Topic 375: 18F PET Tracer For Imaging PD-L1 (Moonshot)

New therapies, designed to enhance anti-tumor immunity are based on the blockade of the checkpoint components, either PD-1 on immune cells or PD-L1 on tumor cells. This strategy, while being spectacularly successful in some patients for some cancers, fails for many other patients. The expression of PD-L1 is highly dynamic and its prevalence within tumors can vary significantly over time. The current practice of immunohistochemical assessment of PD-1 and PD-L1 prevalence in tumor biopsies is slow and the results may not accurately represent overall PD-L1 prevalence at the time of treatment leading to controversial results. We propose to develop a 18F PET tracer, comprising three 14 kDa soluble ectodomains of PD-1 (ePD-1) multiplexed by site-specific conjugation to a 4-arm polyethylene glycol, with the 4th arm carrying trans-cyclooctene (TCO) for facile click-chemistry conjugation of Tetrazine-NODA/Al18F complex. The advantages of the resulting tracer include a relatively small size, high avidity due to tri-valent binding, and a low level of immunogenicity. We hypothesize that proposed molecular tracer will characterize overall prevalence of PD-L1 in primary tumor and metastatic lesions in a timely, noninvasive manner, thus helping to more accurately identify and monitor patients who are likely to respond to immune checkpoint therapy.