CpG-coated prussian blue nanoparticles-based photothermal therapy combined with anti-CTLA-4 immune checkpoint blockade triggers a robust abscopal effect against neuroblastoma

Juliana Cano-Mejia; Anshi Shukla; Debbie K Ledezma; Erica Palmer; Alejandro Villagra; Rohan Fernandes

doi:10.1016/j.tranon.2020.100823

CpG-coated prussian blue nanoparticles-based photothermal therapy combined with anti-CTLA-4 immune checkpoint blockade triggers a robust abscopal effect against neuroblastoma

Transl Oncol. 2020 Oct;13(10):100823. doi: 10.1016/j.tranon.2020.100823. Epub 2020 Jul 8.

Authors

Juliana Cano-Mejia¹, Anshi Shukla², Debbie K Ledezma³, Erica Palmer², Alejandro Villagra², Rohan Fernandes⁴

Affiliations

¹ The George Washington Cancer Center, The George Washington University, Washington, DC 20052, USA; Fischell Department of Bioengineering, University of Maryland, College Park, MD 20742, USA.
² The George Washington Cancer Center, The George Washington University, Washington, DC 20052, USA.
³ Fischell Department of Bioengineering, University of Maryland, College Park, MD 20742, USA; The Institute for Biomedical Sciences, The George Washington University, Washington, DC 20037, USA.
⁴ The George Washington Cancer Center, The George Washington University, Washington, DC 20052, USA; The Institute for Biomedical Sciences, The George Washington University, Washington, DC 20037, USA; Department of Medicine, The George Washington University, Washington, DC 20037, USA. Electronic address: rfernandes@gwu.edu.

Abstract

High-risk neuroblastoma, which is associated with regional and systemic metastasis, is a leading cause of cancer-related mortality in children. Responding to this need for novel therapies for high-risk patients, we have developed a "nanoimmunotherapy," which combines photothermal therapy (PTT) using CpG oligodeoxynucleotide-coated Prussian blue nanoparticles (CpG-PBNPs) combined with anti-CTLA-4 (aCTLA-4) immunotherapy. Our in vitro studies demonstrate that in addition to causing ablative tumor cell death, our nanoimmunotherapy alters the surface levels of co-stimulatory, antigen-presenting, and co-inhibitory molecules on neuroblastoma tumor cells. When administered in a syngeneic, murine model of neuroblastoma bearing synchronous Neuro2a tumors, the CpG-PBNP-PTT plus aCTLA-4 nanoimmunotherapy elicits complete tumor regression in both primary (CpG-PBNP-PTT-treated) and secondary tumors, and long-term survival in a significantly higher proportion (55.5%) of treated-mice compared with the controls. Furthermore, the surviving, nanoimmunotherapy-treated animals reject Neuro2a rechallenge, suggesting that the therapy generates immunological memory. Additionally, the depletion of CD4⁺, CD8⁺, and NK⁺ populations abrogate the observed therapeutic responses of the nanoimmunotherapy. These findings demonstrate the importance of concurrent PTT-based cytotoxicity and the antitumor immune effects of PTT, CpG, and aCTLA-4 in generating a robust abscopal effect against neuroblastoma.

Keywords: Abscopal effect; CpG oligodeoxynucleotides; Immune checkpoint blockade; Nanoimmunotherapy; Neuroblastoma; Prussian blue nanoparticles-based photothermal therapy.

Grants and funding

R37 CA226171/CA/NCI NIH HHS/United States