nELISA high-throughput proteomic profiling of RADIOHEAD: insights from the largest plasma study of patients receiving checkpoint inhibitor therapy 2257210

Abstract Introduction Proteomics holds great promise for cancer immunotherapy, with intensive efforts being exerted for early disease identification, patients selection, and adverse event prediction. Despite this potential, the high cost and low throughput of existing tools to profile circulating proteins render such studies prohibitively slow and costly. Methods The Nomic platform, based on highly multiplexed immunoassay nELISA® technology, enables profiling of 1000 proteins at high throughput and low cost. Here, we leverage the Nomic platform to quantify ∼600 circulating proteins across ∼3000 samples from the RADIOHEAD cohort, a prospective study of 1070 immunotherapy naive pan-tumor patients on standard of care immune checkpoint inhibitor (ICI) therapy regimens. Results As previously reported, PD-1/PD-L1 inhibitors resulted in increased circulating levels of sPD-1/sPD-L1, and as well as several chemokines (CXCL9, CXCL10). We also identified 216 proteins associated with response to treatment, including established markers such as IL-6, and novel ones including Syndecan-1. Leveraging the longitudinal nature of the RADIOHEAD cohort, we used a window of 60 days prior to the onset of immune-related adverse events (irAEs) to identify 151 markers predicting their onset. Surprisingly, many of the markers most strongly associated with irAEs were cell surface receptors that were cleaved and released in circulation, including several immune receptors that are targets for immunotherapies in development. While PD-1 or PD-L1 cleavage is likely beneficial, other therapies require cell surface localization of their target to mediate cell killing, such as CAR Ts or ADCs. Conclusion We will discuss the implications of these findings for the development of immunotherapy combinations, as well as the potential role for circulating receptors in controlling irAE risk. Funding Source n/a Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)