A Novel Imaging Strategy to Optimize Brain Tumor Immunotherapy

About This Grant

ABSTRACT. Immunotherapy has emerged as a successful therapeutic strategy for a variety of cancers. The recent success of immunotherapies in other solid tumors has sparked increased attention to treatments targeting the immune system in glioblastoma (GBM) and other brain cancers. One of the key challenges in the successful treatment of brain tumors with immunotherapy is our lack of appropriate methods to visualize and quantify the killing of cancer cells by the immune system within the brain. Currently, contrast-enhanced magnetic resonance imaging (MRI) is used to evaluate treatment response and progression in these patients. However, the accurate determination of tumor progression from treatment-associated inflammation, remains an unmet clinical challenge. The lack of a useful response assessment has complicated patient care and the clinical development of these therapies. This proposal aims to address this by developing a novel imaging strategy to visualize and quantify the specific protein, known as perforin, which immune cells utilize to gain access to kill cancer cells. Herein, we will develop a first-in-class, small molecule positron emission tomography (PET) probe which is capable of passively crossing the blood brain barrier and binding to perforin, permitting differentiation between response to immunotherapy and non-response. This strategy would permit non-invasive visualization of perforin levels with minimal off-target activity as perforin is expressed exclusively by cytotoxic cells of the immune system. We will develop a library of novel fluorine-containing small molecules targeting perforin and advance the top 10 binding molecules for radiolabeling with fluorine-18 (SA1). We will then characterize their brain penetration, biodistribution, and stability and use quantitative benchmarks to advance the top 3 performing radiotracers for treatment monitoring studies (SA2). Lastly, we will assess the utility of perforin-PET to detect therapeutic response and predict outcomes in established syngeneic orthotopic mouse models of glioblastoma following treatment with immune checkpoint blockade (SA3). Success of this approach would allow for rapid translation and incorporation into clinical studies. This would permit clinicians and researchers to visualize and have real-time information of the killing of brain cancer cells by the immune system and make informed decisions regarding the effectiveness of immunotherapy for any particular patient. The significance of the proposed research is that it demonstrates a generalizable mechanism to monitor multiple types of immunotherapy in glioblastoma and other brain tumors (including pediatric brain tumors and brain metastases). Such work has the potential to improve response determination in brain tumor immunotherapy, spare unnecessary treatment side effects, and through this eventually improve the management of this disease.