Keli L Hippen1, Scott N Furlan2, Rahul Roychoudhuri3, Ena Wang4, Yigang Zhang5, Mark J Osborn5, Sarah C Merkel5, Sophia Hani5, Margaret L MacMillan5, Frank Cichocki6, Jeffrey S Miller6, John E Wagner5, Nicholas P Restifo7, Leslie S Kean8, Bruce R Blazar9. 1. Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota Cancer Center, Minneapolis, Minnesota, USA. Electronic address: hippe002@umn.edu. 2. Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, Washington, USA; Department of Pediatrics, University of Washington, Seattle, Washington, USA. 3. Laboratory of Lymphocyte Signaling and Development, Babraham Institute, Cambridge, UK. 4. Translational Oncology, Allogene Therapeutics, San Francisco, California, USA. 5. Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota Cancer Center, Minneapolis, Minnesota, USA. 6. Department of Medicine, Division of Hematology/Oncology and Transplantation, University of Minnesota, Minneapolis, Minnesota, USA. 7. Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA. 8. Division of Pediatric Hematology/Oncology, Boston Children's Hospital and Dana-Farber Cancer Institute, Boston, Massachusetts, USA. 9. Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota Cancer Center, Minneapolis, Minnesota, USA. Electronic address: blaza001@umn.edu.
Abstract
BACKGROUND AIMS: Adoptive transfer of suppressive CD4+CD25+ thymic regulatory T cells (tTregs) can control auto- and alloimmune responses but typically requires in vitro expansion to reach the target cell number for efficacy. Although the adoptive transfer of expanded tTregs purified from umbilical cord blood ameliorates graft-versus-host disease in patients receiving hematopoietic stem cell transplantation for lymphohematopoietic malignancy, individual Treg products of 100 × 106 cells/kg are manufactured over an extended 19-day time period using a process that yields variable products and is both laborious and costly. These limitations could be overcome with the availability of 'off the shelf' Treg. RESULTS: Previously, the authors reported a repetitive restimulation expansion protocol that maintains Treg phenotype (CD4+25++127-Foxp3+), potentially providing hundreds to thousands of patient infusions. However, repetitive stimulation of effector T cells induces a well-defined program of exhaustion that leads to reduced T-cell survival and function. Unexpectedly, the authors found that multiply stimulated human tTregs do not develop an exhaustion signature and instead maintain their Treg gene expression pattern. The authors also found that tTregs expanded with one or two rounds of stimulation and tTregs expanded with three or five rounds of stimulation preferentially express distinct subsets of a group of five transcription factors that lock in Treg Foxp3expression, Treg stability and suppressor function. Multiply restimulated Tregs also had increased transcripts characteristic of T follicular regulatory cells, a Treg subset. DISCUSSION: These data demonstrate that repetitively expanded human tTregs have a Treg-locking transcription factor with stable FoxP3 and without the classical T-cell exhaustion gene expression profile-desirable properties that support the possibility of off-the-shelf Treg therapeutics.
BACKGROUND AIMS: Adoptive transfer of suppressive CD4+CD25+ thymic regulatory T cells (tTregs) can control auto- and alloimmune responses but typically requires in vitro expansion to reach the target cell number for efficacy. Although the adoptive transfer of expanded tTregs purified from umbilical cord blood ameliorates graft-versus-host disease in patients receiving hematopoietic stem cell transplantation for lymphohematopoietic malignancy, individual Treg products of 100 × 106 cells/kg are manufactured over an extended 19-day time period using a process that yields variable products and is both laborious and costly. These limitations could be overcome with the availability of 'off the shelf' Treg. RESULTS: Previously, the authors reported a repetitive restimulation expansion protocol that maintains Treg phenotype (CD4+25++127-Foxp3+), potentially providing hundreds to thousands of patient infusions. However, repetitive stimulation of effector T cells induces a well-defined program of exhaustion that leads to reduced T-cell survival and function. Unexpectedly, the authors found that multiply stimulated human tTregs do not develop an exhaustion signature and instead maintain their Treg gene expression pattern. The authors also found that tTregs expanded with one or two rounds of stimulation and tTregs expanded with three or five rounds of stimulation preferentially express distinct subsets of a group of five transcription factors that lock in Treg Foxp3expression, Treg stability and suppressor function. Multiply restimulated Tregs also had increased transcripts characteristic of T follicular regulatory cells, a Treg subset. DISCUSSION: These data demonstrate that repetitively expanded human tTregs have a Treg-locking transcription factor with stable FoxP3 and without the classical T-cell exhaustion gene expression profile-desirable properties that support the possibility of off-the-shelf Treg therapeutics.
Authors: Jeff E Mold; Shivkumar Venkatasubrahmanyam; Trevor D Burt; Jakob Michaëlsson; Jose M Rivera; Sofiya A Galkina; Kenneth Weinberg; Cheryl A Stoddart; Joseph M McCune Journal: Science Date: 2010-12-17 Impact factor: 47.728
Authors: Claudio G Brunstein; Jeffrey S Miller; Qing Cao; David H McKenna; Keli L Hippen; Julie Curtsinger; Todd Defor; Bruce L Levine; Carl H June; Pablo Rubinstein; Philip B McGlave; Bruce R Blazar; John E Wagner Journal: Blood Date: 2010-10-15 Impact factor: 22.113
Authors: Bertram Bengsch; Takuya Ohtani; Omar Khan; Manu Setty; Sasikanth Manne; Shaun O'Brien; Pier Federico Gherardini; Ramin Sedaghat Herati; Alexander C Huang; Kyong-Mi Chang; Evan W Newell; Niels Bovenschen; Dana Pe'er; Steven M Albelda; E John Wherry Journal: Immunity Date: 2018-05-15 Impact factor: 31.745
Authors: Andrew C Scott; Friederike Dündar; Paul Zumbo; Smita S Chandran; Christopher A Klebanoff; Mojdeh Shakiba; Prerak Trivedi; Laura Menocal; Heather Appleby; Steven Camara; Dmitriy Zamarin; Tyler Walther; Alexandra Snyder; Matthew R Femia; Elizabeth A Comen; Hannah Y Wen; Matthew D Hellmann; Niroshana Anandasabapathy; Yong Liu; Nasser K Altorki; Peter Lauer; Olivier Levy; Michael S Glickman; Jonathan Kaye; Doron Betel; Mary Philip; Andrea Schietinger Journal: Nature Date: 2019-06-17 Impact factor: 49.962