure all cancer because of the challenges, this one has so many challenges."

In the small clinical trial — which was approved by the Food and Drug Administration — genetic material called RNA was extracted from each of the four patients' surgically removed tumors. Then, mRNA — the blueprint of what's inside every cell, including tumor cells — was amplified and wrapped in the newly designed packaging of biocompatible lipid nanoparticles, to make tumor cells “look” like a dangerous virus when reinjected into the bloodstream, therefore prompting a response from the patient's immune system. The vaccine was personalized to each patient to get the most out of their immune systems.

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“Instead of us injecting single particles, we’re injecting clusters of particles that are wrapping around each other like onions, like a bag full of onions,” said Sayour in a news release. “And the reason we’ve done that in the context of cancer is these clusters alert the immune system in a much more profound way than single particles would.”

Sayour is also a principal investigator of the RNA Engineering Laboratory at UF’s Preston A. Wells Jr. Center for Brain Tumor Therapy and a McKnight Brain Institute investigator who led the research team. Additionally, he is a pediatric oncologist with the goal of eradicating pediatric brain cancer, which Sayour said is the number one cancer killer of children in the country.

"It's been really important for me, and for our group, to develop vaccines targeted against childhood brain cancer," he said. "We had to start in adults because this is a brand new therapy that's never been done before, but our hope, really, is to move this into into pediatric patients as quickly as possible."

Sayour said in a news release that one of the most impressive findings of the new method — delivered intravenously — was how quickly it triggered an immune-system response to reject the tumor.

“In less than 48 hours, we could see these tumors shifting from what we refer to as ‘cold’ — immune cold, very few immune cells, very silenced immune response — to ‘hot,’ very active immune response,” he said in a news release.

Similar to other immunotherapies, the mRNA vaccine attempts to teach the immune system that a tumor is foreign.

"The personalized RNA material, the cluster, the onion cluster approach of using an RNA therapeutic and the intravenous route of administration, all of those things coupled together, we found can elicit [very] rapid immune responses in these patients within a few hours," Sayour said in an interview. "What we were seeing in the blood matched what we were seeing in the tumor: very, very, rapid immune responses..."

A news release said glioblastoma has a median survival of around 15 months and usually involves surgery, radiation and some combination of chemotherapy. Although too early in the trial to assess the clinical effects of the vaccine, a news release said, the four patients either lived disease-free or survived for longer than expected.

Preliminary trials

The results of the human trial mirror the results from a clinical trial of 10 pet dog patients suffering from naturally occurring brain tumors as well as results from preclinical mouse models.

UF was given permission by the owners of the dogs, which had developed terminal brain cancer with no other treatment options, to conduct the trial in collaboration with UF's College of Veterinary Medicine. In a news release, Sheila Carrera-Justiz, UF College of Veterinary Medicine veterinary neurologist (who is partnering with Sayour on the clinical trials), said that dogs offer a naturally occurring model for malignant glioma because they are the only other species that develops spontaneous brain tumors with some frequency.

Gliomas (a tumor which forms when certain glial cells grow out of control) in dogs are universally terminal, Carrera-Justiz said, and a median survival of 30 to 60 days is typical for dogs with the condition. The 10 dogs in the clinical trial lived a median of 139 days.

"It's been a phenomenal opportunity for us to demonstrate this is feasible, this is safe and potentially effective in these animals, provide that data to the Food and Drug Administration and get approval," said Sayour in an interview.

Sayour noted that the dogs had terminal diseases and were enrolled in the trial with their owners' consent.

Next steps

Authors of the study's research paper said that despite promising results, one limitation is the continued uncertainty regarding the best way to harness the immune system while minimizing the possibility of adverse side effects.

"Safety is a concern when we're manipulating the immune response," Sayour said in an interview. "The immune system is like fire and if you activate it too strongly, too quickly — which again, I think is important for cancer — it can also be uncontrolled, so much so that it could lead to death. So, it's been a slow and steady approach. We are hoping to identify a safe and maximally tolerated dose that's feasible and yet effective."

With support from the FDA as well as the CureSearch for Children’s Cancer foundation, the next step will involve an expanded Phase I clinical trial that will include up to 24 adult and pediatric patients to validate the findings of the vaccine. Then, after an optimal and safe dose is confirmed, around 25 children will participate in Phase 2.

For the new clinical trial, Sayour’s lab will partner with the Pediatric Neuro-Oncology Consortium (PNOC) to send the immunotherapy treatment to children’s hospitals across the country. In order to create the individualized vaccine, a news release said, the team will receive an individual patient’s tumor and manufacture the personalized vaccine at UF, then send it back to the patient’s medical team.

"We want to be able to learn how to combine this with other immunotherapies so we can get even greater effect, more long-lived effect, and ultimately cures," Sayour said in an interview. "Not just in glioblastoma, but childhood cancer and then other cancers. And in my heart, I believe this is an important tool in the war on cancer, but [it] will likely need to be combined with other therapies to achieve maximal effect."

Additionally, he said, UF hopes to partner with PNOC sites in Israel and the Netherlands as part of the trial. Through these partnerships, Sayour said, they hope to enroll "enough pediatric patients to show safety, feasibility and, hopefully, immunologic effects and improved survivorship."

This article originally appeared on The Gainesville Sun: University of Florida creates cancer vaccine for brain tumors