One of the major mechanisms for tumor cells to survive immunosurveillance is through the protein-protein interaction between programmed death-1 (PD-1) and its endogenous ligand, PD-L1. Drugs targeting PD-1/PD- L1 axis unleash patient?s immune cells to attack cancer cells, and have contributed to substantial gains in the overall survival of cancer patients. Because current anti-PD-1/PD-L1 therapies are expensive, effective for only a small fraction of patients, and susceptible to potentially severe immune-related side effects, selecting patients for treatment based on their PD-L1 expression levels is an integral part of the regimen. Current FDA approved companion tests for PD-L1 expression use qualitative immunohistochemistry (IHC). However, due to the heterogeneity of PD-L1 expression in the tumor microenvironment, IHC tests do not reflect the whole picture, or the dynamics of PD-L1 expression. Thus, they offer low sensitivity and limited information for physicians to predict therapeutic response. We hypothesize that PD-L1-targeted positron emission tomography (PET) imaging can change the current paradigm of cancer immunotherapy through accurate patient stratification, therapeutic response assessment, and prevention of immune-related adverse events, based on individual?s systemic PD-L1 expression. Currently, we are evaluating PD-L1 PET imaging in clinical trials at Yale, using protein/peptide-based PD-L1 targeted PET tracers. Although these protein/peptide-based imaging agents have better tissue penetration and improved pharmacokinetics than antibodies, they cannot penetrate intact blood-brain barrier (BBB), which makes the in vivo quantification of PD-L1 in the brain challenging, e.g., in brain tumor/metastasis. Clinically, there is an urgent need to establish a reliable way to predict and monitor immunotherapeutic effects in primary and metastatic brain tumors. Therefore, we propose to develop novel BBB permeable small molecules as PD-L1 PET imaging agents. Successful completion of this project will provide us with a sensitive tool to reliably quantify PD-L1 expression throughout the whole body, including the central nervous system. After systematic characterization and preclinical validation of the newly developed PD-L1 PET imaging agents, we will apply for IND approval and translate them to first-in-human studies in patients with primary or metastatic neuro-oncological malignancies. Moreover, these novel BBB permeable PET imaging agents will enable, for the first time, in vivo probing of immune inhibition in patients with neurodegenerative diseases, e.g., Alzheimer?s disease, which may unveil new therapeutic targets in the future.
Immune checkpoint inhibitor-based immunotherapies have improved outlook for cancer patients. However, there is still an urgent need to establish a reliable method to select patients for these therapies and predict therapeutic outcomes and potential side effects. This project aims to develop blood brain barrier (BBB) permeable programmed death ligand 1 (PD-L1)-targeted PET imaging agents for non- invasive, reliable, and sensitive whole-body quantification of PD-L1 in patients.