Researchers at the University of Hawaii's John A. Burns School of Medicine (JABSOM) have developed a novel mRNA-based nanobody therapy that demonstrated significant efficacy against colorectal cancer in preclinical studies, potentially offering a breakthrough for a cancer type that typically resists immunotherapy.
The research, published in eGastroenterology, describes how Stefan Moisyadi, PhD, and his colleagues discovered a method to use mRNA technology to produce tiny proteins called nanobodies that block PD-L1, a molecule tumors use to evade immune detection.
Overcoming Immunotherapy Resistance
Traditional immunotherapy has shown limited success in colorectal cancer, where conventional antibody treatments "hardly work at all," according to Moisyadi. The new approach addresses this challenge by using nanobodies to prevent tumors from "turning off" T-cells through PD-L1 signaling.
"Antibodies won the Nobel Prize for immunotherapy," Moisyadi said. "They work in some cancers, but not all. In colorectal cancer, they hardly work at all. But when we used nanobodies, bingo, it worked."
In mouse models of colorectal cancer, the nanobody treatment reduced tumor growth by approximately 50%, representing a striking result in a cancer that doesn't typically respond to immunotherapy.
Technical Advantages of Nanobodies
The nanobodies offer several advantages over conventional monoclonal antibodies. They are one-tenth the size of traditional antibodies, allowing better tumor penetration, and demonstrate superior stability under stress conditions.
"They don't trigger an immune response in the patient," Moisyadi explains. "They penetrate better because they're small. They can even refold back to their original shape when the condition they find themselves in changes for the better. Basically, they're indestructible — they work much better and they're cheaper."
Cost-Effective mRNA Delivery
The therapy utilizes mRNA delivery technology similar to COVID-19 vaccines, enabling patients' own cells to produce the therapeutic nanobodies without genomic modification. This approach could dramatically reduce treatment costs compared to traditional antibody therapies.
"People can't afford antibody treatments," Moisyadi said, noting that conventional treatments can cost cancer patients more than $200,000 annually. "Here we make an RNA version. The patient's own cells turn it into a protein, without touching the genome. It goes into the circulation, finds the tumor, and blocks PD-L1. It's thousands of dollars, not hundreds of thousands."
Broad Cancer Applications
The research team believes the nanobody approach has potential across multiple cancer types. "They work in every cancer. They will work in everything," Moisyadi said. "We've shown that both with DNA and mRNA, the monoclonal antibodies don't work well with PD-L1 in colon cancer. In our case, nanobodies knock the colon cancer right down."
Moisyadi is now collaborating with the University of Maryland, Baltimore County to explore nanobody therapies for aggressive brain tumors, expanding the potential applications of this technology beyond colorectal cancer.
