In a world’s first, researchers from RCSI University of Medicine and Health Sciences in Dublin, Ireland, have developed an mRNA vaccine for neuroblastoma that has shown promising results in early laboratory testing.
Led by Olga Piskareva, senior lecturer in the RCSI Department of Anatomy and Regenerative Medicine, the study demonstrates the therapeutic potential of the vaccine for treating neuroblastoma and paves the way for further studies.
“We are at the beginning of the mRNA vaccine development journey, but we have successfully completed the first milestone, and we are very proud of it,” Piskareva told Inside Precision Medicine.
Neuroblastoma is an aggressive pediatric solid tumor that accounts for 15% of cancer-related deaths in children. Despite recent advances in treatment options, around 80% of patients with clinically aggressive disease do not show sustained responses, highlighting the need for novel treatments.
Piskareva has worked in neuroblastoma research since 2011 and felt the time was right to develop a vaccine. Her proposal was strongly endorsed in funding calls and supported by the Conor Foley Neuroblastoma Cancer Research Foundation. This support was particularly important to Piskareva as the charity was founded by a family who lost their son after a 14-year battle with neuroblastoma.
Unlike many mRNA vaccines that use lipid nanoparticles to deliver their payload, Piskareva and team instead used self-assembling peptide nanoparticles.
The self-assembling peptide, known as RALA, is composed of a repeating amino acid sequence of arginine (R), alanine (A), leucine (L), and alanine (A) that come together to form stable nanoparticles that protect mRNA encoding glypican 2 (RALA/mGPC2), a potent tumor-associated antigen in neuroblastoma. After entering a cell, the RALA nanoparticles react with the intracellular environment and change their structure, which allows them to deliver the GPC2 mRNA.
Piskareva and co-authors explain in Molecular Therapy Oncology that the RALA technology offers several advantages over more commonly used lipid nanoparticle delivery including high mRNA encapsulation efficiency, straightforward purification, no immune response to RALA itself, no restriction on the size or number of mRNA cargos to be delivered, stability at room temperature, and lower costs.
After initial experiments showing the viability of the vaccine in vitro, the researchers tested its efficacy in mouse models.
They showed that RALA/mGPC2 vaccination generated an antigen-specific cellular immune response against GPC2, with significant increases in interferon-γ and interleukin-2 expression by splenocytes and tumor necrosis factor-α expression by CD4+ and CD8+ T cells.
Investigating tumor control, the team demonstrated that immunization delayed tumor development by 10–11 days and reduced tumor volume by 70% compared with unvaccinated controls in a subcutaneous murine model of neuroblastoma, with the potential further to reduce tumor progression via prolonged administration.
Piskareva noted that as biological ageing in mice does not follow the same pattern as it does in humans, it is fair to assume that a 10–11 day delay in mice would equate to two years in preadolescent humans and one year in adulthood.
“However, the most important clinical message from this number is that there is significant potential to further delay tumor growth by trying a different vaccination schedule or dose, or by co-treating with immune-stimulating drugs,” she remarked.
The vaccine also has the potential to be highly personalized. “We can profile a given patient with neuroblastoma, select its shared and unique targets, design and synthesize mRNA, coat it with peptides, and have a personalized vaccine ready for use,” said Piskareva. “We can also create a pool of the most common targets and have the mRNA vaccine on demand.”
“By developing mRNA for multiple targets, we can increase the vaccine’s ability to help the host’s immune system kill cancer cells. The mRNA vaccine technology is like LEGO bricks. By combining different bricks, we can tailor the vaccine to the individual’s needs with high precision,” she added.
Piskareva and team are now planning further studies to investigate optimal vaccination doses and frequency, and characterize the immune response on a wider scale and in greater detail.
“The move to clinical trials will depend largely on the quality and quantity of data collected in pre-clinical studies. We will closely monitor developments in clinical trials for adult mRNA vaccines, learn from their experience and adopt the best approaches to avoid unnecessary delays,” Piskareva concluded.
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