Baseline autoantibody profiling in patients with NSCLC with pre-existing autoimmune diseases or who had received prior anti-PD-1 therapy before enrolling in the TAIL study.
Authors: Rodriguez-Abreu Delvys , Budde Petra Ilse , Zucht Hans-Dieter , Shrivastava Divya , Kilian Annika Loredana , Höglander Elen , Shoshkova Stefaniya , Markovic Marija , Kaul Monika Dulloo , Cardona Jose Vicente , Chandler G Scott , Mohindra Rajat 
Published: June 2023

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Background: Patients (pts) with pre-existing autoimmune diseases (AID) and prior immune checkpoint inhibitor (ICI) experience were historically excluded from studies with ICIs. Moreover, about 50% pts with pre-existing autoimmunity have a flare up when given ICI therapies (1). In this post-hoc exploratory analysis, we characterized the baseline autoantibody (AAb) profiles and evaluated its correlation with efficacy and safety outcomes in NSCLC pts with either pre-existing AID or who had prior ICI therapy and received atezolizumab in the TAIL study (2). Methods: Plasma samples were obtained from 57 NSCLC pts prior to receiving atezolizumab (TAIL study, NCT03285763). AAb testing was performed using tailored immuno-oncology bead-based antigen arrays comprising 1,340 tumor, AID and immune pathway antigens (3, 4). The cohort includes 39 pts with prior ICI therapy or prior AID (experimental group) and 18 pts without prior ICI therapy or AID (control group). Differences in IgG AAbs were compared between the experimental and control group in pts with or w/o irAE and overall survival (OS) longer or shorter than 11.1 months (median OS in overall population in TAIL). Furthermore, the AAb profiles of a subgroup of pts with therapeutic benefit (OS ≥ 11.1 months) and no or low grade irAEs (standard toxicity grade ≤ 2) were analyzed. Statistical analysis included 2-way permutation-based ANOVA (factors: outcome, study group) and Significance Analysis of Microarrays (SAM). Results: While pre-treatment AAbs were detected in the overall cohort, significant differences in AAb were observed between the experimental and control group at baseline, which were associated with OS and irAEs. In experimental group pts, pre-existing AAbs to AQP4 and NCOA1 predicted the development of irAEs. Differences were also observed in AAbs predicting longer OS. AAbs to CENPT were specifically identified in pts in the experimental group with longer OS, whereas AAbs to SOX5 were elevated in pts of the control group with longer OS. In the subgroup of pts with therapeutic benefit and no or low risk of irAE, AAbs to IL6, CENPT and the cancer testis antigens NY-ESO-2 and MAGEB2 were elevated in the experimental group. Conclusions: This AAb analysis provides important preliminary data in helping to understand the drivers of clinical outcomes with ICIs in pts with pre-existing AID and prior ICI therapy. The findings seem biologically plausible as some of the identified antigens refer to the breach of tolerance to classical AAb targets e.g. CENPT, AQP4 and to an immune response to classic tumor antigens e.g. NY-ESO-2 and MAGEB2. Further validation of the AAb profiling approach is warranted to shed insights on potential therapeutically actionable antigens and generate data orthogonal to efforts to identify biomarkers that are predictive of efficacy and safety outcomes with ICI therapies.