Abstract B95: PD-L1-mediated nanotherapeutic targeting of glioma-infiltrating myeloid cells synergizes with radiotherapy for glioblastoma

Abstract

Abstract Massive infiltration of tumor-associated myeloid cells (TAMCs), reaching 30-50% of the tumor mass, is a distinctive characteristic of glioblastoma (GBM). These cells are a critical player in generating highly immunosuppressive microenvironment in GBM. Thus, therapeutic targeting of TAMCs might dampen the immunosuppression and improve the outcome of antiglioma therapies. In this work, we developed a novel nano-immunotherapy platform to actively and specifically target glioma-infiltrating TAMCs in vivo. Based on our finding that glioma-infiltrating TAMCs exhibit the highest expression of PD-L1 among all the immune cell infiltrates, we designed a lipid nanoparticle system (LNP) with surface-engineered anti-PD-L1 therapeutic antibody. Decoration of anti-PD-L1 antibody rendered our LNP highly capable of specifically targeting TAMCs and, interestingly, routing PD-L1 to lysosomal degradation. Co-encapsulation of dinaciclib, a cyclin-dependent kinase inhibitor, into LNP caused a dramatic elimination of TAMCs and inhibition of immunosuppression in glioma. Notably, the targeting efficiency of TAMC-targeted LNP was further increased when combined with radiation therapy (RT), a standard care of GBM. The superior therapeutic efficacy in mice treated by RT+LNP combination over the RT or LNP monotherapy was demonstrated in two syngeneic murine glioma models, GL261 and CT2A. We also demonstrated that our LNP successfully targeted TAMCs harvested from human resection specimens, which further validated the translational potential and clinical relevance of our nano-immunotherapy approach. In conclusion, our work established a new nanotechnology-based immunotherapeutic approach with great potential to improve the clinical outcome in patients with GBM. Citation Format: Peng Zhang, Jason Miska, Catalina Lee-Chang, Aida Rashidi, Wojciech K. Panek, Shejuan An, Markella Zannikou, Aurora Lopez-Rosas, Yu Han, Ting Xiao, Irina V. Balyasnikova, Maciej S. Lesniak. PD-L1-mediated nanotherapeutic targeting of glioma-infiltrating myeloid cells synergizes with radiotherapy for glioblastoma [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr B95.