Regulatory T-Cell Therapy in Transplantation: Moving to the Clinic

doi:10.1101/CSHPERSPECT.A015552

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Regulatory T-Cell Therapy in Transplantation: Moving to the Clinic

Journal Article•DOI•

Regulatory T-Cell Therapy in Transplantation: Moving to the Clinic

Qizhi Tang¹, Jeffrey A. Bluestone¹•Institutions (1)

University of California, San Francisco¹

01 Nov 2013-Cold Spring Harbor Perspectives in Medicine (Cold Spring Harbor Laboratory Press)-Vol. 3, Iss: 11

TL;DR: Technical advances in Treg manufacturing are summarized and guidelines for identity and purity assurance of Treg products are provided to help harnessing the tolerogenic potential of T Reg therapy in transplantation.

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Abstract: Regulatory T cells (Tregs) are essential to transplantation tolerance and their therapeutic efficacy is well documented in animal models. Moreover, human Tregs can be identified, isolated, and expanded in short-term ex vivo cultures so that a therapeutic product can be manufactured at relevant doses. Treg therapy is being planned at multiple transplant centers around the world. In this article, we review topics critical to effective implementation of Treg therapy in transplantation. We will address issues such as Treg dose, antigen specificity, and adjunct therapies required for transplant tolerance induction. We will summarize technical advances in Treg manufacturing and provide guidelines for identity and purity assurance of Treg products. Clinical trial designs and Treg manufacturing plans that incorporate the most up-to-date scientific understanding in Treg biology will be essential for harnessing the tolerogenic potential of Treg therapy in transplantation.

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Journal Article•DOI•

Type 1 diabetes immunotherapy using polyclonal regulatory T cells.

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Jeffrey A. Bluestone¹, Jane H. Buckner², Mark Fitch³, Stephen E. Gitelman¹, Shipra Gupta², Marc K. Hellerstein³, Kevan C. Herold⁴, Angela P. Lares¹, Michael R. Lee¹, Kelvin W. Li, Weihong Liu¹, S. Alice Long², Lisa M. Masiello¹, Vinh Son Nguyen¹, Amy L. Putnam¹, Mary Rieck¹, Peter H. Sayre¹, Qizhi Tang¹ - Show less +14 more•Institutions (4)

University of California, San Francisco¹, Benaroya Research Institute², University of California, Berkeley³, Yale University⁴

25 Nov 2015-Science Translational Medicine

TL;DR: A phase 1 trial of adoptive Treg immunotherapy to repair or replace Tregs in type 1 diabetics was reported, and the therapy was safe, supporting efficacy testing in further trials and support the development of a phase 2 trial to test efficacy of the Treg therapy.

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Abstract: Type 1 diabetes (T1D) is an autoimmune disease that occurs in genetically susceptible individuals. Regulatory T cells (Tregs) have been shown to be defective in the autoimmune disease setting. Thus, efforts to repair or replace Tregs in T1D may reverse autoimmunity and protect the remaining insulin-producing β cells. On the basis of this premise, a robust technique has been developed to isolate and expand Tregs from patients with T1D. The expanded Tregs retained their T cell receptor diversity and demonstrated enhanced functional activity. We report on a phase 1 trial to assess safety of Treg adoptive immunotherapy in T1D. Fourteen adult subjects with T1D, in four dosing cohorts, received ex vivo-expanded autologous CD4(+)CD127(lo/-)CD25(+) polyclonal Tregs (0.05 × 10(8) to 26 × 10(8) cells). A subset of the adoptively transferred Tregs was long-lived, with up to 25% of the peak level remaining in the circulation at 1 year after transfer. Immune studies showed transient increases in Tregs in recipients and retained a broad Treg FOXP3(+)CD4(+)CD25(hi)CD127(lo) phenotype long-term. There were no infusion reactions or cell therapy-related high-grade adverse events. C-peptide levels persisted out to 2+ years after transfer in several individuals. These results support the development of a phase 2 trial to test efficacy of the Treg therapy.

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734 citations

Journal Article•DOI•

A pilot study of operational tolerance with a regulatory T-cell-based cell therapy in living donor liver transplantation.

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Satoru Todo, Kenichiro Yamashita, Ryoichi Goto, Masaaki Zaitsu, Akihisa Nagatsu, Tetsu Oura, Masaaki Watanabe, Takeshi Aoyagi, Tomomi Suzuki, Tsuyoshi Shimamura¹, Toshiya Kamiyama, Norihiro Sato, Junichi Sugita, Kanako C. Hatanaka, Hisashi Bashuda, Sonoko Habu, Anthony J. Demetris, Ko Okumura - Show less +14 more•Institutions (1)

Hokkaido University¹

01 Aug 2016-Hepatology

TL;DR: A cell therapy using an ex vivo‐generated regulatory T‐cell‐enriched cell product is safe and effective for drug minimization and operational tolerance induction in living donor liver recipients with nonimmunological liver diseases.

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310 citations

Cites methods or result from "Regulatory T-Cell Therapy in Transp..."

...Using a transplant model in mice, >33% Tregs in the CD4(1) T-cell fraction are required to prevent rejection; this proportion is estimated to consist of >30 3 10(9) Tregs in humans.((29)) Clinically, they were applied at ranges between 10 3 10(6)/kg and 20 3 10(6)/kg....
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...This value is much lower than that those in previous therapies, which indicated that donor-antigen specific iTregs generated by the indirect pathway are more potent than nTregs for transplant cell therapy.((29)) Mechanisms underlying immune inhibition by Tregs have been described....
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Journal Article•DOI•

Next-generation regulatory T cell therapy.

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Leonardo M. R. Ferreira¹, Yannick D. Muller¹, Jeffrey A. Bluestone¹, Qizhi Tang¹•Institutions (1)

University of California, San Francisco¹

20 Sep 2019-Nature Reviews Drug Discovery

TL;DR: The increased understanding of how regulatory T cells suppress immune responses has led to their use in early-phase clinical trials for inflammatory disorders, with promising results.

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Abstract: Regulatory T cells (Treg cells) are a small subset of immune cells that are dedicated to curbing excessive immune activation and maintaining immune homeostasis. Accordingly, deficiencies in Treg cell development or function result in uncontrolled immune responses and tissue destruction and can lead to inflammatory disorders such as graft-versus-host disease, transplant rejection and autoimmune diseases. As Treg cells deploy more than a dozen molecular mechanisms to suppress immune responses, they have potential as multifaceted adaptable smart therapeutics for treating inflammatory disorders. Indeed, early-phase clinical trials of Treg cell therapy have shown feasibility, tolerability and potential efficacy in these disease settings. In the meantime, progress in the development of chimeric antigen receptors and in genome editing (including the application of CRISPR–Cas9) over the past two decades has facilitated the genetic optimization of primary T cell therapy for cancer. These technologies are now being used to enhance the specificity and functionality of Treg cells. In this Review, we describe the key advances and prospects in designing and implementing Treg cell-based therapy in autoimmunity and transplantation. Our increased understanding of how regulatory T cells suppress immune responses has led to their use in early-phase clinical trials for inflammatory disorders, with promising results. This Review describes the key advances and prospects in designing and implementing regulatory T cells as multifaceted, adaptable smart therapeutics in autoimmunity and transplantation.

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260 citations

Journal Article•DOI•

Control of Foxp3 stability through modulation of TET activity.

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Xiaojing Yue¹, Sara Trifari¹, Tarmo Äijö¹, Tarmo Äijö², Ageliki Tsagaratou¹, William A. Pastor¹, Jorge A. Zepeda-Martínez¹, Chan-Wang J. Lio¹, Xiang Li¹, Yun Huang¹, Pandurangan Vijayanand¹, Harri Lähdesmäki², Anjana Rao - Show less +9 more•Institutions (2)

La Jolla Institute for Allergy and Immunology¹, Aalto University²

07 Mar 2016-Journal of Experimental Medicine

TL;DR: TET2 and TET3 redundantly regulate Foxp3 stability, and their activity can be modulated by vitamin C.

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Abstract: Ten-eleven translocation (TET) enzymes oxidize 5-methylcytosine (5mC) to 5-hydroxymethylcytosine and other oxidized methylcytosines, intermediates in DNA demethylation. In this study, we examine the role of TET proteins in regulating Foxp3, a transcription factor essential for the development and function of regulatory T cells (T reg cells), a distinct lineage of CD4(+) T cells that prevent autoimmunity and maintain immune homeostasis. We show that during T reg cell development in the thymus, TET proteins mediate the loss of 5mC in T reg cell-specific hypomethylated regions, including CNS1 and CNS2, intronic cis-regulatory elements in the Foxp3 locus. Similar to CNS2-deficient T reg cells, the stability of Foxp3 expression is markedly compromised in T reg cells from Tet2/Tet3 double-deficient mice. Vitamin C potentiates TET activity and acts through Tet2/Tet3 to increase the stability of Foxp3 expression in TGF-β-induced T reg cells. Our data suggest that targeting TET enzymes with small molecule activators such as vitamin C might increase induced T reg cell efficacy.

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243 citations

Journal Article•DOI•

Stem Cell Therapies for Treating Diabetes: Progress and Remaining Challenges

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Julie B. Sneddon¹, Qizhi Tang¹, Peter G. Stock¹, Jeffrey A. Bluestone¹, Shuvo Roy¹, Tejal A. Desai¹, Matthias Hebrok¹ - Show less +3 more•Institutions (1)

University of California, San Francisco¹

01 Jun 2018-Cell Stem Cell

TL;DR: Current efforts aimed at generating a sustainable source of functional human stem cell-derived insulin-producing islet cells for cell transplantation are described and state-of-the-art efforts to protect such cells via immune modulation and encapsulation strategies are presented.

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181 citations

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Journal Article•DOI•

Chimeric Antigen Receptor–Modified T Cells in Chronic Lymphoid Leukemia

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David L. Porter¹, Bruce L. Levine, Michael Kalos, Adam Bagg, Carl H. June - Show less +1 more•Institutions (1)

University of Pennsylvania¹

24 Aug 2011-The New England Journal of Medicine

TL;DR: A low dose of autologous chimeric antigen receptor-modified T cells reinfused into a patient with refractory chronic lymphocytic leukemia expanded to a level that was more than 1000 times as high as the initial engraftment level in vivo, with delayed development of the tumor lysis syndrome and with complete remission.

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Abstract: We designed a lentiviral vector expressing a chimeric antigen receptor with specificity for the B-cell antigen CD19, coupled with CD137 (a costimulatory receptor in T cells [4-1BB]) and CD3-zeta (a signal-transduction component of the T-cell antigen receptor) signaling domains. A low dose (approximately 1.5×10(5) cells per kilogram of body weight) of autologous chimeric antigen receptor-modified T cells reinfused into a patient with refractory chronic lymphocytic leukemia (CLL) expanded to a level that was more than 1000 times as high as the initial engraftment level in vivo, with delayed development of the tumor lysis syndrome and with complete remission. Apart from the tumor lysis syndrome, the only other grade 3/4 toxic effect related to chimeric antigen receptor T cells was lymphopenia. Engineered cells persisted at high levels for 6 months in the blood and bone marrow and continued to express the chimeric antigen receptor. A specific immune response was detected in the bone marrow, accompanied by loss of normal B cells and leukemia cells that express CD19. Remission was ongoing 10 months after treatment. Hypogammaglobulinemia was an expected chronic toxic effect.

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3,204 citations

"Regulatory T-Cell Therapy in Transp..." refers background in this paper

...For example, using autologous cytotoxic T cells engineered to express a chimeric receptor that recognizes CD19, 19 out 20 patients with endstage therapy-refractory B-cell lymphoma have been successfully treated (Porter et al. 2011; Scholler et al. 2012)....
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Journal Article•DOI•

CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells

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Weihong Liu¹, Amy L. Putnam¹, Zhou Xu-yu¹, Gregory L. Szot¹, Michael R. Lee¹, Shirley Zhu¹, Peter A. Gottlieb², Philipp Kapranov³, Thomas R. Gingeras³, Barbara Fazekas de St Groth⁴, Carol Clayberger⁵, David M. Soper⁶, Steven F. Ziegler⁶, Jeffrey A. Bluestone¹ - Show less +10 more•Institutions (6)

University of California, San Francisco¹, Anschutz Medical Campus², Affymetrix³, Centenary Institute of Cancer Medicine and Cell Biology⁴, Stanford University⁵, University of Washington⁶

10 Jul 2006-Journal of Experimental Medicine

TL;DR: It is found that the IL-7 receptor (CD127) is down-regulated on a subset of CD4+ T cells in peripheral blood and can be used to quantitate T reg cell subsets in individuals with type 1 diabetes supporting the use of CD127 as a biomarker for human T reg cells.

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Abstract: Regulatory T (T reg) cells are critical regulators of immune tolerance. Most T reg cells are defined based on expression of CD4, CD25, and the transcription factor, FoxP3. However, these markers have proven problematic for uniquely defining this specialized T cell subset in humans. We found that the IL-7 receptor (CD127) is down-regulated on a subset of CD4+ T cells in peripheral blood. We demonstrate that the majority of these cells are FoxP3+, including those that express low levels or no CD25. A combination of CD4, CD25, and CD127 resulted in a highly purified population of T reg cells accounting for significantly more cells that previously identified based on other cell surface markers. These cells were highly suppressive in functional suppressor assays. In fact, cells separated based solely on CD4 and CD127 expression were anergic and, although representing at least three times the number of cells (including both CD25+CD4+ and CD25−CD4+ T cell subsets), were as suppressive as the “classic” CD4+CD25hi T reg cell subset. Finally, we show that CD127 can be used to quantitate T reg cell subsets in individuals with type 1 diabetes supporting the use of CD127 as a biomarker for human T reg cells.

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2,506 citations

"Regulatory T-Cell Therapy in Transp..." refers methods in this paper

...Tregs selected based on CD4þCD25þCD127lo/2 markers have been found to be more effective than CD4þCD25þ Tregs in controlling alloimmune-mediated arte- Table 1....
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...The additional use of CD127 allowed high-yield and high-purity recovery human Tregs based on the cell-surface phenotype of CD4þCD25þCD127lo/2 (Liu et al. 2006), and on average 1 106 Tregs can be isolated from 100 mL of blood using this approach....
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...The additional use of CD127 allowed high-yield and high-purity recovery human Tregs based on the cell-surface phenotype of CD4þCD25þCD127 (Liu et al. 2006), and on average 1 10(6) Tregs can be isolated from 100 mL of blood using this approach....
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...We have found that CD4þCD25þCD127lo/2 Tregs contain both CD45RAþ and CD45RA2 populations and the CD45RAþ subset preferentially expands in culture (Putnam et al. 2009), as others have reported (Miyara et al. 2009), and the presence of the CD45RA2 subset does not negatively impact the purity of the Tregs at the end of the expansion....
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Journal Article•DOI•

Functional Delineation and Differentiation Dynamics of Human CD4+ T Cells Expressing the FoxP3 Transcription Factor

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Makoto Miyara¹, Yumiko Yoshioka¹, Akihiko Kitoh¹, Tomoko Shima¹, Kajsa Wing¹, Akira Niwa¹, Christophe Parizot², Cécile Taflin², Toshio Heike¹, Dominique Valeyre, Alexis Mathian², Tatsutoshi Nakahata¹, Tomoyuki Yamaguchi¹, Takashi Nomura¹, Masahiro Ono¹, Zahir Amoura³, Guy Gorochov², Guy Gorochov³, Shimon Sakaguchi⁴, Shimon Sakaguchi¹ - Show less +16 more•Institutions (4)

Kyoto University¹, French Institute of Health and Medical Research², Pierre-and-Marie-Curie University³, Osaka University⁴

19 Jun 2009-Immunity

TL;DR: The dissection of FoxP3(+) cells into subsets enables one to analyze Treg cell differentiation dynamics and interactions in normal and disease states, and to control immune responses through manipulating particular FoxP 3(+) subpopulations.

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1,979 citations

"Regulatory T-Cell Therapy in Transp..." refers background in this paper

...…Tregs contain both CD45RAþ and CD45RA2 populations and the CD45RAþ subset preferentially expands in culture (Putnam et al. 2009), as others have reported (Miyara et al. 2009), and the presence of the CD45RA2 subset does not negatively impact the purity of the Tregs at the end of the expansion....
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...It has also been reported that human Tregs can be identified on the basis of CD4, CD25, and CD45RA expression with naı̈ve Tregs having the CD4þCD25midCD45RAþ phenotype and antigen-experienced effector Tregs having a CD4þCD25hiCD45RA2 phenotype (Miyara et al. 2009)....
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...2009), as others have reported (Miyara et al. 2009), and the presence of the CD45RA(2) subset does not negatively impact the purity of the Tregs at the end of the expansion....
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Journal Article•DOI•

Chronic renal failure after transplantation of a nonrenal organ.

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Akinlolu O. Ojo¹, Philip J. Held¹, Friedrich K. Port, Robert A. Wolfe¹, Alan B. Leichtman, Eric W. Young, J.A Arndorfer¹, Laura L. Christensen¹, Robert M. Merion - Show less +5 more•Institutions (1)

University of Michigan¹

04 Sep 2003-The New England Journal of Medicine

TL;DR: The five-year risk of chronic renal failure after transplantation of a nonrenal organ ranges from 7 to 21 percent, depending on the type of organ transplanted, and is associated with an increase by a factor of more than four in the risk of death.

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Abstract: Background Transplantation of nonrenal organs is often complicated by chronic renal disease with multifactorial causes. We conducted a population-based cohort analysis to evaluate the incidence of chronic renal failure, risk factors for it, and the associated hazard of death in recipients of nonrenal transplants. Methods Pretransplantation and post-transplantation clinical variables and data from a registry of patients with end-stage renal disease (ESRD) were linked in order to estimate the cumulative incidence of chronic renal failure (defined as a glomerular filtration rate of 29 ml per minute per 1.73 m2 of body-surface area or less or the development of ESRD) and the associated risk of death among 69,321 persons who received nonrenal transplants in the United States between 1990 and 2000. Results During a median follow-up of 36 months, chronic renal failure developed in 11,426 patients (16.5 percent). Of these patients, 3297 (28.9 percent) required maintenance dialysis or renal transplantation. The five-year risk of chronic renal failure varied according to the type of organ transplanted - from 6.9 percent among recipients of heart-lung transplants to 21.3 percent among recipients of intestine transplants. Multivariate analysis indicated that an increased risk of chronic renal failure was associated with increasing age (relative risk per 10-year increment, 1.36; P Conclusions The five-year risk of chronic renal failure after transplantation of a nonrenal organ ranges from 7 to 21 percent, depending on the type of organ transplanted. The occurrence of chronic renal failure among patients with a nonrenal transplant is associated with an increase by a factor of more than four in the risk of death.

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1,940 citations

"Regulatory T-Cell Therapy in Transp..." refers background in this paper

...In addition to these immunological complications, immunosuppressive drugs are often causes of morbidity owing to their off-target effects such as nephrotoxicity, diabetes, hyperlipidemia, hypertension, cardiovascular diseases, and obesity (Berenson et al. 1992; Textor et al. 2000; Nair et al. 2002; Ojo et al. 2003)....
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...…immunological complications, immunosuppressive drugs are often causes of morbidity owing to their off-target effects such as nephrotoxicity, diabetes, hyperlipidemia, hypertension, cardiovascular diseases, and obesity (Berenson et al. 1992; Textor et al. 2000; Nair et al. 2002; Ojo et al. 2003)....
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Journal Article•DOI•

Regulatory T cells: key controllers of immunologic self-tolerance.

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Shimon Sakaguchi¹•Institutions (1)

Kyoto University¹

26 May 2000-Cell

TL;DR: Shimon et al. as discussed by the authors showed that more than one population of regulatory T cells seem to be engaged in the maintenance of self-tolerance and these populations function in different ways.

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1,899 citations