An experimental nanoparticle therapy has shown preclinical activity against a range of B-cell malignancies, researchers have reported.
The therapy, SNS01-T, inhibited tumor growth and improved survival in mouse models of multiple myeloma, mantle cell lymphoma, and diffuse large B-cell lymphoma.
The treatment exhibited single-agent activity in these mice but also demonstrated synergy with lenalidomide and bortezomib.
Sarah Francis, PhD, of the University of Waterloo in Ontario, Canada, and her colleagues conducted this research and recounted the results in Molecular Therapy.
SNS01-T consists of 3 components: small interfering RNA targeting the native eukaryotic translation initiation factor 5A (eIF5A), plasmids expressing a pro-apoptotic mutant of elF5A under the control of a B-cell specific promoter, and a synthetic cationic polymer polyethylenimine, which serves as the delivery vehicle.
The small interfering RNA component of SNS01-T suppresses elF5A expression, thereby interfering with translation of eIF5A and reducing levels of hypusinated elF5A in cancer cells. This inhibits activation of NF-kB and induces apoptosis.
The B-cell specific plasmid component of SNS01-T expresses an arginine substituted form of eIF5A—eIF5AK50R—that cannot be hypusinated, which leads to selective induction of apoptosis in B cells.
Dr Francis and her colleagues found that SNS01-T is preferentially taken up by malignant B cells. In myeloma cells, uptake of SNS01-T was up to 5-fold higher than uptake by normal, naïve B cells.
Uptake into myeloma cells induced 45% cell death within 24 hours, but there was almost no measureable death of normal, naïve B cells.
SNS01-T also prompted dose-dependent inhibition of tumor growth in mouse models of multiple myeloma, mantle cell lymphoma, and diffuse large B-cell lymphoma, with up to 90% inhibition at the highest doses.
When administered at doses of 0.18 mg/kg or more, SNS01-T significantly extended the life span of treated mice. The researchers observed a reduction in the pro-survival form of the eIF5A protein in tumor tissue, which was consistent with drug activity.
SNS01-T also demonstrated synergy with bortezomib and lenalidomide. Mice that received SNS01-T and lenalidomide in combination had a 100% survival rate, compared to 60% for mice that received SNS01-T alone and 20% for mice that received lenalidomide alone.
A single 6-week cycle of SNS01-T and lenalidomide eradicated tumors in 67% of mice, and there was no regrowth after an additional 8 weeks without further treatment.
Similarly, combination SNS01-T and bortezomib inhibited tumor growth by 89%, compared to 59% for SNS01-T alone and 39% for bortezomib alone.
This research was supported by Senesco Technologies, Inc., the company developing SNS01-T.
