Lipid Nanoparticles of Type-A CpG D35 Suppress Tumor Growth by Changing Tumor Immune-microenvironment and Activate CD8 T Cells in Mice


Authors: L. Munakata, Y. Tanimoto, A. Osa, J. Meng, Y. Haseda, Y. Naito, H. Machiyama, A. Kumanogoh, D. Omata, K. Maruyama, Y. Yoshioka, Y. Okada, S. Koyama, R. Suzuki, and T. Aoshi

Journal: Journal of Controlled Release

DOI: 10.1016/j.jconrel.2019.09.011

Publication - Abstract

November 30, 2019

Oncology Nucleic Acid Lipid Nanoparticles mRNA

Abstract


Type-A CpG oligodeoxynucleotides (ODNs), which have a natural phosphodiester backbone, is one of the highest IFN-α inducer from plasmacytoid dendritic cells (pDC) via Toll-like receptor 9 (TLR9)-dependent signaling. However, the in vivo application of Type-A CpG has been limited because the rapid degradation in vivo results in relatively weak biological effect compared to other Type-B, -C, and -P CpG ODNs, which have nuclease-resistant phosphorothioate backbones. To overcome this limitation, we developed lipid nanoparticles formulation containing a Type-A CpG ODN, D35 (D35LNP). When tested in a mouse tumor model, intratumoral and intravenous D35LNP administration significantly suppressed tumor growth in a CD8 T cell-dependent manner, whereas original D35 showed no efficacy. Tumor suppression was associated with Th1-related gene induction and activation of CD8 T cells in the tumor. The combination of D35LNP and an anti-PD-1 antibody increased the therapeutic efficacy. Importantly, the therapeutic schedule and dose of intravenous D35LNP did not induce apparent liver toxicity. These results suggested that D35LNP is a safe and effective immunostimulatory drug formulation for cancer immunotherapy.

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