Leveraging Biologically Specific PET/MRI Monitoring and Therapeutic Modulation of the Hypoxic Glioblastoma Tumor Immune Microenvironment into Improved Outcomes

ABSTRACT Leveraging neuroinflammation to improve treatment outcomes for patients with glioblastoma is challenging because the hypoxic tumor immune microenvironment (TIME), mostly comprised of immuno-suppressive tumor-associated macrophages (TAMs), remains incompletely quantified and therapeutically modulated. The

long-term goal is to accelerate the development of clinically meaningful imaging technologies as a way to advance therapeutic approaches for patients with deadly brain malignancies. The overall objective in this application is to use novel iron nanoparticle enhanced 18F-fluoromisonidazole PET/MRI derived Segregation

and Extravascular Localization of Ferumoxytol Imaging (SELFI) hypoxic fraction to quantitatively determine how hypoxia and TAM based neuroinflammation relate to treatment sensitivity. The central hypothesis is that therapeutic modulation of TAMs, as monitored by SELFI Hypoxic Fraction, ameliorates hypoxic TIME

immunosuppression leading to improved treatment outcomes. The rationale for the proposed research is that quantitative elucidation of how the hypoxic TIME relates to treatment outcomes is likely to provide a strong scientific framework whereby new TAM based therapeutic strategies can be developed. The central hypothesis

will be tested by pursuing two specific aims: 1) Define a biologically specific imaging measure of the immuno- suppressive hypoxic TIME; and 2) Determine the effect of TAM modulators on the TIME of glioblastoma. Under the first aim, SELFI hypoxic fraction will be optimized and biologically validated in a cohort of 27 patients with

IDH wild type glioblastoma needing surgical intervention for the diagnosis of treatment outcome. Additionally, the diagnostic and prognostic performance will be determined through longitudinal assessment of the hypoxic TIME in a prospective phase II clinical trial of 50 adult patients with newly diagnosed IDH wild type

glioblastoma scheduled for standard therapy. For the second aim, syngeneic and patient derived xenograft intracerebral glioblastoma rodent models will be used to determine the cytotoxicity and neuroinflammatory capability of concurrent TAM modulation and activation. Additionally, the TIME alterations responsible for

treatment efficacy will be defined. The research proposed in this application is innovative, in the applicant's opinion, because the SELFI hypoxic fraction is likely to provide a new method for quantifying treatment outcomes. This capability is likely to directly monitor biological features of efficacious therapeutic TAM

modulation. The proposed research is significant because it is expected to improve upon standard gadolinium- enhanced MRI and provide strong evidence-based proof of principle for further development and clinical trials of therapeutically induced TAM based neuroinflammation. We foresee future clinical trials using the SELFI

Hypoxic Fraction to specifically monitor the neuroinflammatory effects of novel immunotherapeutic techniques.