mRNA nanobodies have shown promise in colorectal cancer, with a preclinical study reporting tumour suppression using lipid nanoparticle-delivered anti-PD-L1 therapy.
An original study published in eGastroenterology describes how lipid nanoparticles carrying nucleoside-modified mRNA encoding anti-PD-L1 nanobodies suppressed tumour growth in both sporadic and colitis-associated colorectal cancer models.
Colorectal cancer is the third most common cancer in the US and the second leading cause of cancer-related deaths.
While immunotherapies targeting immune checkpoint proteins such as PD-1 and PD-L1 have changed cancer treatment, their effectiveness in colorectal cancer has been limited.
Most patients have microsatellite stable tumours, meaning they respond poorly to current checkpoint therapies.
Conventional monoclonal antibodies used in immunotherapy face several limitations.
Their large molecular size can restrict tumour penetration, they may trigger immune-related adverse effects and they are costly to produce.
Anti-PD-L1 antibodies have also shown limited benefit in colitis-associated colorectal cancer, an aggressive form linked to chronic intestinal inflammation.
Nanobodies, first identified in camelids and sharks, are single-domain antibodies around one-tenth the size of conventional antibodies.
Their small size allows improved tumour penetration, and they tend to have lower immunogenicity, meaning they are less likely to trigger unwanted immune reactions.
However, they are rapidly cleared by the kidneys, shortening their time in circulation.
To address this, researchers developed both monomeric and quadruple anti-PD-L1 nanobody mRNA formats.
The quadruple format links four nanobodies together to form a larger molecule designed to remain in circulation for longer while retaining tissue penetration.
In mouse models, the quadruple nanobody mRNA lipid nanoparticle treatment remained in circulation for approximately twice as long as the monomeric version.
It significantly inhibited tumour progression in sporadic colorectal cancer, with effects becoming apparent after the third injection.
Serum analysis showed higher blood levels and slower clearance for the quadruple format.
The treatment also reduced tumour incidence in colitis-associated colorectal cancer in both wild-type mice and genetically susceptible models that typically develop more aggressive disease.
Researchers found the therapy reshaped the tumour immune microenvironment by reducing infiltration of myeloid-derived suppressor cells and tumour-associated macrophages, both of which suppress immune responses, while increasing CD8+ T cells, the immune system’s primary cancer-fighting cells.
Further in vitro experiments showed that treating bone marrow haematopoietic stem cells with nanobody mRNA lipid nanoparticles inhibited their differentiation into macrophages and reduced expression of immunosuppressive markers including PD-L1, CD80, CD86 and CD206.
This suggests the therapy may both activate anti-tumour immunity and limit the development of new immune-suppressing cells.
Researchers propose that human versions of the quadruple anti-PD-L1 nanobody mRNA lipid nanoparticle therapy could represent a potential new immunotherapy approach for colorectal cancer.
They also suggest that combining the strategy with other immune checkpoint targets in a single construct, or with chemotherapy or radiotherapy, may enhance outcomes.
The work has not yet progressed to human trials.
