Cancer Vaccine Triggers Fierce Immune Response to Fight Malignant Brain Tumors

Dr Elias Sayour (left) – the University of Florida

In a first-ever human clinical trial, an mRNA cancer vaccine developed at the University of Florida successfully reprogrammed patients’ immune systems to fiercely attack glioblastoma, the most aggressive and lethal brain tumor.

The results in four adult patients mirrored those in 10 pet dog patients suffering from brain tumors whose owners approved of their participation.

The discovery represents a potential new way to recruit the immune system to fight treatment-resistant cancers using an iteration of mRNA technology and lipid nanoparticles, similar to COVID-19 vaccines, but with two key differences: use of a patient’s own tumor cells to create a personalized vaccine, and a newly engineered complex delivery mechanism within the vaccine.

“Instead of us injecting single particles, we’re injecting clusters of particles that are wrapping around each other like onions,” said senior author Elias Sayour, M.D., Ph.D., a UF Health pediatric oncologist who pioneered the new vaccine, which like other immunotherapies attempts to “educate” the immune system that a tumor is foreign.

“These clusters alert the immune system in a much more profound way than single particles would.”

Among the most impressive findings was how quickly the new method spurred a vigorous immune-system response to reject the tumor, said Sayour, principal investigator at the University’s RNA Engineering Laboratory and McKnight Brain Institute investigator who led the multi-institution research team.

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

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“That was very surprising given how quick this happened, and what that told us is we were able to activate the early part of the immune system very rapidly against these cancers, and that’s critical to unlock the later effects of the immune response,” he explained in a video (below).

Glioblastoma is among the most devastating diagnoses, with median survival around 15 months. Current standard of care involves surgery, radiation and some combination of chemotherapy.

The new report, published May 1 in the journal Cell, is the culmination of seven years of promising studies, starting in preclinical mouse models.

In the cohort of four patients, genetic material called RNA was extracted from each patient’s own surgically removed tumor, and then messenger RNA (mRNA)—the blueprint of what is inside every cell, including tumor cells—was amplified and wrapped in the newly designed high-tech packaging of biocompatible lipid nanoparticles, to make tumor cells “look” like a dangerous virus when reinjected into the bloodstream to prompt an immune-system response.

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The vaccine was personalized to each patient with a goal of getting the most out of their unique immune system.

“The demonstration that making an mRNA cancer vaccine in this fashion generates similar and strong responses across mice, pet dogs, and human patients is a really important finding, because oftentimes we don’t know how well the preclinical studies in animals are going to translate into similar responses in patients,” said Duane Mitchell, M.D., Ph.D., director of the UF Clinical and Translational Science Institute and a co-author of the paper. “This is a novel and unique way of delivering the mRNA to generate these really significant and rapid immune responses that we’re seeing across animals and humans.”

While too early in the trial to assess the clinical effects of the vaccine, the patients either lived disease-free longer than expected or survived longer than expected. The 10 pet dogs lived a median of 4.5 months, compared with a median survival of 30-60 days typical for dogs with the condition.

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The next step, with support from the Food and Drug Administration and the CureSearch for Children’s Cancer foundation, will be an expanded Phase I clinical trial to include up to 24 adult and pediatric patients to validate the findings. Once an optimal and safe dose is confirmed, an estimated 25 children would participate in Phase 2.

For the new clinical trial, Sayour’s lab will partner with the multi-institution 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 vaccine at UF and sending it back to the patient’s medical team, said Sayour, co-leader of the Immuno-Oncology and Microbiome research program at the UF Health Cancer Center.

“I am hopeful that this could be a new paradigm for how we treat patients, a new platform technology for how we can modulate the immune system,” said Sayour in a UF Health news report by Michelle Jaffee. “We showed in this paper that you actually can have synergy with other types of immunotherapies, so maybe now we can have a combination approach to unlock those immunotherapies.”

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