More recently, the combination of anti-CTLA-4 and anti-PD-1 has been shown to be more efficacious than single agent therapy [2]. and postanti-CTLA-4 treatment samples (n?=?39 pairs). 12967_2018_1452_MOESM3_ESM.pdf (295K) GUID:?9FE4CB7B-CC2E-448A-878E-B564FD0EEC94 Additional file 4: Table S3. Sample details. Severity and site of toxicity (gastrointestinal (GI), endocrine, skin and/or other) and treatment termination status for baseline sera samples from anti-CTLA-4 (n?=?39), anti-PD-1 (n?=?28), and combination (n?=?11) melanoma patients. Two anti-CTLA-4 patients were sampled twice (11-311, in 2011 and 2013; and 12-071, in 2012 and 2013), and one anti-PD-1 patient was sampled twice SID 3712249 (13-185, in 2015 and 2016). 12967_2018_1452_MOESM4_ESM.xlsx (23K) GUID:?3B7D0D12-4401-4DDD-930A-D821B3272417 Additional file 5: Table S4. Summary of toxicity- and termination-associated antibodies. Numbers of differentially expressed (DE), strongly differentially expressed (strong DE), filtered and curated antibodies are shown for comparisons of none/mild vs. severe toxicity, across three different treatment groups (anti-CTLA-4, anti-PD-1, and combination). 12967_2018_1452_MOESM5_ESM.docx (11K) GUID:?71954900-DE07-4BF5-9A07-1CFF4C71DB8E Additional file 6: Table S5. Toxicity- and termination-associated antibodies. Lists of differentially expressed, strongly differentially expressed, filtered and curated FAXF antibodies associated with severe toxicity for anti-CTLA-4, anti-PD-1, or the combination. 12967_2018_1452_MOESM6_ESM.xlsx (291K) GUID:?1BE0EC5D-FEE8-4B88-A1E5-D50AA5FC1A5E Additional file 7: Table S6. Pathway analysis of protein targets of toxicity-associated antibodies. Lists of functional pathways (derived from WikiPathways; http://www.wikipathways.org/) enriched for protein targets of filtered toxicity-associated antibodies from anti-CTLA-4, anti-PD-1, or combination treatment groups. 12967_2018_1452_MOESM7_ESM.xlsx (91K) GUID:?2B529297-98A7-4281-88DE-D12E792688A1 Additional file 8: Table S7. Functions of protein targets of treatment termination-associated antibodies. Functional analysis of protein targets for top SID 3712249 15 DE toxicity-associated antibodies for each of the anti-CTLA-4, anti-PD-1, and combination treatment groups. Associations of each antibody target with immune toxicity are given, based on literature findings. 12967_2018_1452_MOESM8_ESM.xlsx (18K) GUID:?C5F4D911-FF95-4DC1-9CB8-B95E44AB0E6C Data Availability StatementAll data generated or analyzed during this study are included in this published article and its Additional files. Abstract Background Immune checkpoint inhibitors (anti-CTLA-4, anti-PD-1, or the combination) enhance anti-tumor immune responses, yielding durable clinical benefit in several cancer types, SID 3712249 including melanoma. However, a subset of patients experience immune-related adverse events (irAEs), which can be severe and result in treatment termination. To date, no biomarker exists that can predict development of irAEs. Methods We hypothesized that pre-treatment antibody profiles identify a subset of patients who possess a sub-clinical autoimmune phenotype that predisposes them to develop severe irAEs following immune system disinhibition. Using a HuProt human proteome array, we profiled baseline antibody levels in sera from melanoma patients treated with anti-CTLA-4, anti-PD-1, or the combination, and used support vector machine models to identify pre-treatment antibody signatures that predict irAE development. Results We identified distinct pre-treatment serum antibody profiles associated with severe irAEs for each therapy group. Support vector machine classifier models identified antibody signatures that could effectively discriminate between toxicity groups with >?90% accuracy, sensitivity, and specificity. Pathway analyses revealed significant enrichment of antibody targets associated with immunity/autoimmunity, including TNF signaling, toll-like receptor signaling and microRNA biogenesis. Conclusions Our results provide the first evidence supporting a predisposition to develop severe irAEs upon immune system disinhibition, which requires further independent validation in a clinical trial setting. Electronic supplementary material The online version of this article (10.1186/s12967-018-1452-4) contains supplementary material, which is available to authorized users. Keywords: Melanoma, Immunotherapy, Antibodies, Toxicity, Biomarker Background Immune checkpoint inhibitors (ICI) target cytotoxic T lymphocyte-associated antigen 4 (CTLA-4, e.g. ipilimumab) or programmed cell death protein 1 (PD-1, e.g. nivolumab, pembrolizumab) to promote T cell mediated anti-tumor immunity and produce durable clinical benefit in a subset of patients with advanced melanoma [1]. More recently, the combination of anti-CTLA-4 and anti-PD-1 has been shown to be more efficacious than single agent therapy SID 3712249 [2]. Despite this progress a substantial proportion of patients receiving ICI develop immune-related adverse events (irAEs) [3], which are often more severe in patients receiving combination regimens [4]. IrAEs can necessitate systemic immunosuppression therapy and/or treatment termination [5]. Hence, there is an urgent clinical need to identify patients who are more likely to develop severe irAEs, particularly as more patients receive these immune therapies due to the approval of ICI for other cancer types (e.g. bladder, lung), and in the adjuvant setting for stage III/IV melanoma [6, 7]. A biomarker predictive of immunotherapy toxicity would facilitate a personalized approach to patient management, enabling more-effective.