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Published on: March 9, 2019
Glycogen kinase 3 inhibitor nanoformulation as an alternative strategy to inhibit PD-1 immune checkpoint
Parisa Badiee1, Michelle F Maritz2, Benjamin Thierry2
1Future Industries Institute and ARC Centre of Excellence Convergent Bio-Nano Science and Technology, University of South Australia, Mawson Lakes Campus, Adelaide, SA 5095, Australia; UniSA Clinical and Health Sciences, University of South Australia, City West Campus, Adelaide, SA 5000, Australia.
Abstract:
Immune checkpoint inhibition with antibodies targeting the programmed cell death-1 (PD-1) pathway is a frontline cancer immunotherapy. Driven by the limited response rates and high off-target toxicity associated to monoclonal antibodies, small molecule inhibitors of PD-1 are under active investigation. Glycogen synthase kinase 3 (GSK3) is an up-stream regulator of PD-1 and small molecule GSK3 inhibitors have been shown to effectively reduce T-cell expression of PD-1 receptors. Towards harnessing the potent anticancer effects of GSK3 inhibition, we report here on the development of a nanoformulation within PEG-PLGA nanoparticles of the small molecule GSK3 inhibitor SB415286. The formulation physicochemical properties were optimised using a novel 3D printed microfluidic nanoprecipitation device and a hydrophobic ion pairing approach was used to increase the loading of the drug. The SB415286 nanoformulation efficiently inhibited PD-1 expression in chimeric antigen receptor (CAR)-T cells co-cultured with tumour cells expressing the CAR target, and improved their survival and proliferation. Treatment of the CAR-T cells with nanoformulation also increased the population of memory T-cells. The nanoformulation of small molecule inhibitor of the GSK3 pathway is a promising alternative to antibody-based checkpoint inhibition that warrants further studies.
Insights
Small molecule inhibitors of glycogen synthase kinase 3 (GSK3) can reduce programmed cell death-1 (PD-1) expression. A novel nanoformulation of a GSK3 inhibitor (SB415286) shows promise for cancer immunotherapy.
Area of Science:
- Oncology
- Immunology
- Nanotechnology
Background:
- Immune checkpoint inhibitors targeting the programmed cell death-1 (PD-1) pathway are key cancer immunotherapies.
- Limitations of current antibody-based therapies include modest response rates and off-target toxicity.
- Small molecule inhibitors of PD-1 are being explored as an alternative therapeutic strategy.
Purpose of the Study:
- To develop and characterize a nanoformulation of the small molecule glycogen synthase kinase 3 (GSK3) inhibitor SB415286.
- To evaluate the efficacy of the SB415286 nanoformulation in enhancing chimeric antigen receptor (CAR)-T cell function.
- To explore a novel approach for improving cancer immunotherapy through GSK3 inhibition.
Main Methods:
- Development of PEG-PLGA nanoparticles encapsulating SB415286 using a 3D printed microfluidic device.
- Optimization of nanoparticle formulation and drug loading using a hydrophobic ion pairing technique.
- Assessment of nanoformulation effects on PD-1 expression, T-cell survival, proliferation, and memory cell population in vitro.
Main Results:
- The SB415286 nanoformulation successfully inhibited PD-1 expression in CAR-T cells.
- Treatment with the nanoformulation improved CAR-T cell survival and proliferation when co-cultured with target tumor cells.
- The nanoformulation treatment led to an increased population of memory T-cells.
Conclusions:
- Nanoformulated small molecule GSK3 inhibitors represent a promising alternative to antibody-based PD-1 checkpoint inhibition.
- This approach warrants further investigation for its potential in cancer immunotherapy.
- The developed nanoformulation technology offers a novel method for drug delivery in cancer treatment.
