Imaging Agents for Inflammatory Components of Malignancy

tr&d 3总结

SUMMARY FOR TR&D 3 TR&D 3 of the BTRC will develop imaging agents to detect inflammation and immunity, with a focus on small molecule PET agents to monitor immunotherapy, an increasing medical need. Inflammation has long been recognized as a promoter of tumor growth. More recently, harnessing innate and adaptive immunity to treat cancer through immune checkpoint inhibition and vaccines has captivated the community of cancer researchers and clinicians alike. We will develop and disseminate agents that address two different aspects of cancer and its relationships to inflammation and immunity, namely, checkpoint inhibition and complement. The immune checkpoint protein programmed death-ligand 1 (PD-L1) and its receptor PD-1 are preferred targets for cancer immunotherapy. PD-L1 is expressed by a variety of tumors, and its over-expression is induced in tumor cells to adapt to tumor infiltrating cytotoxic T cells. PD-L1 immunohistochemistry (IHC) is the best predictive biomarker for therapeutic monitoring of PD-L1/PD-1 targeted therapies. However, PD-L1 IHC is fraught with use of discordant antibodies, intra- and inter-tumoral heterogeneity of expression as well as limited bio-specimen availability such that we believe non-invasive imaging can help. Furthermore, despite the promise of immune checkpoint therapy, the majority of patients do not respond for reasons unclear. The complement system is central to recruiting inflammatory cells and promoting release of factors that can promote tumor growth and progression, confounding immunotherapy. We will synthesize, validate and disseminate agents targeting PD-L1 (Aim 1) and complement receptors C3aR and C5aR (Aim 2), which are bound by their cognate tumor-promoting anaphylatoxins. In Aim 3 we will validate – with correlation to post-imaging surgical tissue – a current BTRC lead PD-L1 imaging agent in patients undergoing immunotherapy for pancreas cancer through support from the Bloomberg-Kimmel Institute for Immunotherapy. Once validated in this ultimate fashion we will be confident to disseminate that agent for human studies elsewhere. TR&D 3 will also serve as the Clinical Validation Core, a hub that will disseminate not only valuable new human agents as noted above, but will also provide precursor and standard for other agents, allow cross-referencing of BTRC INDs and provide analysis to meet the evolving needs of the driving Collaborative Projects and service recipients.