Investigating the Effects of Immune Checkpoint Inhibition and Combined Treatment with Evofosfamide on the Tumor Microenvironment Through Hypoxia Imaging

Abstract

Colorectal cancer (CRC) is a prevalent and deadly cancer worldwide. While immunotherapy, particularly immune checkpoint inhibition, shows promise in various cancers, its efficacy in CRC and other tumor types is limited. Hypoxia, characterized by inadequate tissue oxygenation, critically drives cancer progression, promoting tumor growth, metastasis, chemotherapy resistance, and poor prognosis. Evofosfamide, a hypoxia-activating prodrug, is being evaluated in clinical trials for combined use with checkpoint blockade as a potential therapeutic strategy. This study investigates the impact of hypoxia on immune checkpoint inhibition, evofosfamide, and combination therapy, while utilizing non-invasive molecular imaging to develop analytical methods for quantifying and characterizing tumor hypoxia severity and distribution.

Hypoxia hampers the effectiveness of immunotherapy by facilitating immune escape and resistance to checkpoint inhibitors, emphasizing the importance of overcoming the immunosuppressive tumor microenvironment. Non-invasive measurement of tumor hypoxia is crucial for understanding its role and developing personalized treatment strategies. Traditional invasive methods have limitations in providing comprehensive spatial and temporal information, necessitating the development of non-invasive techniques. Molecular imaging, particularly positron emission tomography (PET), revolutionizes oncology by enabling longitudinal cancer detection, monitoring, and prognosis. PET imaging with hypoxia-specific tracers like [18F]-fluoromisonidazole (FMISO) provides quantitative and spatially resolved information on tumor hypoxia. FMISO selectively accumulates in hypoxic regions, identifying poorly oxygenated areas associated with aggressive tumor behavior and therapy resistance.

This study non-invasively quantifies tumor hypoxia in murine CRC models using molecular imaging techniques, specifically PET with FMISO, across diverse treatment groups to assess interventions' effects on tumor hypoxia. Various PET metrics, including tumor maximum FMISO uptake (tMax) and tumor average FMISO uptake (tAvg), characterize and quantify tumor hypoxia. Muscle metrics, such as muscle average FMISO uptake (mAvg) and muscle standard deviation (mSD), serve as reference values for normalization. PET histograms provide insights into the spatial distribution and heterogeneity of hypoxia within the tumor. This research enhances our understanding of the interplay between hypoxia and immune checkpoint inhibition in the tumor microenvironment, facilitating personalized treatment strategies targeting tumor hypoxia. Non-invasive quantification of tumor hypoxia using molecular imaging provides valuable information for treatment planning, predicting treatment response, and improving patient outcomes in various cancers and tumor microenvironments.