A Prospective Controlled Trial to Evaluate Safety and Efficacy of in vitro Expanded Recipient Regulatory T Cell Therapy and Tocilizumab Together With Donor Bone Marrow Infusion in HLA-Mismatched Living Donor Kidney Transplant Recipients (Trex001)

Rainer Oberbauer, Matthias Edinger, Gabriela Berlakovich, Peter Kalhs, Nina Worel, Georg Heinze, Michael Wolzt, Thomas Lion, Thomas Wekerle, Rainer Oberbauer, Matthias Edinger, Gabriela Berlakovich, Peter Kalhs, Nina Worel, Georg Heinze, Michael Wolzt, Thomas Lion, Thomas Wekerle

Abstract

Background: The induction of donor-specific immunological tolerance could improve outcome after kidney transplantation. However, no tolerance protocol is available for routine clinical use. Chimerism-based regimens hold promise, but their widespread application is impeded in part by unresolved safety issues. This study tests the hypothesis that therapy with polyclonal recipient regulatory T cells (Tregs) and anti-IL6R (tocilizumab) leads to transient chimerism and achieves pro-tolerogenic immunomodulation in kidney transplant recipients also receiving donor bone marrow (BM) without myelosuppressive conditioning of the recipient. Methods/design: A prospective, open-label, controlled, single-center, phase I/IIa academic study is performed in HLA-mismatched living donor kidney transplant recipients. Study group: Recipients of the study group receive in vitro expanded recipient Tregs and a donor bone marrow cell infusion within 3 days after transplantation and tocilizumab for the first 3 weeks post-transplant. In addition they are treated with thymoglobulin, belatacept, sirolimus, and steroids as immunosuppression. Starting 6 months post-transplant, sirolimus and steroids are withdrawn in a step-wise manner in stable patients. Control group: Recipients of the control group are treated with thymoglobulin, belatacept, sirolimus, and steroids as immunosuppression. Co-primary endpoints of safety (impaired graft function [eGFR <35 mL/min/1.73 m2], graft-vs.-host disease or patient death by 12 months) and efficacy (total leukocyte donor chimerism within 28 days post-transplant) are assessed. Secondary endpoints include frequency of biopsy-proven acute rejection episodes and subclinical rejection episodes on surveillance biopsies, assessment of kidney graft function, and the evaluation whether the study protocol leads to detectable changes in the immune system indicative of pro-tolerogenic immune modulation. Discussion: The results of this trial will provide evidence whether treatment with recipient Tregs and donor BM is feasible, safe and efficacious in leading to transient chimerism. If successful, this combination cell therapy has the potential to become a novel treatment option for immunomodulation in organ transplantation without the toxicities associated with myelosuppressive recipient conditioning. Trial registration: European Clinical Trials Database EudraCT Nr 2018-003142-16 and clinicaltrials.gov NCT03867617.

Keywords: belatacept; bone marrow; cell therapy; chimerism; kidney transplantation; regulatory T cells; tocilizumab; tolerance.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Oberbauer, Edinger, Berlakovich, Kalhs, Worel, Heinze, Wolzt, Lion and Wekerle.

Figures

Figure 1
Figure 1
Summary of the study concept. Living donor kidney transplant recipients are treated with in vitro expanded polyclonal recipient Tregs, donor BM cells and anti-IL6R mAb (tocilizumab). In addition, they receive belatacept-based immunosuppression (not depicted).
Figure 2
Figure 2
Schematic illustration of the treatment protocols for the study (A) and the control (B) groups and the immune monitoring plan (C). Thymo denotes thymoglobulin.

References

    1. Wekerle T, Segev D, Lechler R, Oberbauer R. Strategies for long-term preservation of kidney graft function. Lancet. (2017) 389:2152–62. 10.1016/S0140-6736(17)31283-7
    1. Eder M, Schwarz C, Kammer M, Jacobsen N, Stavroula ML, Cowan MJ, et al. . Allograft and patient survival after sequental HSCT and kidney transplantation from the same donor–a multicenter analysis. Am J Transplant. (2019) 19:475–87. 10.1111/ajt.14970
    1. Oura T, Cosimi AB, Kawai T. Chimerism-based tolerance in organ transplantation: preclinical and clinical studies. Clin Exp Immunol. (2017) 189:190–6. 10.1111/cei.12969
    1. Mahr B, Granofszky N, Muckenhuber M, Wekerle T. Transplantation tolerance through hematopoietic chimerism: progress and challenges for clinical translation. Front Immunol. (2017) 8:1762. 10.3389/fimmu.2017.01762
    1. Billingham RE, Lampkin GH, Medawar PB, Williams HL. Tolerance to homografts, twin diagnosis, and the freemartin condition in cattle. Heredity. (1952) 6:200–12. 10.1038/hdy.1952.20
    1. Billingham RE, Brent L, Medawar PB. Actively acquired tolerance of foreign cells. Nature. (1953) 172:603–6. 10.1038/172603a0
    1. Morris H, DeWolf S, Robins H, Sprangers B, LoCascio SA, Shonts BA, et al. Tracking donor-reactive T cells: evidence for clonal deletion in tolerant kidney transplant patients. Sci Transl Med. (2015) 7:272ra10 10.1126/scitranslmed.3010760
    1. Manilay JO, Pearson DA, Sergio JJ, Swenson KG, Sykes M. Intrathymic deletion of alloreactive T cells in mixed bone marrow chimeras prepared with a nonmyeloablative conditioning regimen. Transplantation. (1998) 66:96–102. 10.1097/00007890-199807150-00015
    1. Wekerle T, Sayegh MH, Hill J, Zhao Y, Chandraker A, Swenson KG, et al. . Extrathymic T cell deletion and allogeneic stem cell engraftment induced with costimulatory blockade is followed by central T cell tolerance. J Exp Med. (1998) 187:2037–44. 10.1084/jem.187.12.2037
    1. Pilat N, Baranyi U, Klaus C, Jaeckel E, Mpofu N, Wrba F, et al. . Treg-therapy allows mixed chimerism and transplantation tolerance without cytoreductive conditioning. Am J Transplant. (2010) 10:751–62. 10.1111/j.1600-6143.2010.03018.x
    1. Savage TM, Shonts BA, Obradovic A, Dewolf S, Lau S, Zuber J, et al. . Early expansion of donor-specific Tregs in tolerant kidney transplant recipients. JCI Insight. (2018) 3:e124086. 10.1172/jci.insight.124086
    1. Kawai T, Cosimi AB, Spitzer TR, Tolkoff-Rubin N, Suthanthiran M, Saidman SL, et al. . HLA-mismatched renal transplantation without maintenance immunosuppression. N Engl J Med. (2008) 358:353–61. 10.1056/NEJMoa071074
    1. Scandling JD, Busque S, Dejbakhsh-Jones S, Benike C, Millan MT, Shizuru JA, et al. . Tolerance and chimerism after renal and hematopoietic-cell transplantation. N Engl J Med. (2008) 358:362–8. 10.1056/NEJMoa074191
    1. Leventhal J, Abecassis M, Miller J, Gallon L, Ravindra K, Tollerud DJ, et al. Chimerism and tolerance without GVHD or engraftment syndrome in HLA-mismatched combined kidney and hematopoietic stem cell transplantation. Sci Transl Med. (2012) 4:124ra28 10.1126/scitranslmed.3003509
    1. Kawai T, Sachs DH, Sprangers B, Spitzer TR, Saidman SL, Zorn E, et al. . Long-term results in recipients of combined HLA-mismatched kidney and bone marrow transplantation without maintenance immunosuppression. Am J Transplant. (2014) 14:1599–611. 10.1111/ajt.12731
    1. Busque S, Scandling JD, Lowsky R, Shizuru J, Jensen K, Waters J, et al. . Mixed chimerism and acceptance of kidney transplants after immunosuppressive drug withdrawal. Sci Transl Med. (2020) 12. 10.1126/scitranslmed.aax8863
    1. Chhabra AY, Leventhal J, Merchak AR, Ildstad S. HSCT-based approaches for tolerance induction in renal transplant. Transplantation. (2017) 101:2682–90. 10.1097/TP.0000000000001837
    1. Yamada Y, Ochiai T, Boskovic S, Nadazdin O, Oura T, Schoenfeld D, et al. . Use of CTLA4Ig for induction of mixed chimerism and renal allograft tolerance in nonhuman primates. Am J Transplant. (2014) 14:2704–12. 10.1111/ajt.12936
    1. Blaha P, Bigenzahn S, Koporc Z, Schmid M, Langer F, Selzer E, et al. . The influence of immunosuppressive drugs on tolerance induction through bone marrow transplantation with costimulation blockade. Blood. (2003) 101:2886–93. 10.1182/blood-2002-10-3014
    1. Granofszky N, Farkas AM, Muckenhuber M, Mahr B, Unger L, Maschke S, et al. . Anti-interleukin-6 promotes allogeneic bone marrow engraftment and prolonged graft survival in an irradiation-free murine transplant model. Front Immunol. (2017) 8:821. 10.3389/fimmu.2017.00821
    1. Pilat N, Granofszky N, Wekerle T. Combining adoptive Treg transfer with bone marrow transplantation for transplantation tolerance. Curr Transplant Rep. (2017) 4:253–61. 10.1007/s40472-017-0164-7
    1. Pilat N, Farkas AM, Mahr B, Schwarz C, Unger L, Hock K, et al. . T-regulatory cell treatment prevents chronic rejection of heart allografts in a murine mixed chimerism model. J Heart Lung Transplant. (2014) 33:429–37. 10.1016/j.healun.2013.11.004
    1. Pilat N, Mahr B, Unger L, Hock K, Schwarz C, Farkas A, et al. . Incomplete clonal deletion as prerequisite for tissue-specific minor antigen tolerization. JCI Insight. (2016) 1:e85911. 10.1172/jci.insight.85911
    1. Duran-Struuck R, Sondermeijer HP, Buhler L, Alonso-Guallart P, Zitsman J, Kato Y, et al. . Effect of ex vivo-expanded recipient regulatory T cells on hematopoietic chimerism and kidney allograft tolerance across MHC barriers in cynomolgus macaques. Transplantation. (2017) 101:274–83. 10.1097/TP.0000000000001559
    1. Sawitzki B, Harden PN, Reinke P, Moreau A, Hutchinson JA, Game DS, et al. . Regulatory cell therapy in kidney transplantation (The ONE Study): a harmonised design and analysis of seven non-randomised, single-arm, phase 1/2A trials. Lancet. (2020) 395:1627–39. 10.1016/S0140-6736(20)30167-7
    1. Roemhild A, Otto NM, Moll G, Abou-El-Enein M, Kaiser D, Bold G, et al. . Regulatory T cells for minimising immune suppression in kidney transplantation: phase I/IIa clinical trial. BMJ. (2020) 371:m3734. 10.1136/bmj.m3734
    1. Sanchez-Fueyo A, Whitehouse G, Grageda N, Cramp ME, Lim TY, Romano M, et al. . Applicability, safety, and biological activity of regulatory T cell therapy in liver transplantation. Am J Transplant. (2020) 20:1125–36. 10.1111/ajt.15700
    1. Hoffmann P, Ermann J, Edinger M, Fathman CG, Strober S. Donor-type CD4(+)CD25(+) regulatory T cells suppress lethal acute graft-versus-host disease after allogeneic bone marrow transplantation. J Exp Med. (2002) 196:389–99. 10.1084/jem.20020399
    1. Edinger M, Hoffmann P, Ermann J, Drago K, Fathman CG, Strober S, et al. . CD4+CD25+ regulatory T cells preserve graft-versus-tumor activity while inhibiting graft-versus-host disease after bone marrow transplantation. Nat Med. (2003) 9:1144–50. 10.1038/nm915
    1. Di Ianni M, Falzetti F, Carotti A, Terenzi A, Castellino F, Bonifacio E, et al. . Tregs prevent GVHD and promote immune reconstitution in HLA-haploidentical transplantation. Blood. (2011) 117:3921–8. 10.1182/blood-2010-10-311894
    1. Todo S, Yamashita K, Goto R, Zaitsu M, Nagatsu A, Oura T, et al. . A pilot study of operational tolerance with a regulatory T-cell-based cell therapy in living donor liver transplantation. Hepatology. (2016) 64:632–43. 10.1002/hep.28459
    1. Koyama I, Bashuda H, Uchida K, Seino KI, Habu S, Nakajima I, et al. . A clinical trial with adoptive transfer of ex vivo-induced, donor-specific immune-regulatory cells in kidney transplantation-a second report. Transplantation. (2020) 104:2415–23. 10.1097/TP.0000000000003149
    1. Hoffmann P, Eder R, Boeld TJ, Doser K, Piseshka B, Andreesen R, et al. . Only the CD45RA+ subpopulation of CD4+CD25high T cells gives rise to homogeneous regulatory T-cell lines upon in vitro expansion. Blood. (2006) 108:4260–7. 10.1182/blood-2006-06-027409
    1. Hoffmann P, Eder R, Kunz-Schughart LA, Andreesen R, Edinger M. Large-scale in vitro expansion of polyclonal human CD4(+)CD25high regulatory T cells. Blood. (2004) 104:895–903. 10.1182/blood-2004-01-0086
    1. Ferguson R, Grinyo J, Vincenti F, Kaufman DB, Woodle ES, Marder BA, et al. . Immunosuppression with belatacept-based, corticosteroid-avoiding regimens in de novo kidney transplant recipients. Am J Transplant. (2011) 11:66–76. 10.1111/j.1600-6143.2010.03338.x
    1. Buchler M, Longuet H, Lemoine R, Herr F, Gatault P, Thibault G, et al. . Pharmacokinetic and pharmacodynamic studies of two different rabbit antithymocyte globulin dosing regimens: results of a randomized trial. Transpl Immunol. (2013) 28:120–6. 10.1016/j.trim.2013.03.001
    1. Ahmadi SM, Holzl MA, Mayer E, Wekerle T, Heitger A. CTLA4-Ig preserves thymus-derived T regulatory cells. Transplantation. (2014) 98:1158–64. 10.1097/TP.0000000000000421
    1. Bestard O, Cassis L, Cruzado JM, Torras J, Franquesa M, Gil-Vernet S, et al. . Costimulatory blockade with mTor inhibition abrogates effector T-cell responses allowing regulatory T-cell survival in renal transplantation. Transpl Int. (2011) 24:451–60. 10.1111/j.1432-2277.2011.01223.x
    1. Pilat N, Klaus C, Schwarz C, Hock K, Oberhuber R, Schwaiger E, et al. . Rapamycin and CTLA4Ig synergize to induce stable mixed chimerism without the need for CD40 blockade. Am J Transplant. (2015) 15:1568–79. 10.1111/ajt.13154
    1. Ciancio G, Sageshima J, Akpinar E, Gaynor JJ, Chen L, Zarak A, et al. . A randomized pilot study of donor stem cell infusion in living-related kidney transplant recipients receiving alemtuzumab. Transplantation. (2013) 96:800–6. 10.1097/TP.0b013e3182a0f68c
    1. Leventhal JR, Mathew JM, Salomon DR, Kurian SM, Suthanthiran M, Tambur A, et al. . Genomic biomarkers correlate with HLA-identical renal transplant tolerance. J Am Soc Nephrol. (2013) 24:1376–85. 10.1681/ASN.2013010068
    1. Kirk AD, Guasch A, Xu H, Cheeseman J, Mead SI, Ghali A, et al. Renal transplantation using belatacept without maintenance steroids or calcineurin inhibitors. Am J Transplant. (2014) 14:1142–51. 10.1111/ajt.12712
    1. Spitzer TR, Sykes M, Tolkoff-Rubin N, Kawai T, McAfee SL, Dey BR, et al. . Long-term follow-up of recipients of combined human leukocyte antigen-matched bone marrow and kidney transplantation for multiple myeloma with end-stage renal disease. Transplantation. (2011) 91:672–6. 10.1097/TP.0b013e31820a3068
    1. Fortschegger M, Preuner S, Printz D, Poetsch AR, Geyeregger R, Pichler H, et al. . Detection and monitoring of lineage-specific chimerism by digital droplet PCR-based testing of deletion/insertion polymorphisms. Biol Blood Marrow Transplant. (2020) 26:1218–24. 10.1016/j.bbmt.2020.02.016
    1. Fontes P, Rao AS, Demetris AJ, Zeevi A, Trucco M, Carroll P, et al. . Bone marrow augmentation of donor-cell chimerism in kidney, liver, heart, and pancreas islet transplantation. Lancet. (1994) 344:151–5. 10.1016/S0140-6736(94)92756-1
    1. Ciancio G, Burke GW, Garcia-Morales R, Suzart K, Rosen A, Ricordi C, et al. . Effect of living-related donor bone marrow infusion on chimerism and in vitro immunoregulatory activity in kidney transplant recipients. Transplantation. (2002) 74:488–96. 10.1097/00007890-200208270-00010
    1. Mahr B, Pilat N, Maschke S, Granofszky N, Schwarz C, Unger L, et al. . Regulatory T cells promote natural killer cell education in mixed chimeras. Am J Transplant. (2017) 17:3049–59. 10.1111/ajt.14342
    1. Hotta K, Oura T, Dehnadi A, Boskovic S, Matsunami M, Rosales I, et al. . Long-term nonhuman primate renal allograft survival without ongoing immunosuppression in recipients of delayed donor bone marrow transplantation. Transplantation. (2018) 102:e128–36. 10.1097/01.tp.0000542956.25922.28
    1. Popow I, Leitner J, Grabmeier-Pfistershammer K, Majdic O, Zlabinger GJ, Kundi M, et al. . A comprehensive and quantitative analysis of the major specificities in rabbit antithymocyte globulin preparations. Am J Transplant. (2013) 13:3103–13. 10.1111/ajt.12514

Source: PubMed

Sponsorzy i współpracownicy

Warunki medyczne

Interwencje lekowe

3
Subskrybuj