Work

Exth-36. Bifunctional Rna Nanoparticles Induce Antitumor Immune Responses and Allow Mri-based Detection of Dendritic Cell Migration as a Biomarker of Antitumor Immune Response

Year: 2018

Type: article

Abstract: Cancer vaccines are a promising approach to personalized cancer immunotherapy, but the lack of meaningful biomarkers of patient response to treatment limits their development. We recently reported in a randomized and blinded pilot clinical trial that RNA-pulsed dendritic cells (DCs) combined with tetanus-diphtheria (Td) booster vaccine prolong progression-free and overall survival in patients with glioblastoma (Mitchell et al, Nature 2015). Furthermore, we demonstrated that DC migration to lymph nodes assessed by SPECT/CT imaging strongly correlates with clinical outcomes. While this finding may provide a novel imaging biomarker for response to DC vaccines, the complexity and regulatory requirements of nuclear medicine-based imaging of radiolabeled cells limits widespread utilization of this technique. We have therefore developed bi-functional RNA-loaded magnetic nanoparticles to load DCs with RNA-encoded antigens, enhance DC migration to lymph nodes, and track migration in vivo using an MRI-based imaging modality. Immune-stimulatorycationic liposomes with iron oxide nanoparticle cores were complexed with mRNA. The resulting iron oxide-loaded RNA-NPs (IO-RNA-NPs) were used to transfect DCs ex vivo in the presence of a magnetic field. IO-RNA-NP-loaded DCs were then injected intradermally into tumor-bearing C57Bl6 mice and tracked noninvasively with T2-weighted 11T MRI. The presence of iron oxide in RNA-NPs did not significantly alter particle characteristics. Additionally, inclusion of iron oxide within RNA-NPs enabled magnetically enhanced transfection through application of external magnetic fields. Compared to RNA electroporation, IO-RNA-NP loading enhanced production of inflammatory cytokines and DC migration to lymph nodes. IO-RNA-NPs also produced a reduction in T2-weighted MRI intensity and an increase in MRI-detected lymph node size that correlated directly with the number of iron oxide loaded DCs in treated lymph nodes, inhibition of tumor growth, and survival in murine tumor models. This data suggests that IO-RNA-NPs enhance DC activation and establish MRI-detected dendritic cell migration as a biomarker of antitumor vaccine response.

Source: Neuro-Oncology

DOI: 10.1093/neuonc/noy148.385