1. Identifying and targeting pathogenic PI3K/AKT/ mTOR signaling in IL-6 blockade-refractory idiopathic multicentric Castleman disease
- Author
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Fajgenbaum, David C., Langan, Ruth-Anne, Japp, Alberto Sada, Partridge, Helen L., Pierson, Sheila K., Singh, Amrit, Arenas, Daniel J., Ruth, Jason R., Nabel, Christopher S., Stone, Katie, Okumura, Mariko, Schwarer, Anthony, Jose, Fabio Freire, Hamerschlak, Nelson, Wertheim, Gerald B., Jordan, Michael B., Cohen, Adam D., Krymskaya, Vera, Rubenstein, Arthur, Betts, Michael R., Kambayashi, Taku, van Rhee, Frits, and Uldrick, Thomas S.
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Precision medicine -- Analysis -- Health aspects ,Interleukins -- Analysis -- Health aspects ,Inflammation -- Care and treatment -- Analysis -- Health aspects ,Tocilizumab -- Analysis -- Health aspects ,C-reactive protein -- Analysis -- Health aspects ,Immunohistochemistry -- Analysis -- Health aspects ,Vascular endothelial growth factor -- Analysis -- Health aspects ,Medical research -- Analysis -- Health aspects ,Siltuximab -- Analysis -- Health aspects ,T cells -- Analysis -- Health aspects ,Cytokines ,Endothelial growth factors ,Proteomics ,Thrombocytopenia ,Rapamycin ,Sirolimus ,University research ,Novels ,Health care industry - Abstract
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. We analyzed tissues and blood samples from 3 IL-6 blockade-refractory iMCD-TAFRO patients. Cytokine panels, quantitative serum proteomics, flow cytometry of PBMCs, and pathway analyses were employed to identify novel therapeutic targets. To confirm elevated mTOR signaling, a candidate therapeutic target from the above assays, immunohistochemistry was performed for phosphorylated S6, a read-out of mTOR activation, in 3 iMCD lymph node tissue samples and controls. Proteomic, immunophenotypic, and clinical response assessments were performed to quantify the effects of administration of the mTOR inhibitor sirolimus. RESULTS. Studies of 3 IL-6 blockade-refractory iMCD cases revealed increased [CD8.sup.+] T cell activation, VEGF-A, and PI3K/Akt/mTOR pathway activity. Administration of sirolimus substantially attenuated [CD8.sup.+] 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). FUNDING. This study was supported by the Castleman's Awareness & Research Effort/Castleman Disease Collaborative Network, Penn Center for Precision Medicine, University Research Foundation, Intramural NIH funding, and the National Heart Lung and Blood Institute., Introduction Multicentric Castleman disease (MCD) is characterized by polyclonal lymphoproliferation, hypervascularized lymph nodes containing dysmorphic germinal centers, cytokine-driven systemic inflammation, cytopenias, and multi-organ dysfunction. The estimated annual incidence of MCD [...]
- Published
- 2019
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