Immune Checkpoint Targeted Immuno-PET to Identify Therapy-Induced Adaptive Resistance
Abstract
Immune checkpoint inhibitors (ICIs) are drugs that use the bodys immune system to fight diseases such as cancer, but most studies conducted in humans have shown that only 10%-25% of patients are treated successfully with ICIs. Most patients do not respond to ICIs, because cancer develops resistance to these drugs. Stereotactic ablative radiation therapy (SAbR) is a powerful, precise type of radiation therapy that is promising when combined with ICI to treat patients with cancer. However, we estimate that SAbR will improve response rates to ICI by only 10% and still will not cure most patients. To improve future treatment for patients with cancer, we need to understand how cancer resists ICI drugs. Cancer can adapt to attacks from chemotherapy, radiation therapy, and immunotherapy using different resistance mechanisms. One way that cancer cells resist SAbR treatment is by increasing the levels of a protein called Programmed Death 1 (PD-1) and its binding partner PD-L1. Both PD-1 and PD-L1 are inhibited by ICI. Many cancers also resist ICI used to treat patients, leading us to believe that similar resistance mechanisms are at play in all ICI therapies. Past studies have tried to identify patients that may respond to ICIs by correlating PD-L1 levels on tumors with clinical outcomes, that is, how patients respond to treatment. Although these studies have shown this correlation, they were hampered by the use of archival tissue from the primary tumor or miniscule amounts of tissue biopsies from metastases. These studies were also limited by the fact that they only evaluated a single site of disease (primary or a metastatic site), and they only assessed at one particular point in time, even though PD-L1 expression varies significantly over time. As a result, they found only a minimal correlation between clinical outcomes and PD-L1 levels. Because tumor biopsy is insufficient to reveal how resistance to cancer therapy develops, we propose an innovative, non-invasive, and quantitative method for imaging the levels of PD-L1 using positron emission tomography (PET) technology. We will use this new method to correlate PD-L1 levels with how patients respond to treatment. We will develop a PET imaging technology called Immuno-PET by attaching a positron emitting radioisotope, zirconium-89 (89Zr), to an FDA-approved antibody that will bind to PD-L1 for non-invasive imaging of the location and expression level of PD-L1. First, we will test and evaluate this imaging technique in mouse models with patient-derived tumor grafts of kidney tumors and correlate the signal intensity with PD-L1 expression levels in the tumor grafts. Then, we will apply for FDA Investigational New Drug (IND) approval to use the imaging technology developed in this project to non-invasively assess how PD-L1 levels change in patients treated with ICI therapy. The Immuno-PET technology developed by this project can be used in the clinic to select appropriate patients for ICI treatment, predict side effects, and monitor treatment resistance to decide if the cancer therapy should be changed. This cutting-edge technology will help us understand the resistance to ICI therapy in real time and allow us to design more effective treatments for patients with cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910711
Entities
People
- Xiankai Sun
Organizations
- United States Army
- University of Texas Southwestern Medical Center