Cancer vaccine tested in glioblastoma patients shows potential of mRNA aggregates

In a first-in-human clinical trial involving four adult glioblastoma patients, an mRNA cancer vaccine developed at the University of Florida (UF) reprogrammed the immune system to attack tumors.

The results mirror those of preclinical studies in mice and those of a recently reported trial with the mRNA vaccine in 10 dogs that developed spontaneous brain tumors. The dog owners had approved treating their animals with the new vaccine since there were no other therapy options. Researchers say the goal is to take the mRNA vaccine to an expanded Phase I clinical trial involving adult and pediatric brain cancer patients.

The mRNA vaccine, similar to other immunotherapies, attempts to “educate” the immune system that a tumor is foreign, but represents a potential new way to recruit the immune system to fight treatment-resistant cancers using an iteration of mRNA and nanoparticle technology. of lipids. Similar to COVID-19 vaccines, but with two key differences. The new strategy uses the patient’s own tumor cells to create a personalized vaccine and also takes advantage of a complex engineered lipid particle (LP) delivery mechanism, generating multilamellar LP aggregates (LPA) that can function simultaneously as vaccines and immunomodulatory agents.

“Instead of injecting individual particles, we’re injecting groups of particles that wrap around each other like onions, like a bag full of onions,” said Elias Sayour, MD, PhD, a pediatric oncologist at UF Health, who pioneered the new vaccine. . . “And the reason we’ve done it in the context of cancer is that these clusters alert the immune system in a much more profound way than individual particles would.” The results from the canine trial showed how the vaccine reprogrammed the tumor microenvironment (TME) in a matter of days, allowing activated cells of the immune system to fight the tumor.

Among the most impressive findings of the reported study was how quickly the new vaccine, administered intravenously, triggered a vigorous immune system response to reject the tumor, said Sayour, principal investigator at the RNA Engineering Laboratory within Preston. A. Wells Jr of UF. Brain Tumor Therapy Center and researcher at the UF Health Cancer Center and the McKnight Brain Institute.

“In less than 48 hours, we were able to see these tumors go from what we call ‘cold’ (immunological cold, very few immune cells, very muted immune response) to a ‘hot’ and very active immune response. “This was very surprising given how quickly it happened, and what that told us is that we were able to activate the initial part of the immune system very quickly against these cancers, and that is critical to unlocking the downstream effects of the immune response.”

Sayour, who led the multi-institution research team, is the lead author of the team’s report published in Cell, titled “RNA Aggregates Harness the Danger Response for Potent Cancer Immunotherapy.” In their paper, the team stated: “In a first-in-human trial, LPA-RNAs elicited rapid cytokine/chemokine release, immune activation/trafficking, tissue-confirmed pseudoprogression, and glioma-specific immune responses in patients with glioblastoma. “These data support LPA-RNAs as a new technology that simultaneously reprograms the TME and at the same time generates rapid and durable cancer immunotherapy.”

Glioblastoma is the most aggressive and lethal type of brain tumor, with a median survival of around 15 months. The current standard of care involves surgery, radiation, and some combination of chemotherapy.

The new publication is the culmination of promising translational results over seven years of studies, beginning in preclinical mouse models and then progressing to a study involving 10 dogs that had spontaneously developed terminal brain cancer and had no other treatment options. . Dogs offer a natural model for malignant glioma because they are the only other species that develop spontaneous brain tumors with any frequency, said Sheila Carrera-Justiz, DVM, a veterinary neurologist at the UF College of Veterinary Medicine, who collaborates with Sayour on the clinical trials. Gliomas in dogs are universally terminal, she noted.

The canine study yielded promising results, the team reported. “In client-owned canines with terminal gliomas, LPA-RNAs improved survival and reprogrammed the TME, which became ‘hot’ within days of a single infusion.” After treating the dogs with personalized mRNA vaccines, Sayour’s team advanced the research to a small FDA-approved clinical trial in four human patients with primary unmethylated glioblastoma (MGMT). The study was designed to ensure safety and test feasibility before expanding to a larger trial.

The vaccine was personalized for each patient, with the goal of maximizing the immune system response. To generate each vaccine, RNA was first extracted from each patient’s surgically removed tumor, and then the messenger RNA was amplified and wrapped in the newly designed package of biocompatible lipid nanoparticles, to make the tumor cells “look like” a dangerous virus when They are reinjected into the bloodstream and trigger an immune system response.

“In a first-in-human accelerated dose titration (ADT) study (n = 3), we demonstrate that LPA-RNAs trigger rapid cytokine/chemokine release, immune activation/trafficking, and expansion of T-cell immunity in patients refractory to immunotherapy. MGMT unmethylated glioblastoma patients,” the team stated. “In the first subject treated in the expanded Phase I trial, we observed a significant immune response after the fourth vaccine, including tissue-confirmed pseudoprogression, supporting the ability of LPA-RNAs to act as peripheral and intratumoral immunomodulators by at the same time that they provoke antigens. specific immunity against glioma-associated antigens.

Co-author Duane Mitchell, MD, PhD, director of the UF Institute for Clinical and Translational Sciences and the UF Brain Tumor Immunotherapy Program, further stated, “The demonstration that making an mRNA vaccine against cancer in this way The way it generates strong, similar responses in mice, dogs that have spontaneously developed cancer, and human brain cancer patients is a really important finding, because we often don’t know how well preclinical animal studies will translate into similar responses in patients. “While mRNA vaccines and therapies are certainly a hot topic since the COVID-19 pandemic, this is a novel and unique way to deliver mRNA to generate these really significant and rapid immune responses that we are seeing in animals and humans.”

The authors acknowledged that it is too early in the trial to evaluate the clinical effects of the vaccine, but the canine patients lived a median of 139 days, compared with a median survival of 30 to 60 days typical of dogs with this condition. The authors also noted that one limitation is the continued uncertainty about how best to harness the immune system while minimizing the potential for adverse side effects. “Although innate and adaptive responses are critical for cancer immunotherapy, it is unclear how to schedule RNA-LPA administration (neoadjuvant versus adjuvant treatment) and booster infusions (weekly, biweekly, monthly), or the associated frequency. (number of total doses). vaccines), while reconciling these administrations with standard care approaches, including chemoradiation,” they added. With this knowledge, they suggested, it might be possible to develop mRNA constructs that then balance innate and adaptive immunity to maximize effects.

But despite the noted limitations, the authors wrote: “The present work reports a different approach to reprogram innate immunity while polarizing adaptive immune responses. These data highlight the importance of innate immunity in overcoming tumor-mediated immunosuppression, which is essential for the long-term success of adaptive immunotherapy in many immunologically “cold” tumors. The results, they noted, “…show that LPA-RNAs rapidly reprogram the TME in less than 24 h, allowing simultaneously activated T cells to exert their effector functions. “This approach overcomes the first step necessary for successful cancer immunotherapy, tumor immunosuppression and systemic tolerance, by allowing effector cells to compete in a hostile immunoregulatory host system to generate rapid and long-lasting immune responses in murine, canine and human cancers.” .

The next step will be an expanded Phase I clinical trial, including up to 24 adult and pediatric patients, to validate the initial findings. Once an optimal, safe dose is confirmed, an estimated 25 children would participate in Phase II, said Sayour, an associate professor in the Lillian S. Wells department of neurosurgery and the department of pediatrics at the UF College of Medicine. part of UF Health. .

For the new clinical trial, Sayour’s lab will partner with a multi-institution consortium, the Pediatric Neuro-Oncology Consortium, to ship 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 shipping it back to the patient’s medical team, said Sayour, who is also co-director of UF Health’s microbiome and immuno-oncology research program. Oncology Center.

“I’m hopeful that this could be a new paradigm for how we treat patients, a new technology platform for how we can modulate the immune system,” Sayour said. “I’m hopeful that this can now synergize with other immunotherapies and perhaps unlock those immunotherapies. “In this paper we showed that you can really have synergy with other types of immunotherapies, so maybe now we can have a combined immunotherapy approach.”

Sayour and Mitchell hold patents related to the vaccine, which are option-licensed by iOncologi, a UF spinoff biotechnology company in which Mitchell has interests.