Using The SomaScan® Assay to Identify Promising Treatment Approaches for Castleman Disease
Background: Idiopathic multicentric Castleman disease (iMCD) is a hematologic illness involving cytokine-induced lymphoproliferation, systemic inflammation, cytopenias, and life-threatening multi-organ dysfunction. The molecular underpinnings of interleukin-6 (IL-6) blockade–refractory patients remain unknown; no targeted therapies exist. In this study, we searched for therapeutic targets in IL-6 blockade–refractory iMCD patients with the thrombocytopenia, anasarca, fever/elevated C-reactive protein, reticulin myelofibrosis, renal dysfunction, organomegaly (TAFRO) clinical subtype.
Methods: Serum and plasma were isolated for iMCD-1 following standard protocols, stored at –80°C, and shipped overnight on dry ice to Myriad RBM (serum) and SomaLogic, Inc. (plasma) for analysis. Proteomic quantifications were performed in accordance with previously published methods for Myriad RBM Discovery MAP v.3.3, a multiplex immunoassay that quantifies the levels of 315 analytes, and a previous version of SomaLogic SomaScan, a modified DNA-aptamer approach that quantifies 1129 analytes (the current version of SomaScan quantifies over 7,000 analytes).
Results: Studies of 3 IL-6 blockade–refractory iMCD cases revealed increased CD8+ T cell activation, VEGF-A, and PI3K/Akt/mTOR pathway activity. Administration of sirolimus substantially attenuated CD8+ T cell activation and decreased VEGF-A levels. Sirolimus induced clinical benefit responses in all 3 patients with durable and ongoing remissions of 66, 19, and 19 months.
Conclusion: This precision medicine approach identifies PI3K/Akt/mTOR signaling as the first pharmacologically targetable pathogenic process in IL-6 blockade–refractory iMCD. Prospective evaluation of sirolimus in treatment-refractory iMCD is planned (NCT03933904).
David Fajgenbaum, MD, MBA, MSc
Assistant Professor of Translational Medicine and Human Genetics, University of Pennsylvania
In addition to his rare disease research credentials at University of Pennsylvania, Dr Fajgenbaum is also a patient battling idiopathic multicentric Castleman disease (iMCD). He became ill during his third year of medical school in 2010, had his last rites read, and had 4 life-threatening iMCD relapses. In 2012, Dr Fajgenbaum cofounded the Castleman Disease Collaborative Network (CDCN). He currently leads 18 translational research studies, including an international natural history study, the first-ever NIH R01 grant studying iMCD, and a clinical trial of sirolimus in iMCD.