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.
