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Baseline antibody profiles predict toxicity in melanoma patients treated with immune checkpoint inhibitors.


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, 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.

SUBMITTER: Gowen MF 

PROVIDER: S-EPMC5880088 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Baseline antibody profiles predict toxicity in melanoma patients treated with immune checkpoint inhibitors.

Gowen Michael F MF   Giles Keith M KM   Simpson Danny D   Tchack Jeremy J   Zhou Hua H   Moran Una U   Dawood Zarmeena Z   Pavlick Anna C AC   Hu Shaohui S   Wilson Melissa A MA   Zhong Hua H   Krogsgaard Michelle M   Kirchhoff Tomas T   Osman Iman I  

Journal of translational medicine 20180402 1


<h4>Background</h4>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, 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.<h4>Methods</h4>We hypothesized that pre-treatment antibody profiles identify a subset  ...[more]

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