Dual agonist immunostimulatory nanoparticles combine with PD1 blockade for curative neoadjuvant immunotherapy of
Prabhani U Atukorale1,2,3, Taylor J Moon1, Alexandr R Bokatch1
1Department of Biomedical Engineering, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA. stathis@case.edu.
Abstract:
Lethal cancer is characterized by drug-resistant relapse and metastasis. Here, we evaluate the efficacy of a neoadjuvant therapeutic strategy prior to surgery that combines the immune checkpoint inhibitor anti-PD1 with a powerful immunostimulatory nanoparticle (immuno-NP). Lipid-based immuno-NPs are uniquely designed to co-encapsulate a STING and TLR4 agonist that are functionally synergistic. Efficacy of neoadjuvant combination immunotherapy was assessed in three aggressive murine tumor models, including B16F10 melanoma and 4T1 and D2.A1 breast cancer. Primary splenocytes treated with dual-agonist immuno-NPs produced a 75-fold increased production of interferon β compared to single-agonist treatments. Systemic delivery facilitated the widespread deposition of immuno-NPs in the perivascular space throughout the tumor mass and their preferential uptake by tumor-resident antigen-presenting cells. Our findings strongly suggested that immuno-NPs, when administered in combination with anti-PD1, harnessed and activated the otherwise "exhausted" CD8+ T cells as key mediators of tumor clearance. Neoadjuvant combination immunotherapy resulted in significant efficacy, curative responses, and protective immunological memory in 71% of good-responding mice bearing B16F10 melanoma tumors and showed similar trends in the two breast cancer models. Finally, this neoadjuvant combination immunotherapy drove the generation of B and T cell de novo epitopes for a comprehensive memory response.
Insights
This study shows that combining anti-PD1 with immunostimulatory nanoparticles (immuno-NPs) effectively combats aggressive cancers. This neoadjuvant therapy activates T cells, leading to tumor clearance and long-lasting immune memory.
Area of Science:
- Oncology
- Immunology
- Nanotechnology
Background:
- Cancer's lethal nature stems from drug-resistant relapse and metastasis.
- Current treatments often struggle with overcoming tumor resistance and immune evasion.
Purpose of the Study:
- To evaluate a neoadjuvant immunotherapy combining anti-PD1 with novel immunostimulatory nanoparticles (immuno-NPs).
- To assess the efficacy of this combination strategy in aggressive murine cancer models.
Main Methods:
- Developed lipid-based immuno-NPs co-encapsulating synergistic STING and TLR4 agonists.
- Assessed efficacy in B16F10 melanoma and 4T1/D2.A1 breast cancer models.
- Analyzed splenocyte cytokine production, nanoparticle tumor deposition, and immune cell activation (CD8+ T cells).
Main Results:
- Dual-agonist immuno-NPs significantly boosted interferon-β production (75-fold increase).
- Systemic immuno-NP delivery targeted tumors and was taken up by antigen-presenting cells.
- Combination therapy activated exhausted CD8+ T cells, mediating tumor clearance.
- Achieved significant efficacy and curative responses in 71% of melanoma models, with similar trends in breast cancer models.
- Generated de novo B and T cell epitopes for comprehensive memory response.
Conclusions:
- Neoadjuvant combination immunotherapy with anti-PD1 and immuno-NPs is a promising strategy against aggressive cancers.
- This approach overcomes tumor resistance by activating anti-tumor immune memory.
- The developed immuno-NPs offer a potent platform for cancer immunotherapy.
