Neuroimaging-guided Immunotherapy for Glioblastoma

Glioblastomas (GBMs) are aggressive and deadly brain tumors, accounting for half of all primary malignant brain tumors. The current standard-of-care for patients diagnosed with GBM is surgery, chemotherapy, radiotherapy and Bevacizumab; however, these treatments have yet to significantly extend patient lives. GBMs overexpress the angiogenesis factor vascular endothelial growth factor (VEGF), causing microvascular proliferation and rapid growth of the tumor. Clinical trials with Bevacizumab, which blocks VEGF, showed some success in reducing angiogenesis yet no increase in the overall survival rate, potentially because Bevacizumab singularly blocks the VEGF angiogenic pathway enabling cancer cells to develop resistance to the treatment. Current in vivo tumor imaging methods lack the spatial resolution and sensitivity to assess treatment resistance at the microvasculature scale. Our project aims to apply advanced optical imaging technologies to better understand the mechanisms of two antiangiogenic treatments, anti-ELTD1 and OKN, by in vivo longitudinal tracking of migrating tumor cells, infiltrating immune cells, and tumor microvascular dynamics. Combined with spatial transcriptomics, a machine learning based platform will be developed to guide the treatments and optimize the clinical translation of anti-ELTD1 and OKN therapies. In Aim 1, we will build the high-resolution multimodal imaging platform consisting of three- and two-photon fluorescence microscopy, optical coherence tomography, and laser speckle contrast imaging. In Aim 2, we will evaluate the efficacy of anti-ELTD1 and OKN therapies in a syngeneic orthotopic GBM mouse model. By longitudinally monitoring macrophages and tumor cells and performing spatial transcriptomics to visualize the tumor immune microenvironment, we will guide the treatment delivery and determine the optimal dosage. In Aim 3, we will develop a machine learning based platform to predict the long-term immune response based on cellular, vascular, and gene expression imaging. Our goal is to produce a novel imaging and computational platform to better understand anti-ELTD1 and OKN treatments for glioblastoma and optimize their clinical translation. Additionally, the platform will serve to evaluate future therapeutics. Project Number: 1P20GM162339-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of General Medical Sciences (NIGMS) | Principal Investigator: David Miller | Institution: UNIVERSITY OF OKLAHOMA, NORMAN, OK | Award Amount: $210,086 | Activity Code: P20 | Study Section: Special Emphasis Panel[ZRG1 MBBC-Q (55)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11269427