Cited by 147IgG4-Related and Inflammatory DiseasesViral-associated cancers and disordersAutoimmune and Inflammatory Disorders Research

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Identifying and targeting pathogenic PI3K/AKT/mTOR signaling in IL-6 blockade–refractory idiopathic multicentric Castleman disease

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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, Fábio Freire, Hamerschlak, Nelson, Wertheim, Gerald B., Jordan, Michael B., Cohen, Adam D., Krymskaya, Vera, Rubenstein, Arthur, Betts, Michael R., Kambayashi, Taku, van Rhee, Frits, Uldrick, Thomas S.·2019·Journal of Clinical Investigation

DOI 10.1172/jci126091PMC PMC6763254

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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 three 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 three 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 three IL-6-blockade refractory iMCD cases revealed increased CD8+ T cell activation, VEGF-A, and PI3K/Akt/mTOR pathway activity. Administration of sirolimus significantly attenuated CD8+ T cell activation and decreased VEGF-A levels. Sirolimus induced clinical benefit responses in all three 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: Castleman's Awareness & Research Effort/Castleman Disease Collaborative Network, Penn Center for Precision Medicine, University Research Foundation, Intramural NIH funding, and National Heart Lung and Blood Institute.

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Authors: Fajgenbaum, D. C., Langan, R.-A., Japp, A. S., Partridge, H. L., Pierson, S. K., Singh, A., Arenas, D. J., Ruth, J. R., Nabel, C. S., Stone, K., Okumura, M., Schwarer, A., Jose, F. F., Hamerschlak, N., Wertheim, G. B., Jordan, M. B., Cohen, A. D., Krymskaya, V., Rubenstein, A., Betts, M. R., Kambayashi, T., van Rhee, F., & Uldrick, T. S.
Affiliations: University of Pennsylvania (US)
Prevention of Organ Failure (CA)
Dana-Farber Cancer Institute (US)
University of Arkansas for Medical Sciences (US)
Eastern Health (AU)
Hospital Israelita Albert Einstein (BR)
Children's Hospital of Philadelphia (US)
Cincinnati Children's Hospital Medical Center (US)
Abramson Cancer Center (US)
Fred Hutch Cancer Center (US)
Corresponding author: Fajgenbaum, David C.
ORCID: Fajgenbaum, David C.
Langan, Ruth-Anne
Japp, Alberto Sada
Partridge, Helen L.
Pierson, Sheila K.
Singh, Amrit
Arenas, Daniel J.
Nabel, Christopher S.
Stone, Katie
Hamerschlak, Nelson
Wertheim, Gerald B.
Jordan, Michael B.
Cohen, Adam D.
Krymskaya, Vera
Betts, Michael R.
Kambayashi, Taku
Uldrick, Thomas S.
Venue: Journal of Clinical Investigation
Publisher: American Society for Clinical Investigation
Published: 2019-09-16
Volume: 129
Issue: 10
Pages: 4451-4463
ISSN: 0021-9738 (ISSN-L)
1558-8238
DOI: 10.1172/jci126091
PMC: PMC6763254
OpenAlex: W2968883182
Cited by: 147
References: 46
Citations by year: 2026: 18 · 2025: 21 · 2024: 23 · 2023: 14 · 2022: 24 · 2021: 21 · 2020: 23 · 2019: 3
FWCI: 13.47
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Journal of Clinical Investigation (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: Castleman’s Awareness & Research Effort (CDCN-2015-001-R)
Penn Center for Precision Medicine (N/A)
University of Pennsylvania (N/A)
National Heart, Lung, and Blood Institute (R01-HL141408)
National Institutes of Health (ZIA BC 011700)
Topics: Health Sciences › Medicine › Rheumatology › IgG4-Related and Inflammatory Diseases
Health Sciences › Medicine › Oncology › Viral-associated cancers and disorders
Health Sciences › Medicine › Hematology › Autoimmune and Inflammatory Disorders Research
Keywords: idiopathic multicentric Castleman disease, PI3K/AKT/mTOR pathway, rapamycin, mTOR inhibition, CD8+ T cell activation, VEGF-A, TAFRO syndrome, drug target identification, precision medicine, lymphoproliferation
MeSH terms: Adolescent, Adult, Female, Castleman Disease, Humans, Male, Middle Aged, Signal Transduction, Interleukin-6, Phosphatidylinositol 3-Kinases, Sirolimus, Proteomics, Proto-Oncogene Proteins c-akt, TOR Serine-Threonine Kinases

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Identifying and targeting pathogenic PI3K/AKT/mTOR signaling in IL-6 blockade–refractory idiopathic multicentric Castleman disease

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