Background
Treatment of melanoma with immune checkpoint inhibitors (ICI) has dramatically changed outcomes.1 Although ICI lack the traditional risks of cytotoxic chemotherapy, up to 50% of treated patients will experience an immune related adverse event (irAE).2 Currently, we are unable to predict which patients will have an irAE. Additionally, some patients will develop more than one irAE, suggesting an underlying predisposition. Autoantibodies, often associated with the development of autoimmune diseases, could be a biomarker to identify at-risk patients.3 There have been several reports of patients with distinct autoantibody profiles being predisposed to irAEs.4–7 Thus, we undertook a peptidome-wide screen to identify autoantibodies which are associated with development of irAEs.
Methods
We collected plasma samples from 62 melanoma patients at both a pre-treatment visit and a visit 3 weeks after treatment initiation. Plasma samples were assayed on a peptidome-wide phage display assay developed by AVAIL BIO for the presence of autoantibodies. Our cohort consisted of 19 female and 43 male patients. Treatments included anti-PD-1 (n=29), anti-CTLA-4 (n=5), and combination anti-PD-1+CTLA-4 (n=28). The cohort included patients with Stage III (n=20) and Stage IV (n=42) disease. We identified patients who experienced 3 unique toxicities, termed ‘multiple toxicity’ samples. Comparisons between samples with multiple toxicities and samples with no toxicity to identify significantly different antigen binding used Wilcoxon-rank sum testing. Comparisons between pre-treatment and post-treatment samples were assessed with paired t-tests.
Results
Over 60% of patients had one toxicity (n=44), with 10% of patients experiencing 3 unique toxicities (n=6). Common toxicities included dermatitis (n=16), colitis (n=13), hepatitis (n=5), and arthritis (n=6). Post-treatment samples from patients with multiple toxicities had a trend to higher number of recognized antigens compared to samples with no toxicity (n=420.5 versus 359.4, p=0.51). Among patients with multiple toxicities, the average number of antigens increased after treatment (281.2 to 420.5, p=0.004). In these multiple toxicity patients, 5 individual antigens in the post treatment samples showed statistically significantly increased binding compared to patients without toxicity (TBATA, SSH3, LOC100129520, EYA1, ARHGAP6).
Conclusions
These preliminary results suggest that distinct autoantibodies could serve as a biomarker of toxicity, if validated. Further study will allow comparison of antigen binding between unique toxicities to identify antigens of particular interest. We will also examine antigen binding at pre-treatment timepoints, allowing potential identification of patients at risk of irAE.
References
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Arbuckle MR, McClain MT, Rubertone MV, et al. Development of autoantibodies before the clinical onset of systemic lupus erythematosus. N Engl J Med. 2003;349(16):1526–1533.
Kimbara S, Fujiwara Y, Iwama S, et al. Association of antithyroglobulin antibodies with the development of thyroid dysfunction induced by nivolumab. Cancer Sci. 2018;109(11):3583–3590.
Johannet P, Liu W, Fenyo D, et al. Baseline Serum Autoantibody Signatures Predict Recurrence and Toxicity in Melanoma Patients Receiving Adjuvant Immune Checkpoint Blockade. Clin Cancer Res. 2022;28(18):4121–4130.
Müller-Jensen L, Knauss S, Ginesta Roque L, et al. Autoantibody profiles in patients with immune checkpoint inhibitor-induced neurological immune related adverse events. Front Immunol. 2023;14.
Ghosh N, Postow M, Zhu C, et al. Lower baseline autoantibody levels are associated with immune-related adverse events from immune checkpoint inhibition. J Immunother Cancer. 2022;10(1):e004008.