mRNA vaccine reprograms immune system to attack glioblastoma
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An mRNA cancer vaccine developed at University of Florida may have the ability to reprogram the immune system against glioblastoma, findings of a first-in-human trial showed.
The trial — results of which appeared in Cell— included four adults with immunotherapy-resistant MGMT unmethylated glioblastoma.
Researchers created what they described as “onion-like” multi-lamellar RNA lipid particle aggregates. This approach is designed to enhance payload packaging, as well as the immunogenicity of tumor mRNA antigens.
Results of the first-in-human trial showed the vaccine triggered rapid cytokine/chemokine release, immune activation and trafficking, as well as an increase in T-cell immunity.
The findings support results observed in preclinical mouse models, as well as in 10 pet dogs with naturally occurring brain tumors.
Researchers now plan to evaluate the vaccine in a phase 1 trial for children with brain cancer.
“We expect this work to create a new paradigm that rapidly activates the immune system against cancer,” Elias J. Sayour, MD, PhD — principal investigator of the RNA Engineering Laboratory within University of Florida’s Preston A. Wells Jr. Center for Brain Tumor Therapy, as well as a UF Health Cancer Center and McKnight Brain Institute investigator — told Healio. “To win the war on cancer, the immune system needs a better head start. We hope this approach gives the immune system the head start it needs to win the race against rapidly evolving tumors.”
Healio spoke with Sayour about the rationale for the study, how the findings build upon encouraging preclinical results, and the potential this vaccine may offer for treatment of one of the deadliest and most treatment-resistant types of cancer.
Healio: How did you develop this therapeutic approach, and why did it seem feasible for glioblastoma?
Sayour: New treatment outcomes are necessary for glioblastoma and pediatric brain tumors, as outcomes have not precipitously changed in several decades. Our brain tumor program has developed promising effects with other forms of immunotherapy against brain cancer. We wanted to evaluate a novel mRNA vaccine design to enhance responses for these difficult-to-treat diseases.
I consider glioblastoma to be the worst of the worst. The tumors are awful — not just in terms of their recalcitrance to therapy, but because of where they are growing in and devastating the human brain.
In many ways, what makes them so challenging is how different these tumors are. The surface of the tumor is different from the core, and each cell is different from other cells, even within the same person. These are such complex, heterogenous tumors, and they’re also very suppressive tumors, meaning they are extraordinarily hostile to the immune response. We believe that if we can get an immune response against this tumor, we could get an immune response against any tumor.
Healio: How did this perform in preclinical studies?
Sayour: These vaccines have elicited strong responses against mouse gliomas, with long-term survival and improved outcomes for pet dogs with natural forms of the disease.
I’m excited and encouraged by the results we have seen in preclinical models, particularly the repeated and more relevant models like pet dogs. Seeing a lot of these same effects in humans certainly was very reassuring.
The mouse work we have done is valuable, because we can do things in mice that we can’t do in humans. People ask me all the time, ‘Did the tumor shrink?’ When you have an immune response against a tumor, everything looks like it’s growing, so it’s very hard to delineate. However, in mice, you can look at the tumor, analyze it and explore it in ways that are very challenging to do in a human. We also can evaluate different cancers in mice, including pediatric and adult types.
This approach is very active across these different models of cancer, so much so that we have launched pet trials for head and neck cancer, bone cancer and brain tumors. We’ve had promising results in these client-owned animals. These are natural forms of cancer. Unlike with mice, we’re not injecting or inducing anything. In many ways, one mouse’s tumor is nearly identical to that of the next mouse. When you treat pet dogs and cats — as with humans — tumors are different. Seeing such promising results in these larger animals was very reassuring and supports the idea of moving this into humans.
Healio: What did you find in your first-in-human trial?
Sayour: Vaccines are feasible to generate and rapidly activate the immune system against glioblastoma. This was a very small cohort of patients. I don’t think it’s possible to draw definitive conclusions outside the descriptions we have regarding the immune responses we’ve seen in the blood and tumors. Hopefully, this evidence suggests that this is improving outcomes.
Healio: What is planned for the phase 1 trial?
Sayour: We expect the phase 1 trial to include up to 24 adult and pediatric patients. Once an optimal and safe dose is confirmed, an estimated 25 children will be enrolled on a phase 2 trial.
Healio: What are the potential long-term implications if this approach is validated?
Sayour: Our group has been working on cancer vaccines for decades. The reason we’ve been pursuing mRNA vaccines is because we genuinely hope that this can be a model to provide personalized vaccine therapy that can be commercialized around the world.
mRNA is very valuable in this context — it’s one of the only approaches I can think of that reconciles personalized immunotherapy with a commercial model in a way that is extraordinarily robust. These findings provide me with a great deal of hope and inspiration to continue to trailblaze and push this forward.
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For more information:
Elias J. Sayour, MD, PhD, can be reached at elias.sayour@neurosurgery.ufl.edu.
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