Rapid Diagnosis and Treatment Response Phenotyping of Immune Checkpoint Inhibitor-Associated Acute Interstitial Nephritis - PROJECT SUMMARY Immune checkpoint inhibitor (ICI) therapy has revolutionized cancer care; however, ICIs can lead to off-target immune-related adverse events (irAEs) such as ICI-induced acute interstitial nephritis (ICI-AIN). There are 3 major challenges in the care of patients who develop ICI-AIN. First, while 20-25% of ICI-treated patients develop acute kidney injury (AKI) in the first year, there is no biomarker to distinguish ICI-AIN from other causes of AKI. Second, a third of the patients with ICI-AIN do not achieve renal function recovery with corticosteroids and could require additional second-line immunosuppressive therapies. However, there is no early biomarker to determine if corticosteroid therapy is working besides monitoring of serum creatinine, the improvement in which is often delayed. Third, the pathways driving refractoriness to corticosteroid therapy in ICI-AIN are poorly understood making selection of second-line immunosuppressive therapies challenging. The overall goals of this project are to address these challenges by testing C-X-C motif ligand (CXCL)9 as a real-time biomarker for ICI-AIN diagnosis and predictor of response to corticosteroid therapy, and to identify dysregulated pathways in steroid-refractory ICI-AIN using proteomics. We will recruit and retain 400 participants from 3 healthcare systems (Yale, Massachusetts General Hospital, and Johns Hopkins) who develop AKI while on ICI therapy, of whom 100 (25%) are expected to have ICI-AIN. In Aim 1, we will determine the accuracy of urine CXCL9 measured using immunoassay and a newly developed point-of-care lateral flow assay in distinguishing ICI-AIN from other causes of AKI. This aim is supported by our studies that identified and validated CXCL9 as a biomarker of AIN and data from others showing that interferon-γ and its downstream chemokine CXCL9 are key drivers of immune-related adverse events in ICI users. In Aim 2, we will collect urine samples 1-2 weeks after initiation of corticosteroid therapy to test if suppression of CXCL9 by corticosteroids is an early marker of renal recovery in ICI-AIN. This is supported by our preliminary data showing that a third of the patients do not achieve renal recovery after corticosteroids and CXCL9 is a strong marker of renal interstitial inflammation, the key histologic feature of ICI- AIN. In Aim 3, we will compare urine and plasma proteomic profiles between steroid-refractory and steroid- sensitive ICI-AIN to determine pathways of steroid-refractoriness in ICI-AIN. We have assembled a multidisciplinary team with complimentary expertise in ICI-related renal complications and AIN (MPI/PDs: Sise, Moledina), oncology (Reynolds, Kluger, Pabani), biomarkers (Parikh), and biostatistics (Zhao). The feasibility is supported by the high-volume cancer care provided at our centers and the MPIs’ strong track record of prospective enrollment and collaboration. Upon completion of this award, we will identify a biomarker for real- time diagnosis and treatment response phenotyping in ICI-AIN, and identify potentially targetable dysregulated pathways to guide selection of second-line therapies for steroid-refractory ICI-AIN in a future clinical trial.
