Phase I/ii Car-Treg Cell Therapy Clinical Trial To Induce Long-term Tolerance In Liver Transplant Patients
1King's College London, London, United Kingdom, 2Quell Therapeutics Ltd, London, United Kingdom
Meeting: 2022 American Transplant Congress
Abstract number: 9014
Keywords: Liver transplantation, Tolerance
Topic: Clinical Science » Liver » 54 - Liver: Immunosuppression and Rejection
Session Information
Session Name: Late Breaking: Clinical
Session Type: Rapid Fire Oral Abstract
Date: Sunday, June 5, 2022
Session Time: 3:30pm-5:00pm
Presentation Time: 3:40pm-3:50pm
Location: Hynes Room 313
*Purpose: Life-long pharmacological immunosuppression (IS) is considered essential to prevent rejection following liver transplantation (LT), but is associated with significant side effects such as infections, malignancies, cardiovascular disease and nephrotoxicity. Consequently, there is a high unmet need to identify alternatives to chronic IS. LT patients can develop spontaneous tolerance towards the transplanted allograft, enabling them to completely discontinue all IS (phenomenon referred to as ‘operational tolerance’). However, operational tolerance occurs only in a small proportion of LT patients usually many years after transplantation, necessitating novel approaches to induce operational tolerance earlier after transplantation in a majority of patients.
*Methods: Regulatory T cells (Tregs) have been identified as key orchestrators of immune tolerance. Preclinical and clinical studies provide evidence that adoptive Treg transfer is safe and, at least partially effective in counter-balancing T-cell mediated organ rejection and establishing tolerance. Chimeric Antigen Receptor (CAR) technology enables the development of antigen-specific CAR-Treg therapies to promote tissue-targeted tolerance induction. Several studies have reported the successful transduction of human Tregs with a CAR targeting the Human Leukocyte Antigen (HLA) class I molecule A2 (HLA-A2-CAR, most prevalent HLA class I allele) to specifically target donor cells in the context of HLA-mismatch transplantation.
*Results: We present here a single-arm, open-label, multi-centre, first-in-human, phase I/II clinical trial employing autologous anti-HLA-A2 CAR-Tregs in adult non-autoimmune HLA-A2 mismatched LT recipients 1-5 years post-transplantation. CAR-Tregs are endowed with a FOXP3 phenotype lock and an inducible safety swich. The trial is composed of two parts: part I as safety cohort (n=3), part 2 (n=15) as expansion/efficacy cohort with conditioning and full IS weaning, and a long-term follow-up phase. Baseline IS includes low-dose Tacrolimus and Everolimus and part 2 participants will receive a conditioning regimen. Endpoints include safety, immunomonitoring/biomarkers, operational tolerance and rejection rates.
*Conclusions: This trial, which is currently recruiting, will provide first evidence in humans whether CAR-Tregs are a safe and/or effective therapeutic approach to induce tolerance in LT patients with broad implications for other transplant and non-transplant indication areas.
To cite this abstract in AMA style:
Sanchez-Fueyo A, Taylor A, Collin D, Nathalie C, Chris S, Martinez-Llordella M, Belmonte N, McGill I, Hartl D. Phase I/ii Car-Treg Cell Therapy Clinical Trial To Induce Long-term Tolerance In Liver Transplant Patients [abstract]. Am J Transplant. 2022; 22 (suppl 3). https://atcmeetingabstracts.com/abstract/phase-i-ii-car-treg-cell-therapy-clinical-trial-to-induce-long-term-tolerance-in-liver-transplant-patients/. Accessed September 7, 2024.« Back to 2022 American Transplant Congress