University of Pennsylvania Philadelphia, PA, United States
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Sokratis Apostolidis1, Kyra Sacksith1, Bria Fulmer1, Zoe Quandt2, Mark Anderson2, Terri Laufer3 and E. John Wherry1, 1University of Pennsylvania, Philadelphia, PA, 2University of California San Francisco, San Franscisco, CA, 3University of Pennsylvania, Philadlephia, PA
Background/Purpose: The use of anti-PD-1 (aPD-1) immunotherapy has seen significant success in clinical practice, corresponding with a continued rise in clinical indications for multiple cancer diagnoses. Immune-related adverse events (irAEs) are a type of secondary autoimmune toxicities arising in the setting of cancer immunotherapy. They can cause significant morbidity and disruption of the treatment of oncologic patients. They also offer a controlled setting for dissecting the cellular and signaling networks of autoimmunity development.
Methods: To better understand irAEs in the setting of aPD-1 immunotherapy, we established a prospective, longitudinal cohort at the University of Pennsylvania enrolling patients before immunotherapy and following them for a year. We stratified the responses in two groups: patients that developed at least one irAE event (irAE+) and patients that never developed an irAE event (irAE-) during that time period.
Results: Using high-dimensional cytometry, we found that irAE+ patients had a larger increase in their activated CD4 T cells after PD-1 inhibition compared to irAE- patients. In addition, plasmablast generation following immunotherapy was higher for irAE+ patients. Using PhIP-Seq, an autoantigen screening assay, we found that irAE+ patients demonstrated robust enrichment in autoantibodies against various tissue antigens after immunotherapy with unique patterns for each patient. Finally, a large-scale proteomic analysis revealed that irAE+ patients at baseline have increased levels of circulating inflammatory mediators.
Conclusion: These results indicate that there are distinct cellular and serological imprints of irAE+ patients that reflect their heightened autoimmune reactivity and can be used to uncover the underlying pathogenic mechanism of irAEs and design predictive algorithms.
S. Apostolidis: None; K. Sacksith: None; B. Fulmer: None; Z. Quandt: None; M. Anderson: MedTronic, 11, Merck, 11; T. Laufer: None; E. Wherry: Arsenal Biosciences, 12, Founder, Danger Bio, 1, 12, Founder, Janssen, 1, Marengo, 1, Pluto Immunotherapeutics, 1, Related Sciences, 1, Rubius Therapeutics, 1, Surface Oncology, 1, 12, Founder, Synthekine, 1.