Development of an immune imaging method to accurately determine the immune status of tumors

点击翻译按钮获取中文摘要

Modern non-invasive imaging is integral to advancing our knowledge of biological processes and disease assessment. Molecular imaging takes the concept of imaging a step further by quantifying the amount and/or function of a specific marker of interest. Because of their high affinity toward cognate antigens, antibodies (Abs) are useful agents for both molecular imaging and therapy. The field of oncology has benefited from Ab-based immunotherapies because numerous antigens have been identified that are overexpressed on certain types of cancer cells compared to normal tissues. Labeling of Abs with radioisotopes can provide an important development for the field by identifying the appropriate target non-invasively. A major challenge with implementation of molecular Ab imaging is to achieve a high contrast signal to background ratio. This will depend on a number of variables including the form of the antibody (variable fragments, single chain variable fragments), the antibody clone, the radioisotope, the chelator and the imaging capabilities. In addition, biological systems will always have an inherent level of unspecific Ab uptake that can be attributed to vascular permeability and which can vary as a function of time and treatment. The objective of our research is to develop adequate methods for precise quantification of Abs in vivo. We will label antibodies against programmed-death ligand-1 (PDL1) with 89Zr, a long-lived PET radioisotope. An originality of our compound is the chelator 4HMSA, which chelates 89Zr more stably compared to standard chelators used for Ab labelling. We will explore pharmacokinetic methods to correct - subject-wise - for the unspecific uptake of the PDL1 tracer. We will also assess vascular permeability by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to determine a correction factor for non-specific tracer uptake. Our research will test the combined application of PET/DCE-MRI for imaging PDL1 in vivo in mouse models of cancer. The long term objective of this program is to: develop quantitative tools and methods to measure immune-related cell surface marker expression, immune cell composition of tissues and the immune response as a whole in cancer model systems. These imaging tools are lacking and would greatly benefit the field of oncology by enabling longitudinal monitoring of the local immune response in various cancers. Our program will provide a base for the design and analysis of new radiolabeled Abs which will expand the number of medical conditions that can benefit from diagnostic PET and MR imaging. Our program is designed such that training of HQP is a cornerstone of advancing our research. The interdisciplinary nature of our research will allow trainees to acquire a unique combination of skills from immunology, radiochemistry, radiobiology and biomedical imaging. The methods we will develop are adaptable to imaging other Abs and therefore can have wide applications in science and medicine.