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

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 + 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).

Inhibition of Growth of TSC2-Null Cells by a PI3K/mTOR Inhibitor but Not by a Selective MNK1/2 Inhibitor

“…For example, it has been shown in T cells purified from lupus patients, treated with 2 mg daily rapamycin, about 50% p4E-BP1 (Thr37/46) was inhibited [22]. Indeed, rapamycin treatment has shown promise in several small clinical trials in autoimmune diseases, including systemic lupus erythematosus [23], rheumatoid arthritis, diffuse cutaneous scleroderma [24], and idiopathic multicentric Castleman disease [25]. Our in vitro cell studies did not investigate the effect of TSC2+/+ immune cells or stromal cells on the TSC2-null cell growth.…”

Targeting the mTOR pathway in idiopathic multicentric Castleman disease

“…Sirolimus treatment normalized VEGF-A levels and decreased circulating activated CD8 + T cells in all three patients. Moreover, the patients have tolerated the sirolimus without significant side effects, have experienced symptomatic benefit, and have been in remission for 64, 17, and 17 months, respectively (14).…”

“…Fajgenbaum et al successfully employ a precision medicine approach to identify and target the mTOR pathway in 3 IL-6 blockade-refractory patients with iMCD (14). Their methodology was innovative and presents a potential roadmap for similar investigations in other rare diseases.…”

“…In this issue, Fajgenbaum et al identify the mTOR pathway as a pharmacologically targetable pathway within IL-6 blockaderefractory iMCD ( Figure 1B) (14). mTOR is an atypical serine/threonine protein kinase that is part of the phosphoinositide 3-kinase-related (PI3K-related) kinase family (15).…”

“…Fajgenbaum et al pinpointed the mTOR pathway using a novel precision medicine approach that utilized in-depth analyses of blood and tissue samples from three IL-6 blockade-refractory patients with the TAFRO subtype of iMCD (14). The authors first measured serum inflammatory mark- signaling is associated with this trigger remain unknown.…”