Abstract 5141: Autoantibody profiling for predictive biomarkers for immune-related adverse events and clinical benefit in rare tumors treated with anti-PD-1 therapy

Abstract Background: Immune checkpoint inhibitors (ICIs) have changed the cancer treatment paradigm; however, with high frequency of immune-related adverse events (irAEs) and limited response rates in select patients. This underscores the unmet need for the development of biomarkers predictive for the development of irAEs and ICI response. Herein, we conducted autoantibody (AAb) profiling to assess baseline (BL) AAb associations with clinical benefit (CB) and irAEs in patients (pts) with rare tumors (RT) treated with programmed cell death protein 1 (anti-PD-1) therapy. Methods: AAbs against 1168 antigens were analyzed using the SeroTag antibody discovery technology. The study included 41 pts with RT who received anti-PD-1 therapy. We conducted a Significance Analysis of Microarray (SAM) to analyze the association between BL AAbs with irAEs and CB (defined as pts achieving complete response (CR), partial response (PR), or stable disease (SD) for ≥4 months by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1). AAb biomaker candidates were discovered based on filtering for SAM hits with p < 0.05 and a delta score |D| >2. Results: Table 1 outlines patients’ demographics. CB and irAEs were observed in 34% and 39% of patients, respectively. Eighteen BL AAbs were significantly associated with CB such as DNA ligase III (LIG3) and small nuclear ribonucleoprotein polypeptide (SNRPA) (p = 0.002 and p = 0.003, respectively). Likewise, 13 BL AAbs showed significant associations with any-grade irAEs, particularly AAbs to breast cancer 2 (BRCA2) DNA repair associated antigen and chromatin-modifying protein 4A (CHMP4A) (p = 0.001 and p = 0.003, respectively). Conclusion: The predictive potential of autoantibodies as biomarkers is promising. Further evaluation in larger cohorts is needed for validation of our findings and understanding the underlying mechanism. Table 1. Patients’ demographics Total patients n=41 Median age in years (range) 66 (35-84) Male n=19 Female n=22 Tumor type Carcinoma of unknown primary n=13 Squamous cell carcinoma of the skin n=9 Small cell malignancies of non-pulmonary origin n=7 Adrenocortical carcinoma n=6 Vascular sarcoma n=5 Other rare histology n=1 Clinical benefit CR, PR, or SD ≥ 4 months n=14 SD <4 months or progressive disease (PD) n=23 Not evaluable n=4 irAEs Yes n=16 No n=25 Citation Format: Mohamed H. Derbala, Joud Hajjar, Bettzy Stephen, Serdar A. Gurses, Evan Kwiatkowski, Petra Budde, Hans-Dieter Zucht, Manuel Bräutigam, Ann-Sophie Schubert, Behnaz Ahangarianabhari, Enedelia Rodriguez, Mohamed Gouda, Lilibeth Castillo, Abdulrazzak Zarifa, Jeffrey A. How, Justin T. Moyers, David S. Hong, Funda Meric-Bernstam, Aung Naing. Autoantibody profiling for predictive biomarkers for immune-related adverse events and clinical benefit in rare tumors treated with anti-PD-1 therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5141.