mRNA cancer vaccine triggers powerful immune response in brain tumors

In a first-in-human clinical trial with four adult patients, an mRNA cancer vaccine quickly reprogrammed the immune system to attack the human body. glioblastoma, the most aggressive and deadly brain tumor.

The results – which are published this week in the journal cell– consistent with data obtained from 10 dogs suffering from natural brain tumors whose owners approved their participation because they had no other treatment options. They are also similar to those observed in preclinical mouse models.

The achievement of a group of researchers from the University of Florida (UF, USA) will now be tested in Phase 1 pediatric clinical trial against brain cancer.

According to the authors, this discovery could provide a new way to mobilize the immune system to fight treatment-resistant cancer through the use of mRNA and lipid nanoparticle technology, similar to vaccines used against Covid-19, but with two key differences: the use of the patient’s own tumor cells to create a personalized vaccine and a complex, newly designed delivery mechanism within the vaccine.

The mRNA technology is similar to Covid vaccine technology, but with two differences: the use of a patient’s tumor cells for a personalized vaccine and a new delivery mechanism.

“Instead of introducing individual particles, we introduce groups of particles. particles that wrap around each other like an onion“, explains the main author, Elias Sayurpediatric oncologist at UF Health, a pioneer of a new vaccine that, like other immunotherapies, attempts to “train” the immune system to understand that a tumor is foreign.

Sayur, who led the research team, explains: ““The reason we did this in the context of cancer is that these clusters alert the immune system much more deeply than individual particles.”

Speed ​​of action of the vaccine

The researcher says one of the most impressive results was how quickly the new method administered intravenouslystimulated a vigorous immune system response to tumor rejection.

“In less than 48 hours, we were able to see these tumors go from what we call ‘cold,’ meaning with very few immune cells and a very suppressed immune response, to ‘hot,’ a very active immune response.” He says. “It was very surprising because of how quickly it happened and it showed us that we were able to very quickly activate the initial part of the immune system against these cancers, and this is important for uncovering the downstream effects of the immune response.”

In less than 48 hours, we were able to see the tumors go from what we call “cold,” meaning few immune cells and a very suppressed immune response, to “hot,” a very active immune response.

Elias Sayur
— Head of work – UF Health

Glioblastoma is one of the most devastating diagnoses, with a median survival of approximately 15 months. Current standard treatment consists of surgery, radiation therapy, and some combination of chemotherapy.

The new publication is the culmination of promising translation results throughout seven years of studywhich began with preclinical mouse models and then clinical trials on 10 companion dogs that spontaneously developed terminal brain cancer and had no other treatment options.

Mice, dogs and people

The test on these animals was carried out with the consent of the owners and in collaboration with the Faculty of Veterinary Medicine at the UF. “Dogs provide a natural model for malignant glioma because they are the only species in which spontaneous brain tumors develop at any frequency,” he explains. Sheila Carrera-Eustice, a doctor of veterinary medicine and veterinary neurologist from the UF College of Veterinary Medicine, who is collaborating with Sayur on clinical research. According to her, gliomas in dogs are incurable.

After treating dogs that spontaneously developed brain cancer with personalized mRNA vaccines, Sayur’s team conducted the study in a small clinical trial approved by the Food and Drug Administration (FDA) to ensure testing was safe and feasible before expanding it to a larger essay.

IN group of four patientsgenetic material called RNA was extracted from the tumors surgically removed from each one, and then the messenger RNA—a sample of what’s inside each cell, including tumor cells—was amplified and wrapped in new, high-tech packaging. biocompatible lipid nanoparticlesso that the tumor cells “looked” like a dangerous virus when reintroduced into the bloodstream and triggered a response from the immune system.

The vaccine was personalized for each patient to make the most of their unique immune system.

“Showing that this mRNA cancer vaccine produces similar strong responses in mice, dogs and human brain tumor patients is a really important discovery because we often don’t know how well preclinical animal studies will translate into clinical trials.” . similar reactions in patients,” emphasizes Dwayne Mitchell Director of the UV Brain Tumor Immunotherapy Program and co-author of the article.

Although it is too early to assess the clinical effects of the vaccine, patients lived disease-free longer than expected or They lived longer than expected.

The 10 dogs lived an average of 139 days, compared with the average survival of 30 to 60 days typical for dogs with the disease.

Pediatric research

Next step, with the support of the FDA and the CureSearch Childhood Cancer Foundation, this will be a Phase I clinical trial expanded to 24 adult and pediatric patients to test the results. Sayur estimates that once the optimal and safe dose is confirmed, about 25 children will participate in the second phase.

As part of the new clinical trial, Sayur’s lab will collaborate with an international consortium, the Pediatric Neuro-Oncology Consortium, to bring the immunotherapy drug to the United States. children’s hospitals throughout the US. To do this, they will obtain each patient’s tumor, make a personalized vaccine in UV and send it to the patient’s medical team, Sayur explains.

The next step will be a phase 1 clinical trial expanded to 24 adults and children to test the results. After confirming the optimal and safe dose

Despite the promising results, the authors note that limitation is the ongoing uncertainty about how best to use the immune system, minimizing the possibility adverse side effects.

Patents

“I hope our breakthrough can become a new paradigm in the way we treat patients,” platform for immune system modulation“, emphasizes the work manager. “In this study, we showed that synergy can be achieved with other immunotherapies, so perhaps we can now use a combination approach to immunotherapy,” he concludes.

Sayour and Mitchell hold patents related to the vaccine, which are licensed to iOncologi, a biotechnology company formed as spin off from UV, which includes Mitchell.

Link: Elias Sayur and others – “RNA Aggregates Harness the Danger Response for Potent Cancer Immunotherapy.” Magazine cell, 2024 | DOI: 10.1016/j.cell.2024.04.003.