In a pioneering first-in-human clinical trial, an mRNA cancer vaccine developed at the University of Florida (UF) has shown promise in treating patients with primary MGMT unmethylated glioblastoma, one of the deadliest brain cancers. Four adult patients participated in the study. The vaccine, which works by reprogramming the immune system to counter the tumors, was first tested in mouse studies and a trial involving dogs with spontaneous brain tumors. As a follow-up to the four-person trial, the researchers hope to study the vaccine in a larger Phase I clinical trial of adult and pediatric patients.
Personalized and Potent
Like other immunotherapies, the strategy of the mRNA vaccine is to trigger an immune response against the tumor. The researchers used the patient’s tumor cells to create a personalized vaccine and leveraged a delivery system that uses clusters of engineered lipid particles (LPs) known as lamellar LP aggregates (LPAs) to enhance the immune system’s response. “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,” explained Elias Sayour, a UF Health pediatric oncologist. “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.”
Swift and Strong Immune Response
The results, published in Cell, were impressive. The vaccine transformed the tumor microenvironment (TME) in less than 48 hours from immune “cold” to “hot,” indicating a vigorous immune response. “That was very surprising given how quickly 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,” Sayour noted.
Animal and Human Trials
The development of this vaccine began with preclinical mouse models and progressed to a study involving 10 dogs with terminal brain cancer. In this study, the vaccine improved survival and reprogrammed the TME, the research team reported.
Following the canine study, researchers conducted the four-person trial with primary MGMT unmethylated glioblastoma. Using RNA extracted from each patient’s own tumor, the vaccine was engineered specifically for each individual. Delivered via the engineered LPA packaging, the vaccine prompts an immune response against the tumor. The initial human trial confirmed the vaccine’s safety and feasibility.
Implications and Challenges
Study co-author Duane Mitchell emphasized the importance of the results. “The demonstration that making an mRNA cancer vaccine in this fashion generates similar and strong responses across mice, 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.”
Despite the promising early results, the researchers acknowledged that there is uncertainty about the optimal timing and frequency of vaccine administration. Balancing innate and adaptive immunity to maximize effects while minimizing side effects remains a critical focus. The vaccine’s ability to reprogram the tumor microenvironment rapidly is essential for overcoming tumor-mediated immunosuppression, a major hurdle in cancer treatment.
A New Paradigm
Next, the researchers hope to enroll up to 24 adult and pediatric patients in a larger Phase I trial. If this second Phase I trial is successful, then they plan to conduct a Phase II trial that will include an estimated 25 pediatric patients. Sayour’s lab will partner with the Pediatric Neuro-Oncology Consortium to manufacture and distribute the personalized vaccines.
Sayour is optimistic. “I am hopeful for how this could now synergize with other immunotherapies and perhaps unlock those immunotherapies. 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 of immunotherapy.”
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