Abstract BACKGROUND Diffuse Midline Glioma (DMG) is an inoperable pediatric brain tumor with insufficient treatment options. Our group has developed a novel treatment modality for this disease and others, using mRNA vaccines consisting of tumor derived antigens in a unique lipid-nanoparticle (NP). METHODS We have treated mice, canines, and human patients with primary brain tumors to define local immunotherapuetic treatment response. We treated our neonatally implanted DMG model with NPs generated from total-tumor mRNA beginning day 31 and used MRI, MR spectroscopy, suprerspectral imaging, and immunofluorescence to visualize and quantify treatment effects. RESULTS In canine glioma patients enrolled in clinical trial, we visualized radiographically enlarging tumors of animals that ultimately became long-term survivors, supporting the concept of a process by which lesion size increases in the absence of true disease progression. In our clinical trials investigating NPs as a treatment for human and canine glioma, we found features of both reactive gliosis and traditional pseudoprogression (immune infiltration), suggesting a new radiographic diagnosis, thus named paraprogression. In mice bearing DMG, NP therapy led to long-term survivors, despite the development of hydrocephalus. We were able to visualize treatment response during the course of NP therapy using MRI. CONCLUSIONS These results are rapidly translatable to aid clinical decision making in patients with brain tumors treated with immunotherapy. Future studies will aim to mitigate effect of paraprogression without compromising benefit of NP therapy.