mRNA technology has become a universal platform for the development of personalized immunotherapy and is highly anticipated to treat a variety of solid tumors. However, the US Food and Drug Administration (FDA) has not yet authorized any therapeutic mRNA cancer vaccines.
A personalized mRNA-based neoantigen vaccination developed by Karin et al. recently received Fast Track designation from the FDA for the treatment of microsatellite-stable colorectal cancer.
In patients with advanced metastatic solid tumors, the vaccination generated potent, long-lasting, and functional tumor-specific T-cell responses, according to a clinical phase 1 study report released last month.
Tumor cells include some abnormal proteins that immune cells can identify and respond to by stimulating the immune system. Neoantigens are proteins that are only created by gene alterations in tumor cells and are absent from normal cells.
They have long been thought of as excellent tumor immunotherapy targets due to their high immunogenicity, which has given rise to an innovative type of cancer treatment called individualized neoantigen immunotherapy.
Patients with various types of malignancies and infectious disorders have been studied for viral-based mRNA vaccines. Non-replicating and self-amplifying mRNA vaccines are the two types that are currently in use. Self-amplifying mRNA vaccines also encode the viral replication process in contrast to non-replicating mRNA, which just encodes the target antigen.
This additional information can increase the duration and level of antigen expression and enhance the vaccine-induced immune responses. Self-amplifying mRNA (samRNA) technology has therefore garnered a lot of interest.
In this study, researchers have constructed a novel heterologous vaccine protocol that combines the chimpanzee adenovirus (ChAd68) vector with Venezuelan equine encephalitis virus-based samRNA to deliver neoantigens for personalized immunotherapy.
Non-human primates (NHPs) and patients with advanced solid tumors were used in the vaccination regimen’s testing and evaluation.
Six well-defined NHP-specific antigens were incorporated into the ChAd68 and self-amplified mRNA vaccine system in a preclinical study to evaluate the effectiveness and durability of this heterologous vaccination protocol in eliciting immunological responses.
Intramuscular doses of ChAd68 were administered to rhesus monkeys, who then received booster doses of the mRNA vaccination 4, 12, and 20 weeks later.
In terms of the human clinical trial, patients with advanced metastatic solid tumors were the first to undergo a clinical biopsy. Then, using the analysis of the tumor samples, patient-specific neoantigens that the tumor cells are most likely to express were predicted.
Finally, each patient received an intramuscular injection of tailored immunotherapy that targeted neoantigens unique to them. Nivolumab and ipilimumab, two checkpoint inhibitors, were also utilized in this experiment to boost the efficacy of immunotherapy.
In both NHP and human trials, a significant number of peptides created by GenScript were used for T cell response assessment.
NHP experiments: Inducing long-lasting T cell responses
Results from the NHP trial demonstrated that ChAd68 produced immunological responses in rhesus monkeys against all six antigens, which were boosted by the mRNA booster doses.
The fact that the T-cell responses persisted 32 weeks after the initial immunization suggests that vaccination in animals caused the development and maintenance of effector memory T cells that were specific to the antigen.
Furthermore, antigen-specific central memory T cells were still found in rhesus monkeys’ peripheral blood 80 weeks after the vaccination was initially administered. In addition, 106 weeks after the first immunization, researchers discovered four or more NHP-specific antigens in all rhesus monkeys.
These findings suggest that this heterologous vaccination regimen may have long-term therapeutic effects for human patients in addition to efficient and durable T-cell responses (up to two years) in non-human primates.
Clinical trial: Safe, well-tolerated, and prolonged overall survival
According to clinical findings, there is no dose-limiting toxicity, and the vaccine is safe and well-tolerated. Furthermore, the vaccine could cause a long-lasting T-cell response in people since the researchers noted substantial numbers of tumor-specific T cells 52 weeks after immunization, similar to that shown in animal trials.
An overall survival percentage of 42.9% was found in the study’s follow-up of seven patients with advanced colorectal cancer, indicating that the treatment provided lasting benefits to more than one patient. In two of the evaluated patients, circulating tumor DNA (ctDNA) was entirely eliminated, and patients with lower ctDNA levels had longer overall survival (OS).
The median OS in this group as of May of this year was over 18 months, and this number is continually rising. For comparison, patients whose ctDNA levels did not drop had a median OS of just 7.8 months.
- Palmer, Christine D., et al. “Individualized, heterologous chimpanzee adenovirus and self-amplifying mRNA neoantigen vaccine for advanced metastatic solid tumors: phase 1 trial interim results.” Nature Medicine (2022): 1–11. doi:10.1038/s41591-022-01937-6
Genscript is the world’s leading biotech company providing life sciences services and products. With gene synthesis, peptide, protein, antibody and preclinical drug development service capabilities, we are internationally recognized as a leading biotech company specializing in fundamental life sciences research and early-phase drug discovery services. As of 2018, more than 30,000 peer-reviewed journal articles cited GenScript’s services and products, making GenScript the most frequently cited biotech company in the world.
After almost two decades of fast growth in developing biological reagents, the company has expanded its business into immunotherapy, CDMO, laboratory equipment, and microbial industry to further fulfill its mission in making people and nature healthier through biotechnology.
Founded in 2002 in New Jersey, United States, GenScript serves as a partner for researchers in basic life sciences, translational and biomedical fields as well as early-stage drug development.
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