Combined low-dose everolimus and low-dose tacrolimus after Alemtuzumab induction therapy: a randomized prospective trial in lung transplantation

Alberto Benazzo, Ara Cho, Anna Nechay, Stefan Schwarz, Florian Frommlet, Thomas Wekerle, Konrad Hoetzenecker, Peter Jaksch, Alberto Benazzo, Ara Cho, Anna Nechay, Stefan Schwarz, Florian Frommlet, Thomas Wekerle, Konrad Hoetzenecker, Peter Jaksch

Abstract

Background: Long-term outcomes of lung transplantation are severely affected by comorbidities and development of chronic rejection. Among the comorbidities, kidney insufficiency is one of the most frequent and it is mainly caused by the cumulative effect of calcineurin inhibitors (CNIs). Currently, the most used immunosuppression protocols worldwide include induction therapy and a triple-drug maintenance immunosuppression, with one calcineurin inhibitor, one anti-proliferative drug, and steroids. Our center has pioneered the use of alemtuzumab as induction therapy, showing promising results in terms of short- and long-term outcomes. The use of alemtuzumab followed by a low-dose double drug maintenance immunosuppression, in fact, led to better kidney function along with excellent results in terms of acute rejection, chronic lung allograft dysfunction, and survival (Benazzo et al., PLoS One 14(1):e0210443, 2019). The hypothesis driving the proposed clinical trial is that de novo introduction of low-dose everolimus early after transplantation could further improve kidney function via a further reduction of tacrolimus. Based on evidences from kidney transplantation, moreover, alemtuzumab induction therapy followed by a low-dose everolimus and low-dose tacrolimus may have a permissive action on regulatory immune cells thus stimulating allograft acceptance.

Methods: A randomized prospective clinical trial has been set up to answer the research hypothesis. One hundred ten patients will be randomized in two groups. Treatment group will receive the new maintenance immunosuppression protocol based on low-dose tacrolimus and low-dose everolimus and the control group will receive our standard immunosuppression protocol. Both groups will receive alemtuzumab induction therapy. The primary endpoint of the study is to analyze the effect of the new low-dose immunosuppression protocol on kidney function in terms of eGFR change. The study will have a duration of 24 months from the time of randomization. Immunomodulatory status of the patients will be assessed with flow cytometry and gene expression analysis.

Discussion: For the first time in the field of lung transplantation, this trial proposes the combined use of significantly reduced tacrolimus and everolimus after alemtuzumab induction. The new protocol may have a twofold advantage: (1) further reduction of nephrotoxic tacrolimus and (2) permissive influence on regulatory cells development with further reduction of rejection episodes.

Trial registration: EUDRACT Nr 2018-001680-24. Registered on 15 May 2018.

Keywords: Alemtuzumab; Everolimus; Immunotolerance; Induction therapy; Kidney function; Lung transplantation.

Conflict of interest statement

All the authors declare that they have no competing interests.

References

    1. Yusen RD, Edwards LB, Dipchand AI, Goldfarb SB, Kucheryavaya AY, Levvey BJ, et al. The Registry of the International Society for Heart and Lung Transplantation: Thirty-third Adult Lung and Heart-Lung Transplant Report-2016; Focus Theme: Primary Diagnostic Indications for Transplant. J Heart Lung Transplant. 2016;35(10):1170–1184. doi: 10.1016/j.healun.2016.09.001.
    1. Hachem RR, Chakinala MM, Yusen RD, Lynch JP, Aloush AA, Patterson GA, et al. A comparison of basiliximab and anti-thymocyte globulin as induction agents after lung transplantation. J Heart Lung Transplant. 2005;24(9):1320–1326. doi: 10.1016/j.healun.2004.09.002.
    1. Burton CM, Andersen CB, Jensen AS, Iversen M, Milman N, Boesgaard S, et al. The incidence of acute cellular rejection after lung transplantation: a comparative study of anti-thymocyte globulin and daclizumab. J Heart Lung Transplant. 2006;25(6):638–647. doi: 10.1016/j.healun.2006.01.011.
    1. Mullen JC, Oreopoulos A, Lien DC, Bentley MJ, Modry DL, Stewart K, et al. A randomized, controlled trial of daclizumab vs anti-thymocyte globulin induction for lung transplantation. J Heart Lung Transplant. 2007;26(5):504–510. doi: 10.1016/j.healun.2007.01.032.
    1. Ailawadi G, Smith PW, Oka T, Wang H, Kozower BD, Daniel TM, et al. Effects of induction immunosuppression regimen on acute rejection, bronchiolitis obliterans, and survival after lung transplantation. J Thorac Cardiovasc Surg. 2008;135(3):594–602. doi: 10.1016/j.jtcvs.2007.10.044.
    1. Hartwig MG, Snyder LD, Appel JZ, 3rd, Cantu E, 3rd, Lin SS, Palmer SM, et al. Rabbit anti-thymocyte globulin induction therapy does not prolong survival after lung transplantation. J Heart Lung Transplant. 2008;27(5):547–553. doi: 10.1016/j.healun.2008.01.022.
    1. Preville X, Flacher M, LeMauff B, Beauchard S, Davelu P, Tiollier J, et al. Mechanisms involved in antithymocyte globulin immunosuppressive activity in a nonhuman primate model. Transplantation. 2001;71(3):460–468. doi: 10.1097/00007890-200102150-00021.
    1. Merion RM, Howell T, Bromberg JS. Partial T-cell activation and anergy induction by polyclonal antithymocyte globulin. Transplantation. 1998;65(11):1481–1489. doi: 10.1097/00007890-199806150-00013.
    1. Mourad G, Morelon E, Noel C, Glotz D, Lebranchu Y. The role of Thymoglobulin induction in kidney transplantation: an update. Clin Transpl. 2012;26(5):E450–E464. doi: 10.1111/ctr.12021.
    1. Heidt S, Hester J, Shankar S, Friend PJ, Wood KJ. B cell repopulation after alemtuzumab induction-transient increase in transitional B cells and long-term dominance of naive B cells. Am J Transplant Off J Am Soc Transplant Am Soc Transplant Surg. 2012;12(7):1784–1792. doi: 10.1111/j.1600-6143.2012.04012.x.
    1. Morris PJ, Russell NK. Alemtuzumab (Campath-1H): a systematic review in organ transplantation. Transplantation. 2006;81(10):1361–1367. doi: 10.1097/01.tp.0000219235.97036.9c.
    1. Noris M, Casiraghi F, Todeschini M, Cravedi P, Cugini D, Monteferrante G, et al. Regulatory T cells and T cell depletion: role of immunosuppressive drugs. J Am Soc Nephrol. 2007;18(3):1007–1018. doi: 10.1681/ASN.2006101143.
    1. De Mercanti S, Rolla S, Cucci A, Bardina V, Cocco E, Vladic A, et al. Alemtuzumab long-term immunologic effect: Treg suppressor function increases up to 24 months. Neurol Neuroimmunol Neuroinflamm. 2016;3(1):e194. doi: 10.1212/NXI.0000000000000194.
    1. Cox AL, Thompson SA, Jones JL, Robertson VH, Hale G, Waldmann H, et al. Lymphocyte homeostasis following therapeutic lymphocyte depletion in multiple sclerosis. Eur J Immunol. 2005;35(11):3332–3342. doi: 10.1002/eji.200535075.
    1. Bouvy AP, Klepper M, Betjes MG, Weimar W, Hesselink DA, Baan CC. Alemtuzumab as antirejection therapy: T cell repopulation and cytokine responsiveness. Transpl Dir. 2016;2(6):e83.
    1. Bloom DD, Chang Z, Fechner JH, Dar W, Polster SP, Pascual J, et al. CD4+ CD25+ FOXP3+ regulatory T cells increase de novo in kidney transplant patients after immunodepletion with Campath-1H. Am J Transplant Off J Am Soc Transplant Am Soc Transplant Surg. 2008;8(4):793–802. doi: 10.1111/j.1600-6143.2007.02134.x.
    1. Zhang X, Tao Y, Chopra M, Ahn M, Marcus KL, Choudhary N, et al. Differential reconstitution of T cell subsets following immunodepleting treatment with alemtuzumab (anti-CD52 monoclonal antibody) in patients with relapsing-remitting multiple sclerosis. J Immunol. 2013;191(12):5867–5874. doi: 10.4049/jimmunol.1301926.
    1. Morales J, Bono MR, Fierro A, Iniguez R, Zehnder C, Rosemblatt M, et al. Alemtuzumab induction in kidney transplantation: clinical results and impact on T-regulatory cells. Transplant Proc. 2008;40(9):3223–3228. doi: 10.1016/j.transproceed.2008.03.066.
    1. Newell KA, Asare A, Kirk AD, Gisler TD, Bourcier K, Suthanthiran M, et al. Identification of a B cell signature associated with renal transplant tolerance in humans. J Clin Invest. 2010;120(6):1836–1847. doi: 10.1172/JCI39933.
    1. Shyu S, Dew MA, Pilewski JM, DeVito Dabbs AJ, Zaldonis DB, Studer SM, et al. Five-year outcomes with alemtuzumab induction after lung transplantation. J Heart Lung Transplant. 2011;30(7):743–754. doi: 10.1016/j.healun.2011.01.714.
    1. Furuya Y, Jayarajan SN, Taghavi S, Cordova FC, Patel N, Shiose A, et al. The impact of alemtuzumab and basiliximab induction on patient survival and time to bronchiolitis obliterans syndrome in double lung transplantation recipients. Am J Transplant Off J Am Soc Transplant Am Soc Transplant Surg. 2016;16(8):2334–2341. doi: 10.1111/ajt.13739.
    1. McAlister VC, Haddad E, Renouf E, Malthaner RA, Kjaer MS, Gluud LL. Cyclosporin versus tacrolimus as primary immunosuppressant after liver transplantation: a meta-analysis. Am J Transplant Off J Am Soc Transplant Am Soc Transplant Surg. 2006;6(7):1578–1585. doi: 10.1111/j.1600-6143.2006.01360.x.
    1. Penninga L, Moller CH, Gustafsson F, Steinbruchel DA, Gluud C. Tacrolimus versus cyclosporine as primary immunosuppression after heart transplantation: systematic review with meta-analyses and trial sequential analyses of randomised trials. Eur J Clin Pharmacol. 2010;66(12):1177–1187. doi: 10.1007/s00228-010-0902-6.
    1. Cheng G, Yu A, Malek TR. T-cell tolerance and the multi-functional role of IL-2R signaling in T-regulatory cells. Immunol Rev. 2011;241(1):63–76. doi: 10.1111/j.1600-065X.2011.01004.x.
    1. Miroux C, Morales O, Ghazal K, Othman SB, de Launoit Y, Pancre V, et al. In vitro effects of cyclosporine A and tacrolimus on regulatory T-cell proliferation and function. Transplantation. 2012;94(2):123–131. doi: 10.1097/TP.0b013e3182590d8f.
    1. Li Q, Shakya A, Guo X, Zhang H, Tantin D, Jensen PE, et al. Constitutive nuclear localization of NFAT in Foxp3+ regulatory T cells independent of calcineurin activity. J Immunol. 2012;188(9):4268–4277. doi: 10.4049/jimmunol.1102376.
    1. Brandt C, Pavlovic V, Radbruch A, Worm M, Baumgrass R. Low-dose cyclosporine A therapy increases the regulatory T cell population in patients with atopic dermatitis. Allergy. 2009;64(11):1588–1596. doi: 10.1111/j.1398-9995.2009.02054.x.
    1. Calvo-Turrubiartes M, Romano-Moreno S, Garcia-Hernandez M, Chevaile-Ramos JA, Layseca-Espinosa E, Gonzalez-Amaro R, et al. Quantitative analysis of regulatory T cells in kidney graft recipients: a relationship with calcineurin inhibitor level. Transpl Immunol. 2009;21(1):43–49. doi: 10.1016/j.trim.2009.02.002.
    1. Gullestad L, Iversen M, Mortensen SA, Eiskjaer H, Riise GC, Mared L, et al. Everolimus with reduced calcineurin inhibitor in thoracic transplant recipients with renal dysfunction: a multicenter, randomized trial. Transplantation. 2010;89(7):864–872. doi: 10.1097/TP.0b013e3181cbac2d.
    1. Gottlieb J, Neurohr C, Müller-Quernheim J, Wirtz H, Sill B, Wilkens H, et al. Benefits of early everolimus-based quadruple immunosuppression early after lung transplantation - results of 4EVERLUNG, a prospective randomized multicenter trial. J Heart Lung Transplant. 2018;37(4):S27–SS8. doi: 10.1016/j.healun.2018.01.046.
    1. Arora S, Gude E, Sigurdardottir V, Mortensen SA, Eiskjaer H, Riise G, et al. Improvement in renal function after everolimus introduction and calcineurin inhibitor reduction in maintenance thoracic transplant recipients: the significance of baseline glomerular filtration rate. J Heart Lung Transplant. 2012;31(3):259–265. doi: 10.1016/j.healun.2011.12.010.
    1. Parada MT, Alba A, Sepulveda C, Melo J. Long-term use of everolimus in lung transplant patients. Transplant Proc. 2011;43(6):2313–2315. doi: 10.1016/j.transproceed.2011.06.010.
    1. Snell GI, Valentine VG, Vitulo P, Glanville AR, McGiffin DC, Loyd JE, et al. Everolimus versus azathioprine in maintenance lung transplant recipients: an international, randomized, double-blind clinical trial. Am J Transplant Off J Am Soc Transplant Am Soc Transplant Surg. 2006;6(1):169–177. doi: 10.1111/j.1600-6143.2005.01134.x.
    1. Zeiser R, Leveson-Gower DB, Zambricki EA, Kambham N, Beilhack A, Loh J, et al. Differential impact of mammalian target of rapamycin inhibition on CD4+CD25+Foxp3+ regulatory T cells compared with conventional CD4+ T cells. Blood. 2008;111(1):453–462. doi: 10.1182/blood-2007-06-094482.
    1. Battaglia M, Stabilini A, Roncarolo MG. Rapamycin selectively expands CD4+CD25+FoxP3+ regulatory T cells. Blood. 2005;105(12):4743–4748. doi: 10.1182/blood-2004-10-3932.
    1. Gao W, Lu Y, El Essawy B, Oukka M, Kuchroo VK, Strom TB. Contrasting effects of cyclosporine and rapamycin in de novo generation of alloantigen-specific regulatory T cells. Am J Transplant Off J Am Soc Transplant Am Soc Transplant Surg. 2007;7(7):1722–1732. doi: 10.1111/j.1600-6143.2007.01842.x.
    1. Hippen KL, Merkel SC, Schirm DK, Sieben CM, Sumstad D, Kadidlo DM, et al. Massive ex vivo expansion of human natural regulatory T cells (T (regs)) with minimal loss of in vivo functional activity. Sci Transl Med. 2011;3(83):83ra41. doi: 10.1126/scitranslmed.3001809.
    1. Spence A, Klementowicz JE, Bluestone JA, Tang Q. Targeting Treg signaling for the treatment of autoimmune diseases. Curr Opin Immunol. 2015;37:11–20. doi: 10.1016/j.coi.2015.09.002.
    1. Furukawa A, Wisel SA, Tang Q. Impact of immune-modulatory drugs on regulatory T cell. Transplantation. 2016;100(11):2288–2300. doi: 10.1097/TP.0000000000001379.
    1. Ruggenenti P, Perico N, Gotti E, Cravedi P, D'Agati V, Gagliardini E, et al. Sirolimus versus cyclosporine therapy increases circulating regulatory T cells, but does not protect renal transplant patients given alemtuzumab induction from chronic allograft injury. Transplantation. 2007;84(8):956–964. doi: 10.1097/01.tp.0000284808.28353.2c.
    1. Gallon L, Traitanon O, Yu Y, Shi B, Leventhal JR, Miller J, et al. Differential effects of calcineurin and mammalian target of rapamycin inhibitors on alloreactive Th1, Th17, and regulatory T cells. Transplantation. 2015;99(9):1774–1784. doi: 10.1097/TP.0000000000000717.
    1. Levitsky J, Mathew JM, Abecassis M, Tambur A, Leventhal J, Chandrasekaran D, et al. Systemic immunoregulatory and proteogenomic effects of tacrolimus to sirolimus conversion in liver transplant recipients. Hepatology (Baltimore, Md) 2013;57(1):239–248. doi: 10.1002/hep.25579.
    1. Benazzo A, Schwarz S, Muckenhuber M, Schweiger T, Murakozy G, Moser B, et al. Alemtuzumab induction combined with reduced maintenance immunosuppression is associated with improved outcomes after lung transplantation: a single centre experience. PLoS One. 2019;14(1):e0210443. doi: 10.1371/journal.pone.0210443.
    1. Meyer KC, Raghu G, Verleden GM, Corris PA, Aurora P, Wilson KC, et al. An international ISHLT/ATS/ERS clinical practice guideline: diagnosis and management of bronchiolitis obliterans syndrome. Eur Respir J. 2014;44(6):1479–1503. doi: 10.1183/09031936.00107514.
    1. Jaksch P, Ankersmit J, Scheed A, Kocher A, Murakozy G, Klepetko W, et al. Alemtuzumab in lung transplantation: an open-label, randomized, prospective single center study. Am J Transplant Off J Am Soc Transplant Am Soc Transplant Surg. 2014;14(8):1839–1845. doi: 10.1111/ajt.12824.
    1. Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature. 2006;441(7090):235–238. doi: 10.1038/nature04753.
    1. Neujahr DC, Larsen CP. Regulatory T cells in lung transplantation--an emerging concept. Semin Immunopathol. 2011;33(2):117–127. doi: 10.1007/s00281-011-0253-0.
    1. Stassen M, Fondel S, Bopp T, Richter C, Muller C, Kubach J, et al. Human CD25+ regulatory T cells: two subsets defined by the integrins alpha 4 beta 7 or alpha 4 beta 1 confer distinct suppressive properties upon CD4+ T helper cells. Eur J Immunol. 2004;34(5):1303–1311. doi: 10.1002/eji.200324656.
    1. Meloni F, Vitulo P, Bianco AM, Paschetto E, Morosini M, Cascina A, et al. Regulatory CD4+CD25+ T cells in the peripheral blood of lung transplant recipients: correlation with transplant outcome. Transplantation. 2004;77(5):762–766. doi: 10.1097/01.TP.0000116565.86752.6B.

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