Immune Reconstitution After Autologous Hematopoietic Stem Cell Transplantation in Crohn’s Disease: Current Status and Future Directions. A Review on Behalf of the EBMT Autoimmune Diseases Working Party and the Autologous Stem Cell Transplantation In Refractory CD—Low Intensity Therapy Evaluation Study Investigators

Abstract

Patients with treatment refractory Crohn’s disease (CD) suffer debilitating symptoms, poor quality of life, and reduced work productivity. Surgery to resect inflamed and fibrotic intestine may mandate creation of a stoma and is often declined by patients. Such patients continue to be exposed to medical therapy that is ineffective, often expensive and still associated with a burden of adverse effects. Over the last two decades, autologous hematopoietic stem cell transplantation (auto-HSCT) has emerged as a promising treatment option for patients with severe autoimmune diseases (ADs). Mechanistic studies have provided proof of concept that auto-HSCT can restore immunological tolerance in chronic autoimmunity via the eradication of pathological immune responses and a profound reconfiguration of the immune system. Herein, we review current experience of auto-HSCT for the treatment of CD as well as approaches that have been used to monitor immune reconstitution following auto-HSCT in patients with ADs, including CD. We also detail immune reconstitution studies that have been integrated into the randomized controlled Autologous Stem cell Transplantation In refractory CD—Low Intensity Therapy Evaluation trial, which is designed to test the hypothesis that auto-HSCT using reduced intensity mobilization and conditioning regimens will be a safe and effective means of inducing sustained control in refractory CD compared to standard of care. Immunological profiling will generate insight into the pathogenesis of the disease, restoration of responsiveness to anti-TNF therapy in patients with recurrence of endoscopic disease and immunological events that precede the onset of disease in patients that relapse after auto-HSCT.

The rise of autologous HCT for autoimmune diseases: what is behind it and what does it mean for the future of treatment? An update on behalf of the EBMT Autoimmune Diseases Working Party

“…However, in a subsequent analysis of the combined cohort of the 40 patients that underwent aHCT (including crossovers), there was a significant improvement in clinical disease activity, quality of life and endoscopic disease activity, with half of the patients having complete responses [23]. The current 'ASTIC-lite' RCT, which incorporates associated mechanistic studies and an EBMT based long term follow up study will evaluate the effect of aHCT delivered using a modified regimen versus standard of care in poor-prognosis treatment-resistant CD [24]. There is also an ongoing high-level inter-specialty collaboration between EBMT and the European Crohn's and Colitis Organization (ECCO) [25].…”

Autologous haematopoietic stem cell transplantation (aHSCT) for severe resistant autoimmune and inflammatory diseases – a guide for the generalist

“…The primary endpoint will be mucosal healing, and patients who are randomised to HSCT but have disease recurrence at 6 months will restart anti-TNF therapy. 21…”

“…In addition to providing insights on immune reconstitution, concurrent scientific studies conducted while destroying and rebuilding dysfunctional immune systems may also provide useful insights into the aetiology and pathogenesis of autoimmune diseases. 7,11,21…”

Autologous Hematopoietic Stem Cell Transplantation for Autoimmune Diseases: From Mechanistic Insights to Biomarkers

“… d Lineage (Lin) cocktail: CD3/CD19/CD20/CD56. Immunophenotyping panels were based on previous reports ( 12 , 66 , 67 , 68 , 69 ) . …”