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 the tumors.

The results mirror those from preclinical mouse studies, and from a newly reported trial with the mRNA vaccine in 10 pet dogs that developed spontaneous brain tumors. The dogs’ owners had approved their animals’ treatment using the new vaccine as there were no other therapy options. The researchers say the aim is to progress the mRNA vaccine into an expanded Phase I clinical trial involving adult and pediatric brain cancer patients.

The mRNA vaccine—akin 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 technology and lipid nanoparticles, 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 harnesses an engineered complex lipid particle (LP) delivery mechanism, generating multi-lamellar LP aggregates (LPA) that can simultaneously function as vaccines and as immunomodulating agents.

“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 Elias Sayour, MD, PhD, a UF Health pediatric oncologist who pioneered the new vaccine. “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.” Results from the canine trial showed how the vaccine reprogrammed the tumor microenvironment (TME) within days, allowing the activated immune system cells to fight the tumor.

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

“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. 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, who led the multi-institution research team, is senior author of the team’s published report 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, RNA-LPAs elicited rapid cytokine/chemokine release, immune activation/trafficking, tissue-confirmed pseudoprogression, and glioma-specific immune responses in glioblastoma patients … These data support RNA-LPAs as a new technology that simultaneously reprograms the TME while eliciting rapid and enduring cancer immunotherapy.”

Glioblastoma is the most aggressive and lethal type of brain tumor, with a median survival time 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, starting in preclinical mouse models and then progressing to a study involving 10 pet dogs that had spontaneously developed terminal brain cancer and had no other treatment options. Dogs offer a naturally occurring model for malignant glioma because they are the only other species that develops spontaneous brain tumors with some frequency, said Sheila Carrera-Justiz, DVM, a veterinary neurologist at the UF College of Veterinary Medicine who is partnering 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, RNA-LPAs improved survivorship and reprogrammed the TME, which became ‘hot’ within days of a single infusion.” After treating the pet dogs with personalized mRNA vaccines, Sayour’s team then advanced the research to a small FDA-approved clinical trial in four human patients with primary MGMT unmethylated glioblastoma. The study was designed to ensure safety and test feasibility before expanding to a larger trial.

The vaccine was personalized to each patient, with the aim of maximizing immune system response. To generate each vaccine, RNA was first extracted from each patient’s own surgically removed tumor, and then the messenger RNA 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 and prompt an immune-system response.

“In a first-in-human accelerated-dose titration [ADT] study (n = 3), we show that RNA-LPAs elicit rapid cytokine/chemokine release, immune activation/trafficking, and expansion of T cell immunity in immunotherapy-refractory MGMT unmethylated glioblastoma patients,” the team stated. “In the first subject treated on the expanded Phase I trial, we observed significant immunologic response after the fourth vaccine, including tissue-confirmed pseudoprogression, supporting the ability of RNA-LPAs to act as both the peripheral and intratumoral immunomodulators while simultaneously eliciting antigen-specific immunity against glioma-associated antigens.”

Co-author Duane Mitchell, MD, PhD, director of the UF Clinical and Translational Science Institute and the UF Brain Tumor Immunotherapy Program, further stated, “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. And while mRNA vaccines and therapeutics are certainly a hot topic since the COVID-19 pandemic, 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.”

The authors acknowledged that it is too early in the trial to assess 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 for dogs with the condition. The authors also noted that one limitation is 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 not clear how to time the administration of RNA-LPAs (neoadjuvant versus adjuvant treatment) and booster infusions (weekly, biweekly, monthly), or the associated frequency (number of total vaccines), all while reconciling these administrations with standard-of-care approaches including chemoradiation,” they added. With this knowledge, they suggested, it may be possible to develop mRNA backbone constructs that then balance innate and adaptive immunity to maximize the effects.

But despite the noted limitations, the authors wrote, “The work herein reports a distinct approach to reprogram innate immunity while simultaneously 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 pointed out, “… show that RNA-LPAs 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, allowing effector cells to compete in a hostile immunoregulatory host system to engender rapid and long-lasting immunologic responses across murine, canine, and human cancer.”

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 and 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 in 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 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, who is also 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,” Sayour said. “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.”

Sayour and Mitchell hold patents related to the vaccine, which are under option to license by iOncologi, a biotech company spun out from UF, in which Mitchell holds interest.

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