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

Area of Science:

• Hematology
• Oncology
• Immunology

Background:

• Idiopathic multicentric Castleman disease (iMCD) is a rare hematologic disorder characterized by cytokine-induced lymphoproliferation and systemic inflammation.
• Patients refractory to interleukin-6 (IL-6) blockade lack targeted therapies, necessitating the identification of novel therapeutic targets.
• The thrombocytopenia, anasarca, fever/elevated C-reactive protein, reticulin myelofibrosis, renal dysfunction, organomegaly (TAFRO) subtype of iMCD presents unique challenges.

Observation:

• Analysis of IL-6 blockade-refractory iMCD-TAFRO patients revealed increased CD8+ T cell activation.
• Elevated levels of VEGF-A and heightened activity within the PI3K/Akt/mTOR signaling pathway were observed.
• Immunohistochemistry confirmed elevated mTOR signaling via phosphorylated S6 in iMCD lymph node tissues.

Findings:

• Administration of the mTOR inhibitor, sirolimus, significantly reduced CD8+ T cell activation and decreased VEGF-A levels.
• Sirolimus treatment resulted in durable clinical responses and ongoing remissions in all three treated iMCD-TAFRO patients.
• The observed responses included remissions lasting 66, 19, and 19 months.

Implications:

• This study identifies the PI3K/Akt/mTOR signaling pathway as the first pharmacologically targetable mechanism in IL-6 blockade-refractory iMCD.
• Precision medicine targeting this pathway offers a new therapeutic strategy for iMCD patients with refractory disease.
• Prospective clinical trials evaluating sirolimus for treatment-refractory iMCD are planned, including NCT03933904.