A personalized mRNA vaccine developed at the University of Florida has demonstrated the ability to rapidly reprogram the immune system to attack glioblastoma, the most aggressive and lethal form of brain cancer, according to results from the first-ever human clinical trial published in the journal Cell.
The Phase 1 trial involving four adult patients showed that the vaccine triggered a vigorous immune response within 48 hours of administration, transforming tumors from "immune cold" states with minimal immune cell activity to "hot" states with robust immune activation. This rapid transformation represents a significant breakthrough in treating a cancer that typically has a median survival of just 12-18 months.
Novel Vaccine Design and Delivery Mechanism
The vaccine employs two key innovations that distinguish it from COVID-19 mRNA vaccines: the use of each patient's own tumor cells to create personalized treatment and a newly engineered complex delivery mechanism. According to senior author Dr. Elias Sayour, a pediatric oncologist at UF Health and co-leader of the UF Health Cancer Center's Immuno-Oncology and Microbiome research program, the vaccine uses clustered lipid nanoparticles rather than single particles.
"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," Sayour explained. "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."
The manufacturing process involves extracting genetic material called RNA from each patient's surgically removed tumor, amplifying the messenger RNA, and wrapping it in biocompatible lipid nanoparticles. This packaging makes tumor cells appear as dangerous viruses when reinjected into the bloodstream, prompting a strong immune system response.
Rapid Immune Activation and Clinical Outcomes
The speed of immune activation surprised researchers, with measurable changes occurring within two days of vaccination. "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," Sayour noted.
While it remains too early to assess the full clinical effects of the vaccine, patients in the trial either lived disease-free longer than expected or survived longer than expected compared to typical outcomes for glioblastoma patients.
Translational Research Success Across Species
The human trial results mirror findings from preclinical studies in mouse models and a clinical trial involving 10 pet dogs with naturally occurring brain tumors. The canine participants, whose owners consented to treatment when no other options remained, lived a median of 139 days compared to the typical 30-60 days for dogs with the condition.
Dr. Duane Mitchell, director of the UF Clinical and Translational Science Institute and co-author of the study, emphasized the significance of consistent results across species. "The demonstration that making an mRNA cancer vaccine in this fashion generates similar and strong responses across mice, pet dogs that have developed cancer spontaneously and human patients with brain cancer 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."
Expanding Clinical Development
Based on these promising initial results, the Food and Drug Administration has approved expansion to a larger Phase 1 clinical trial that will include up to 24 adult and pediatric patients. The trial will be conducted through a multi-institution consortium, the Pediatric Neuro-Oncology Consortium, with UF manufacturing personalized vaccines for patients at children's hospitals across the country.
Following dose optimization and safety confirmation, an estimated 25 children would participate in a Phase 2 trial. The research team plans to explore combination approaches with other immunotherapies, as the study demonstrated potential synergy with additional immune-based treatments.
Addressing Treatment-Resistant Cancer
Glioblastoma affects more than 3,000 people annually in the UK alone and represents one of the most challenging cancers to treat. Current standard of care involves surgery, radiotherapy, and chemotherapy, but options remain severely limited with no cure available.
Dr. Karen Noble, Director of Research, Policy and Innovation at Brain Tumour Research, highlighted the significance of the breakthrough: "This devastating form of cancer is notoriously difficult to treat, the options are very limited and there is no cure. News of this potential breakthrough and the fact it can now progress to a larger clinical trial is therefore hugely exciting for our community."
The research represents seven years of translational studies and exemplifies the collaborative approach between the UF Health Cancer Center, McKnight Brain Institute, Preston A. Wells Jr. Center for Brain Tumor Therapy, and the Lillian S. Wells Department of Neurosurgery. The breakthrough demonstrates how institutional investment in research infrastructure can enable direct translation from laboratory discoveries to patient care.
Despite the promising results, researchers acknowledge continued uncertainty about optimally harnessing the immune system while minimizing potential adverse effects. However, Sayour expressed optimism about the platform's potential: "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."
