Hurdles in therapy with regulatory T cells

Translating regulatory T cell therapy to the clinic in Europe is making progress but has remaining challenges. Improper activation of the immune system contributes to a variety of clinical conditions, including autoimmune and allergic diseases as well as solid organ and bone marrow transplantation. One approach to counteract this activation is through adoptive therapy with regulatory T cells (Tregs). Efforts to manufacture these cells have led to good maunfacturing practice–compliant protocols, and Treg products are entering early clinical trials. Here, we report the stance of the European Union Cooperation in Science and Technology Action BM1305, “Action to Focus and Accelerate Cell-based Tolerance-inducing Therapies—A FACTT,” which identifies hurdles hindering Treg clinical applications in Europe and provides possible solutions.

[1]  A. Secchi,et al.  Generation of Donor-specific T Regulatory Type 1 Cells From Patients on Dialysis for Cell Therapy After Kidney Transplantation , 2015, Transplantation.

[2]  E. Bonifacio,et al.  Adoptive transfer of allogeneic regulatory T cells into patients with chronic graft-versus-host disease. , 2015, Cytotherapy.

[3]  P. Witkowski,et al.  Islet cell transplant and the incorporation of Tregs , 2014, Current opinion in organ transplantation.

[4]  Lydia Villa-Komaroff,et al.  Purification of regulatory T cells with the use of a fully enclosed high-speed microfluidic system. , 2014, Cytotherapy.

[5]  P. Harden,et al.  Demethylation of the TSDR Is a Marker of Squamous Cell Carcinoma in Transplant Recipients , 2014, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[6]  James A. Hutchinson,et al.  Laser Ablation–Inductively Coupled Plasma Mass Spectrometry: An Emerging Technology for Detecting Rare Cells in Tissue Sections , 2014, The Journal of Immunology.

[7]  B. Falini,et al.  HLA-haploidentical transplantation with regulatory and conventional T-cell adoptive immunotherapy prevents acute leukemia relapse. , 2014, Blood.

[8]  W. Młynarski,et al.  Therapy of type 1 diabetes with CD4(+)CD25(high)CD127-regulatory T cells prolongs survival of pancreatic islets - results of one year follow-up. , 2014, Clinical immunology.

[9]  R. Lechler,et al.  PTU-122 A Gmp Treg Expansion Protocol Restores Treg Suppressor Function In End-stage Liver Disease; Implications For Adoptive Transfer Therapy , 2014, Gut.

[10]  H. Volk,et al.  Novel GMP‐Compatible Protocol Employing an Allogeneic B Cell Bank for Clonal Expansion of Allospecific Natural Regulatory T Cells , 2014, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[11]  J. Wagner,et al.  Prevention of graft-versus-host disease by adoptive T regulatory therapy is associated with active repression of peripheral blood Toll-like receptor 5 mRNA expression. , 2014, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[12]  M. Roncarolo,et al.  Immunological Outcome in Haploidentical-HSC Transplanted Patients Treated with IL-10-Anergized Donor T Cells , 2013, Front. Immunol..

[13]  H. Volk,et al.  Generation of highly effective and stable murine alloreactive Treg cells by combined anti‐CD4 mAb, TGF‐β, and RA treatment , 2013, European journal of immunology.

[14]  Qizhi Tang,et al.  Regulatory T-cell therapy in transplantation: moving to the clinic. , 2013, Cold Spring Harbor perspectives in medicine.

[15]  A. Lares,et al.  Clinical Grade Manufacturing of Human Alloantigen‐Reactive Regulatory T Cells for Use in Transplantation , 2013, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[16]  James A. Hutchinson,et al.  Standardization of whole blood immune phenotype monitoring for clinical trials: panels and methods from the ONE study , 2013, Transplantation research.

[17]  James A. Hutchinson,et al.  Single cell tracking of gadolinium labeled CD4+ T cells by laser ablation inductively coupled plasma mass spectrometry. , 2013, Analytical chemistry.

[18]  Graham M Lord,et al.  Comparison of regulatory T cells in hemodialysis patients and healthy controls: implications for cell therapy in transplantation. , 2013, Clinical journal of the American Society of Nephrology : CJASN.

[19]  M. Karlsson,et al.  Obtaining regulatory T cells from uraemic patients awaiting kidney transplantation for use in clinical trials , 2013, Clinical and experimental immunology.

[20]  J. Wagner,et al.  Adoptive transfer of umbilical cord blood-derived regulatory T cells and early viral reactivation. , 2013, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[21]  R. Lechler,et al.  Differential effects of rapamycin and retinoic acid on expansion, stability and suppressive qualities of human CD4+CD25+FOXP3+ T regulatory cell subpopulations , 2013, Haematologica.

[22]  J. Siebert,et al.  Clinical application of regulatory T cells in type 1 diabetes , 2013, Pediatric diabetes.

[23]  Ling-jia Wang,et al.  Impact of culture medium on CD4(+) CD25(high)CD127(lo/neg) Treg expansion for the purpose of clinical application. , 2013, International immunopharmacology.

[24]  Michael Ringel,et al.  What matters most in commercial success: first-in-class or best-in-class? , 2013, Nature Reviews Drug Discovery.

[25]  Clelia Di Serio,et al.  Coexpression of CD49b and LAG-3 identifies human and mouse T regulatory type 1 cells , 2013, Nature Medicine.

[26]  A. Rudensky,et al.  Regulatory T cells: recommendations to simplify the nomenclature , 2013, Nature Immunology.

[27]  P. Svingen,et al.  Regulatory T cell kinetics in the peripheral blood of patients with Crohn's disease. , 2013, Human immunology.

[28]  C. Loddenkemper,et al.  A Converse 4-1BB and CD40 Ligand Expression Pattern Delineates Activated Regulatory T Cells (Treg) and Conventional T Cells Enabling Direct Isolation of Alloantigen-Reactive Natural Foxp3+ Treg , 2012, The Journal of Immunology.

[29]  A. Foussat,et al.  Safety and efficacy of antigen-specific regulatory T-cell therapy for patients with refractory Crohn's disease. , 2012, Gastroenterology.

[30]  E. Geissler The ONE Study compares cell therapy products in organ transplantation: introduction to a review series on suppressive monocyte-derived cells , 2012, Transplantation research.

[31]  H. Volk,et al.  Permanent CNI Treatment for Prevention of Renal Allograft Rejection in Sensitized Hosts Can Be Replaced by Regulatory T Cells , 2012, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[32]  W. Młynarski,et al.  Administration of CD4+CD25highCD127− Regulatory T Cells Preserves β-Cell Function in Type 1 Diabetes in Children , 2012, Diabetes Care.

[33]  P. Witkowski,et al.  The Time is Crucial for Ex Vivo Expansion of T Regulatory Cells for Therapy , 2011, Cell transplantation.

[34]  R. Lechler,et al.  In Vivo SPECT Reporter Gene Imaging of Regulatory T Cells , 2011, PloS one.

[35]  M. Edinger,et al.  Regulatory T cells in stem cell transplantation: strategies and first clinical experiences. , 2011, Current opinion in immunology.

[36]  M. Hara,et al.  Coating Human Pancreatic Islets With CD4+CD25highCD127− Regulatory T Cells as a Novel Approach for the Local Immunoprotection , 2011, Annals of surgery.

[37]  M. Battaglia,et al.  Immune intervention with T regulatory cells: past lessons and future perspectives for type 1 diabetes. , 2011, Seminars in immunology.

[38]  R. Lechler,et al.  Human Regulatory T Cells with Alloantigen Specificity Are More Potent Inhibitors of Alloimmune Skin Graft Damage than Polyclonal Regulatory T Cells , 2011, Science Translational Medicine.

[39]  B. Falini,et al.  Tregs prevent GVHD and promote immune reconstitution in HLA-haploidentical transplantation. , 2011, Blood.

[40]  J. Wagner,et al.  Infusion of ex vivo expanded T regulatory cells in adults transplanted with umbilical cord blood: safety profile and detection kinetics. , 2011, Blood.

[41]  E. Hauben,et al.  Differentiation of type 1 T regulatory cells (Tr1) by tolerogenic DC-10 requires the IL-10-dependent ILT4/HLA-G pathway. , 2010, Blood.

[42]  K. Wood,et al.  In vivo Prevention of Transplant Arteriosclerosis by ex vivo Expanded Human Regulatory T Cells , 2010, Nature Medicine.

[43]  J. Myśliwska,et al.  First-in-man clinical results of the treatment of patients with graft versus host disease with human ex vivo expanded CD4+CD25+CD127- T regulatory cells. , 2009, Clinical immunology.

[44]  James L Riley,et al.  Human T regulatory cell therapy: take a billion or so and call me in the morning. , 2009, Immunity.

[45]  J. Myśliwska,et al.  Ex vivo expansion of CD4+CD25+ T regulatory cells for immunosuppressive therapy , 2009, Cytometry. Part A : the journal of the International Society for Analytical Cytology.

[46]  N. Litjens,et al.  Impaired immune responses and antigen-specific memory CD4+ T cells in hemodialysis patients. , 2008, Journal of the American Society of Nephrology : JASN.

[47]  K. Kretschmer,et al.  DNA methylation controls Foxp3 gene expression , 2008, European journal of immunology.

[48]  M. Battaglia,et al.  Regulatory T-cell immunotherapy for tolerance to self antigens and alloantigens in humans , 2007, Nature Reviews Immunology.

[49]  D. Busch,et al.  Reversible HLA multimers (Streptamers) for the isolation of human cytotoxic T lymphocytes functionally active against tumor- and virus-derived antigens. , 2007 .

[50]  P. Lipsky,et al.  Deficient CD4+CD25high T Regulatory Cell Function in Patients with Active Systemic Lupus Erythematosus1 , 2007, The Journal of Immunology.

[51]  S. Sánchez-Ramón,et al.  Interferon beta-1a therapy enhances CD4+ regulatory T-cell function: An ex vivo and in vitro longitudinal study in relapsing−remitting multiple sclerosis , 2007, Journal of Neuroimmunology.

[52]  A. Akbar,et al.  Human CD4+ CD25hi Foxp3+ regulatory T cells are derived by rapid turnover of memory populations in vivo , 2006 .

[53]  D. Klatzmann,et al.  Ex Vivo-Expanded CD4+CD25+ Immunoregulatory T Cells Prevent Graft-versus-Host-Disease by Inhibiting Activation/Differentiation of Pathogenic T Cells1 , 2006, The Journal of Immunology.

[54]  C. Meisel,et al.  Monitoring temporary immunodepression by flow cytometric measurement of monocytic HLA-DR expression: a multicenter standardized study. , 2005, Clinical chemistry.

[55]  C. Baecher-Allan,et al.  Functional analysis of highly defined, FACS-isolated populations of human regulatory CD4+CD25+ T cells. , 2005, Clinical immunology.

[56]  J. Serody,et al.  L-Selectin(hi) but not the L-selectin(lo) CD4+25+ T-regulatory cells are potent inhibitors of GVHD and BM graft rejection. , 2004, Blood.

[57]  J. Myśliwska,et al.  CD4+CD25+ T regulatory cells inhibit cytotoxic activity of T CD8+ and NK lymphocytes in the direct cell-to-cell interaction. , 2004, Clinical immunology.

[58]  R. Andreesen,et al.  Large scale in vitro expansion of polyclonal human CD4+CD25high regulatory T cells , 2004, Cancer Cell International.

[59]  H. Waldmann,et al.  Regulating the immune response to transplants. a role for CD4+ regulatory cells? , 2001, Immunity.

[60]  M. Toda,et al.  Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. , 1995, Journal of immunology.

[61]  R. Gershon,et al.  Cell interactions in the induction of tolerance: the role of thymic lymphocytes. , 1970, Immunology.

[62]  M. Battaglia,et al.  Tr1 cells and the counter-regulation of immunity: natural mechanisms and therapeutic applications. , 2014, Current topics in microbiology and immunology.

[63]  REPORT FROM THE COMMISSION TO THE EUROPEAN PARLIAMENT AND THE COUNCIL , 2011 .

[64]  D. Klatzmann,et al.  Ex Vivo-Expanded CD4 CD25 Immunoregulatory T Cells Prevent Graft-versus-Host-Disease by Inhibiting Activation/ Differentiation of Pathogenic T Cells , 2005 .