Researchers at the University of Florida shared in May 2024 that in a first in human trial of four adult patients, an mRNA cancer vaccine “quickly reprogrammed the immune system” against glioblastoma, the “most aggressive and lethal” brain tumour. Their results, published in Cell (not open access), reportedly mirror data from dogs and preclinical mouse models, and represent a “potential new way to recruit the immune system” to defend against “notoriously treatment-resistant cancers”.
Glioblastomas
Glioblastomas are a “fast-growing” type of brain tumour in the glioma group, develop from glial cells, which support the brain and the spinal cord. As the “most common type” of malignant brain tumour in adults, it’s “among the most devastating diagnoses”, with “median survival around 15 months”. The current standard of care is surgery, radiation, and some combination of chemotherapy.
Revolutionary technology
The technology is an “iteration” of mRNA technology and lipid nanoparticles with “two key differences”: the vaccine is personalised with the patient’s tumour cells and incorporates a “newly engineered complex delivery mechanism”. Instead of single particles, the injection contains “clusters of particles” that wrap around each other “like onions”, suggests senior author Dr Elias Sayour.
“The reasons 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.”
Dr Sayour remarks that the team was impressed by the quick response to the vaccine, which took place in “less than 48 hours”.
“We could see these tumours shifting to what we refer to as ‘cold’ – immune cold, very few immune cells, very silenced immune response – to ‘hot’, very active immune response.”
This was a surprise but told the team that the early response of the immune system had been activated “very rapidly”, which is “critical to unlock the later effects”.
The research progression into humans
The latest publication comes after seven years of studies, from preclinical mouse models and a clinical trial of 10 pet dogs. These dogs, who had no other treatment options, offered a naturally occurring model for malignant glioma, because they are the “only other species” to develop spontaneous brain tumours with “some frequency”, says Dr Sheila Carrera-Justiz, who partnered with Dr Sayour in the trials. These tumours are often fatal for dogs.
The trial involved four patients. After surgical removal of the tumour, the team extracted RNA and then amplified their mRNA and “wrapped” it in the biocompatible lipid nanoparticles “packaging”. This presented the tumour cells as a threat to the immune system when reintroduced. Dr Duane Mitchell, co-author of the paper, suggests that the progression from mice to dogs to humans is a “really important finding” because it’s hard to predict how animal studies will translate into human contexts.
“While mRNA vaccines and therapeutics are certainly a hot topic since the COVID pandemic, this in 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.”
Early indications
Although it is too soon in the trial to evaluate the clinical effects of the vaccine, patients either lived disease-free longer than expected or survived longer than expected. The dogs lived a median of 139 days, compared with the median survival of dogs with the condition: 30-60 days.
However, the authors recognise that there is “continued uncertainty” about balancing the immune response with the potential for adverse side effects. Dr Sayour is “hopeful” that this could be a “new paradigm for how we treat patients”.
“I am hopeful for how this could now synergise 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.”
Next steps
With support from the FDA and the CureSearch for Children’s Cancer Foundation, the researchers intend to conduct an expanded Phase I clinical trial, including up to 24 adults and paediatric patients. After an optimal and safe dose has been confirmed, up to 25 children would participate in Phase II. This next clinical trial will deliver the immunotherapy to children’s hospitals across the country through a partnership with the Paediatric Neuro-Oncology Consortium.
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