Johanna C Wagner1,2, Qizhi Tang1,3. 1. Division of Transplantation, Department of Surgery, University of California San Francisco, 513 Parnassus Ave, San Francisco, CA 94143, USA. 2. University Hospital Würzburg, Department of General, Visceral, Transplantation, Vascular and Pediatric Surgery, Oberdürrbacherstr. 6, 97080 Würzburg, Germany. 3. UCSF Diabetes Center, University of California San Francisco, 513 Parnassus Ave, San Francisco, CA 94143, USA.
Abstract
PURPOSE OF THE REVIEW: The adoptive transfer of alloantigen-specific regulatory T cells (Tregs) following organ transplantation is an emerging treatment paradigm that may induce tolerance and reduce the risk for graft rejection. In particular, redirecting Treg specificity via expression of synthetic chimeric antigen receptors (CARs) has demonstrated therapeutic promise in several preclinical studies. In this review, we highlight recent progress and remaining barriers to the clinical translation of CAR-Treg therapies. RECENT FINDINGS: CAR Tregs targeting human leukocyte antigen (HLA)-A2 showed antigen-specific in vitro activation and superior in vivo protective function relative to polyclonal Tregs. Adoptively transferred anti-HLA-A2 CAR Tregs prolonged the survival of HLA-A2-positive grafts in humanized mouse models. SUMMARY: Donor HLA molecules are attractive candidate antigens to target with CAR Tregs in transplantation due to mismatched HLA only expressed on the transplanted organ. The feasibility of this approach has been demonstrated by several independent groups in recent years. However, substantial challenges in CAR design and preclinical modeling must be more extensively addressed prior to clinical application.
PURPOSE OF THE REVIEW: The adoptive transfer of alloantigen-specific regulatory T cells (Tregs) following organ transplantation is an emerging treatment paradigm that may induce tolerance and reduce the risk for graft rejection. In particular, redirecting Treg specificity via expression of synthetic chimeric antigen receptors (CARs) has demonstrated therapeutic promise in several preclinical studies. In this review, we highlight recent progress and remaining barriers to the clinical translation of CAR-Treg therapies. RECENT FINDINGS: CAR Tregs targeting human leukocyte antigen (HLA)-A2 showed antigen-specific in vitro activation and superior in vivo protective function relative to polyclonal Tregs. Adoptively transferred anti-HLA-A2 CAR Tregs prolonged the survival of HLA-A2-positive grafts in humanized mouse models. SUMMARY: Donor HLA molecules are attractive candidate antigens to target with CAR Tregs in transplantation due to mismatched HLA only expressed on the transplanted organ. The feasibility of this approach has been demonstrated by several independent groups in recent years. However, substantial challenges in CAR design and preclinical modeling must be more extensively addressed prior to clinical application.
Authors: Barbara Savoldo; Carlos Almeida Ramos; Enli Liu; Martha P Mims; Michael J Keating; George Carrum; Rammurti T Kamble; Catherine M Bollard; Adrian P Gee; Zhuyong Mei; Hao Liu; Bambi Grilley; Cliona M Rooney; Helen E Heslop; Malcolm K Brenner; Gianpietro Dotti Journal: J Clin Invest Date: 2011-04-11 Impact factor: 14.808
Authors: D A Boardman; C Philippeos; G O Fruhwirth; M A A Ibrahim; R F Hannen; D Cooper; F M Marelli-Berg; F M Watt; R I Lechler; J Maher; L A Smyth; G Lombardi Journal: Am J Transplant Date: 2017-02-01 Impact factor: 8.086