T1DM Immunotherapy Using Polyclonal Tregs + IL-2

Summary

The purpose of this study is to assess the safety of Tregs + IL-2 and survival of Tregs in patients with recent onset T1DM who receive infusions of autologous Tregs + IL-2.

Timeline

Start

2016-08

Primary completion

2021-08-27

Completion

2021-08-27

Publications

• Background Chatenoud L, Bluestone JA. CD3-specific antibodies: a portal to the treatment of autoimmunity. Nat Rev Immunol. 2007 Aug;7(8):622-32. doi: 10.1038/nri2134. Epub 2007 Jul 20.
• Background Ahmadzadeh M, Rosenberg SA. IL-2 administration increases CD4+ CD25(hi) Foxp3+ regulatory T cells in cancer patients. Blood. 2006 Mar 15;107(6):2409-14. doi: 10.1182/blood-2005-06-2399. Epub 2005 Nov 22.
• Background Ash S, Yarkoni S, Askenasy N. Lymphopenia is detrimental to therapeutic approaches to type 1 diabetes using regulatory T cells. Immunol Res. 2014 Jan;58(1):101-5. doi: 10.1007/s12026-013-8476-x.
• Background Atkins MB. Interleukin-2: clinical applications. Semin Oncol. 2002 Jun;29(3 Suppl 7):12-7. doi: 10.1053/sonc.2002.33077.
• Background Bailey-Bucktrout SL, Martinez-Llordella M, Zhou X, Anthony B, Rosenthal W, Luche H, Fehling HJ, Bluestone JA. Self-antigen-driven activation induces instability of regulatory T cells during an inflammatory autoimmune response. Immunity. 2013 Nov 14;39(5):949-62. doi: 10.1016/j.immuni.2013.10.016.
• Background Bayer AL, Pugliese A, Malek TR. The IL-2/IL-2R system: from basic science to therapeutic applications to enhance immune regulation. Immunol Res. 2013 Dec;57(1-3):197-209. doi: 10.1007/s12026-013-8452-5.
• Background Bluestone JA. Regulatory T-cell therapy: is it ready for the clinic? Nat Rev Immunol. 2005 Apr;5(4):343-9. doi: 10.1038/nri1574.
• Background Buckner JH. Mechanisms of impaired regulation by CD4(+)CD25(+)FOXP3(+) regulatory T cells in human autoimmune diseases. Nat Rev Immunol. 2010 Dec;10(12):849-59. doi: 10.1038/nri2889.
• Background Castela E, Le Duff F, Butori C, Ticchioni M, Hofman P, Bahadoran P, Lacour JP, Passeron T. Effects of low-dose recombinant interleukin 2 to promote T-regulatory cells in alopecia areata. JAMA Dermatol. 2014 Jul;150(7):748-51. doi: 10.1001/jamadermatol.2014.504.
• Background Churlaud G, Jimenez V, Ruberte J, Amadoudji Zin M, Fourcade G, Gottrand G, Casana E, Lambrecht B, Bellier B, Piaggio E, Bosch F, Klatzmann D. Sustained stimulation and expansion of Tregs by IL2 control autoimmunity without impairing immune responses to infection, vaccination and cancer. Clin Immunol. 2014 Apr;151(2):114-26. doi: 10.1016/j.clim.2014.02.003. Epub 2014 Feb 19.
• Background Couri CE, Oliveira MC, Stracieri AB, Moraes DA, Pieroni F, Barros GM, Madeira MI, Malmegrim KC, Foss-Freitas MC, Simoes BP, Martinez EZ, Foss MC, Burt RK, Voltarelli JC. C-peptide levels and insulin independence following autologous nonmyeloablative hematopoietic stem cell transplantation in newly diagnosed type 1 diabetes mellitus. JAMA. 2009 Apr 15;301(15):1573-9. doi: 10.1001/jama.2009.470.
• Background Diaz-de-Durana Y, Lau J, Knee D, Filippi C, Londei M, McNamara P, Nasoff M, DiDonato M, Glynne R, Herman AE. IL-2 immunotherapy reveals potential for innate beta cell regeneration in the non-obese diabetic mouse model of autoimmune diabetes. PLoS One. 2013 Oct 24;8(10):e78483. doi: 10.1371/journal.pone.0078483. eCollection 2013.
• Background Dirice E, Kahraman S, Jiang W, El Ouaamari A, De Jesus DF, Teo AK, Hu J, Kawamori D, Gaglia JL, Mathis D, Kulkarni RN. Soluble factors secreted by T cells promote beta-cell proliferation. Diabetes. 2014 Jan;63(1):188-202. doi: 10.2337/db13-0204. Epub 2013 Oct 2.
• Background Garg G, Tyler JR, Yang JH, Cutler AJ, Downes K, Pekalski M, Bell GL, Nutland S, Peakman M, Todd JA, Wicker LS, Tree TI. Type 1 diabetes-associated IL2RA variation lowers IL-2 signaling and contributes to diminished CD4+CD25+ regulatory T cell function. J Immunol. 2012 May 1;188(9):4644-53. doi: 10.4049/jimmunol.1100272. Epub 2012 Mar 28.
• Background Grinberg-Bleyer Y, Baeyens A, You S, Elhage R, Fourcade G, Gregoire S, Cagnard N, Carpentier W, Tang Q, Bluestone J, Chatenoud L, Klatzmann D, Salomon BL, Piaggio E. IL-2 reverses established type 1 diabetes in NOD mice by a local effect on pancreatic regulatory T cells. J Exp Med. 2010 Aug 30;207(9):1871-8. doi: 10.1084/jem.20100209. Epub 2010 Aug 2.
• Background Hartemann A, Bensimon G, Payan CA, Jacqueminet S, Bourron O, Nicolas N, Fonfrede M, Rosenzwajg M, Bernard C, Klatzmann D. Low-dose interleukin 2 in patients with type 1 diabetes: a phase 1/2 randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol. 2013 Dec;1(4):295-305. doi: 10.1016/S2213-8587(13)70113-X. Epub 2013 Oct 8.
• Background Johnson MC, Garland AL, Nicolson SC, Li C, Samulski RJ, Wang B, Tisch R. beta-cell-specific IL-2 therapy increases islet Foxp3+Treg and suppresses type 1 diabetes in NOD mice. Diabetes. 2013 Nov;62(11):3775-84. doi: 10.2337/db13-0669. Epub 2013 Jul 24.
• Background Liu R, Zhou Q, La Cava A, Campagnolo DI, Van Kaer L, Shi FD. Expansion of regulatory T cells via IL-2/anti-IL-2 mAb complexes suppresses experimental myasthenia. Eur J Immunol. 2010 Jun;40(6):1577-89. doi: 10.1002/eji.200939792.
• Background Macallan DC, Asquith B, Zhang Y, de Lara C, Ghattas H, Defoiche J, Beverley PC. Measurement of proliferation and disappearance of rapid turnover cell populations in human studies using deuterium-labeled glucose. Nat Protoc. 2009;4(9):1313-27. doi: 10.1038/nprot.2009.117. Epub 2009 Aug 20.
• Background Malek TR, Pugliese A. Low-dose IL-2 as a therapeutic agent for tolerance induction. Immunotherapy. 2011 Nov;3(11):1281-4. doi: 10.2217/imt.11.120. No abstract available.
• Background Marek-Trzonkowska N, Mysliwiec M, Dobyszuk A, Grabowska M, Derkowska I, Juscinska J, Owczuk R, Szadkowska A, Witkowski P, Mlynarski W, Jarosz-Chobot P, Bossowski A, Siebert J, Trzonkowski P. Therapy of type 1 diabetes with CD4(+)CD25(high)CD127-regulatory T cells prolongs survival of pancreatic islets - results of one year follow-up. Clin Immunol. 2014 Jul;153(1):23-30. doi: 10.1016/j.clim.2014.03.016. Epub 2014 Apr 1.
• Background Marek-Trzonkowska N, Mysliwiec M, Dobyszuk A, Grabowska M, Techmanska I, Juscinska J, Wujtewicz MA, Witkowski P, Mlynarski W, Balcerska A, Mysliwska J, Trzonkowski P. Administration of CD4+CD25highCD127- regulatory T cells preserves beta-cell function in type 1 diabetes in children. Diabetes Care. 2012 Sep;35(9):1817-20. doi: 10.2337/dc12-0038. Epub 2012 Jun 20.
• Background Miller KM, Foster NC, Beck RW, Bergenstal RM, DuBose SN, DiMeglio LA, Maahs DM, Tamborlane WV; T1D Exchange Clinic Network. Current state of type 1 diabetes treatment in the U.S.: updated data from the T1D Exchange clinic registry. Diabetes Care. 2015 Jun;38(6):971-8. doi: 10.2337/dc15-0078.
• Background Monti P, Heninger AK, Bonifacio E. Differentiation, expansion, and homeostasis of autoreactive T cells in type 1 diabetes mellitus. Curr Diab Rep. 2009 Apr;9(2):113-8. doi: 10.1007/s11892-009-0020-y.
• Background Putnam AL, Brusko TM, Lee MR, Liu W, Szot GL, Ghosh T, Atkinson MA, Bluestone JA. Expansion of human regulatory T-cells from patients with type 1 diabetes. Diabetes. 2009 Mar;58(3):652-62. doi: 10.2337/db08-1168. Epub 2008 Dec 15.
• Background Salomon B, Bluestone JA. Complexities of CD28/B7: CTLA-4 costimulatory pathways in autoimmunity and transplantation. Annu Rev Immunol. 2001;19:225-52. doi: 10.1146/annurev.immunol.19.1.225.
• Background Sitrin J, Ring A, Garcia KC, Benoist C, Mathis D. Regulatory T cells control NK cells in an insulitic lesion by depriving them of IL-2. J Exp Med. 2013 Jun 3;210(6):1153-65. doi: 10.1084/jem.20122248. Epub 2013 May 6.
• Background Tang Q, Adams JY, Penaranda C, Melli K, Piaggio E, Sgouroudis E, Piccirillo CA, Salomon BL, Bluestone JA. Central role of defective interleukin-2 production in the triggering of islet autoimmune destruction. Immunity. 2008 May;28(5):687-97. doi: 10.1016/j.immuni.2008.03.016. Epub 2008 May 8.
• Background Tang Q, Bluestone JA. Regulatory T-cell physiology and application to treat autoimmunity. Immunol Rev. 2006 Aug;212:217-37. doi: 10.1111/j.0105-2896.2006.00421.x.
• Background Tang Q, Bluestone JA. The Foxp3+ regulatory T cell: a jack of all trades, master of regulation. Nat Immunol. 2008 Mar;9(3):239-44. doi: 10.1038/ni1572.
• Background Tang Q, Boden EK, Henriksen KJ, Bour-Jordan H, Bi M, Bluestone JA. Distinct roles of CTLA-4 and TGF-beta in CD4+CD25+ regulatory T cell function. Eur J Immunol. 2004 Nov;34(11):2996-3005. doi: 10.1002/eji.200425143.
• Background Tang Q, Henriksen KJ, Bi M, Finger EB, Szot G, Ye J, Masteller EL, McDevitt H, Bonyhadi M, Bluestone JA. In vitro-expanded antigen-specific regulatory T cells suppress autoimmune diabetes. J Exp Med. 2004 Jun 7;199(11):1455-65. doi: 10.1084/jem.20040139.
• Background Waldron-Lynch F, Kareclas P, Irons K, Walker NM, Mander A, Wicker LS, Todd JA, Bond S. Rationale and study design of the Adaptive study of IL-2 dose on regulatory T cells in type 1 diabetes (DILT1D): a non-randomised, open label, adaptive dose finding trial. BMJ Open. 2014 Jun 4;4(6):e005559. doi: 10.1136/bmjopen-2014-005559.
• Background Bluestone JA, Buckner JH, Fitch M, Gitelman SE, Gupta S, Hellerstein MK, Herold KC, Lares A, Lee MR, Li K, Liu W, Long SA, Masiello LM, Nguyen V, Putnam AL, Rieck M, Sayre PH, Tang Q. Type 1 diabetes immunotherapy using polyclonal regulatory T cells. Sci Transl Med. 2015 Nov 25;7(315):315ra189. doi: 10.1126/scitranslmed.aad4134.
• Dong S, Hiam-Galvez KJ, Mowery CT, Herold KC, Gitelman SE, Esensten JH, Liu W, Lares AP, Leinbach AS, Lee M, Nguyen V, Tamaki SJ, Tamaki W, Tamaki CM, Mehdizadeh M, Putnam AL, Spitzer MH, Ye CJ, Tang Q, Bluestone JA. The effect of low-dose IL-2 and Treg adoptive cell therapy in patients with type 1 diabetes. JCI Insight. 2021 Sep 22;6(18):e147474. doi: 10.1172/jci.insight.147474.

Drugs

Indications