Clinical Use of the mTOR Pathway Inhibitor Sirolimus (rapamycin) to Treat Children with Autoimmune Lymphoproliferative Syndrome (ALPS)
Clinical trials are underway at the Center for Childhood Cancer Research to evaluate the use of sirolimus as a treatment for refractory pediatric autoimmune diseases.
Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of abnormal lymphocyte survival. It’s caused by dysregulation of the FAS apoptotic (programmed cell death) pathway.
Patients with ALPS develop chronic, non-malignant lymphoproliferation, autoimmune disease, and approximately 10 percent develop secondary malignancies. ALPS was originally thought to be extremely rare, but may be more common: More patients are being increasingly diagnosed because of growing clinical awareness.
Preclinical studies using mouse xenograft models of ALPS conducted by David T. Teachey, MD, and researchers at the Center for Childhood Cancer Research demonstrated that PI3K/AKT/mTOR protein kinase signaling is dysregulated in ALPS. They also found that targeting ALPS with the mTOR inhibitor sirolimus (rapamycin) is effective.
Pilot clinical studies with as many as 50 pediatric ALPS patients revealed that sirolimus treatments resulted in a complete and durable response in over 90 percent of sirolimus-treated patients with minimal toxicity. Prior to using sirolimus for ALPS, there was no effective treatment that could improve the lymphoproliferative and autoimmune manifestations of the disease.
Based on the results of the pilot study, clinical trials are underway at the Center for Childhood Cancer Research to evaluate the use of sirolimus as a treatment for refractory pediatric autoimmune diseases.
Sirolimus has revolutionized the treatment of ALPS and is quickly becoming the standard of care as a single agent targeted therapy for to treat children with ALPS.