Case Report: Delayed Onset Multi-Organ Toxicities in a Melanoma Patient Achieving Complete Response to BRAF/MEK Inhibition

• Type of Material: Article
• Authors: Hannah M Knochelmann, Medical University of South Carolina; Michael B Ware, Emory University; Aditya Rali, Emory University; Susanne Linderman, Emory University; Jessica Shantha, Emory University; David Lawson, Emory University; Melinda Yushak, Emory University; Robert Swerlick, Emory University; Chrystal Paulos, Emory University; Steven Yeh, Emory University; Ragini Kudchadkar, Emory University
• Language: English
• Date: 2022-03-31
• Publisher: FRONTIERS MEDIA SA
• Publication Version: Final Published Version
• Copyright Statement: © 2022 Knochelmann, Ware, Rali, Linderman, Shantha, Lawson, Yushak, Swerlick, Paulos, Yeh and Kudchadkar
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.3389/fonc.2022.836845
• Title of Journal or Parent Work: FRONTIERS IN ONCOLOGY
• Volume: 12
• Start Page: 836845
• End Page: 836845
• Grant/Funding Information: This work was supported by the NCI F30 243307 and the NIH GM008716 to HK, the NCI grants R01 CA175061 and R01 CA208514 to CP, and the V Foundation Translational Award to CP and RK.
• Keywords: BRAF; MEKi; Th17; CELLS; Life Sciences & Biomedicine; Science & Technology; uveitis; autoimmune toxicity; melanoma; Tc17; UVEITIS; Oncology; IMMUNOTHERAPY
• Research Categories: Health Sciences, Immunology; Health Sciences, Oncology; Biology, Microbiology

Abstract

Autoimmune toxicities, while common following treatment with cancer immunotherapies, are not well-characterized in patients treated with BRAF/MEK inhibitors. Emerging data suggest that autoimmune effects may be linked with superior responses to both treatment modalities; however, there is little evidence describing mechanisms of immune-related toxicity for patients on BRAF/MEK inhibitors. Here we describe the experience of a 59-year-old HLA-A2, A29, B27-positive male with recurrent/metastatic melanoma. After progression on checkpoint inhibitor therapy, he was treated with dabrafenib/trametinib followed by encorafenib/binimetinib, which were well-tolerated and resulted in a complete response. Eighteen months into BRAF/MEK inhibitor therapy, and three months after initially finding a complete response, he developed a series of sudden-onset, severe toxicities: namely, bilateral panuveitis, cytopenias, joint pain, skin rash, hypercalcemia, and interstitial nephritis, which led to BRAF/MEKi cessation. Immunological analyses revealed induction of a peripheral type-17 cytokine signature characterized by high IL-23, IL-6, IL-10, IL-17A/F, IL-1β, and IL-21 among other cytokines in plasma corresponding with the height of symptoms. These findings highlight a novel instance of delayed autoimmune-like reaction to BRAF/MEK inhibition and identify a possible role for Th/Tc17 activation in their pathogenesis thus warranting future clinical and immunological characterization.