A Pilot Study to Assess the Safety and Efficacy of Alefacept in de Novo Kidney Transplant Recipients

Summary

The purpose of this study is to assess Alefacept in combination with alemtuzumab induction and calcineurin inhibitor and corticosteroid withdrawal.

Timeline

Start

2010-07

Primary completion

2011-09

Completion

2012-08

Publications

• Background Ansari MJ, Sayegh MH. The arduous road to achieving an immunosuppression-free state in kidney transplant recipients. Nat Clin Pract Nephrol. 2007 Sep;3(9):464-5. doi: 10.1038/ncpneph0568. Epub 2007 Jul 24. No abstract available.
• Background Antonysamy MA, Fanslow WC, Fu F, Li W, Qian S, Troutt AB, Thomson AW. Evidence for a role of IL-17 in alloimmunity: a novel IL-17 antagonist promotes heart graft survival. Transplant Proc. 1999 Feb-Mar;31(1-2):93. doi: 10.1016/s0041-1345(98)01453-5. No abstract available.
• Background Beninga J, Kropff B, Mach M. Comparative analysis of fourteen individual human cytomegalovirus proteins for helper T cell response. J Gen Virol. 1995 Jan;76 ( Pt 1):153-60. doi: 10.1099/0022-1317-76-1-153.
• Background Besse T, Malaise J, Mourad M, Pirson Y, Hope J, Awwad M, White-Scharf M, Squifflet JP. Prevention of rejection with BTI-322 after renal transplantation (results at 9 months). Transplant Proc. 1997 Aug;29(5):2425-6. doi: 10.1016/s0041-1345(97)00432-6. No abstract available.
• Background Bishop DK, Chan Wood S, Eichwald EJ, Orosz CG. Immunobiology of allograft rejection in the absence of IFN-gamma: CD8+ effector cells develop independently of CD4+ cells and CD40-CD40 ligand interactions. J Immunol. 2001 Mar 1;166(5):3248-55. doi: 10.4049/jimmunol.166.5.3248.
• Background Bobadilla JL, Love RB, Jankowska-Gan E, Xu Q, Haynes LD, Braun RK, Hayney MS, Munoz del Rio A, Meyer K, Greenspan DS, Torrealba J, Heidler KM, Cummings OW, Iwata T, Brand D, Presson R, Burlingham WJ, Wilkes DS. Th-17, monokines, collagen type V, and primary graft dysfunction in lung transplantation. Am J Respir Crit Care Med. 2008 Mar 15;177(6):660-8. doi: 10.1164/rccm.200612-1901OC. Epub 2008 Jan 3.
• Background Burlingham WJ, Love RB, Jankowska-Gan E, Haynes LD, Xu Q, Bobadilla JL, Meyer KC, Hayney MS, Braun RK, Greenspan DS, Gopalakrishnan B, Cai J, Brand DD, Yoshida S, Cummings OW, Wilkes DS. IL-17-dependent cellular immunity to collagen type V predisposes to obliterative bronchiolitis in human lung transplants. J Clin Invest. 2007 Nov;117(11):3498-506. doi: 10.1172/JCI28031.
• Background Chamian F, Lin SL, Lee E, Kikuchi T, Gilleaudeau P, Sullivan-Whalen M, Cardinale I, Khatcherian A, Novitskaya I, Wittkowski KM, Krueger JG, Lowes MA. Alefacept (anti-CD2) causes a selective reduction in circulating effector memory T cells (Tem) and relative preservation of central memory T cells (Tcm) in psoriasis. J Transl Med. 2007 Jun 7;5:27. doi: 10.1186/1479-5876-5-27.
• Background Chisholm PL, Williams CA, Jones WE, Majeau GR, Oleson FB, Burrus-Fischer B, Meier W, Hochman PS. The effects of an immunomodulatory LFA3-IgG1 fusion protein on nonhuman primates. Ther Immunol. 1994 Aug;1(4):205-16.
• Background Cooper JC, Morgan G, Harding S, Subramanyam M, Majeau GR, Moulder K, Alexander DR. Alefacept selectively promotes NK cell-mediated deletion of CD45R0+ human T cells. Eur J Immunol. 2003 Mar;33(3):666-75. doi: 10.1002/eji.200323586.
• Background Crawford K, Gabuzda D, Pantazopoulos V, Xu J, Clement C, Reinherz E, Alper CA. Circulating CD2+ monocytes are dendritic cells. J Immunol. 1999 Dec 1;163(11):5920-8.
• Background Crispim JC, Grespan R, Martelli-Palomino G, Rassi DM, Costa RS, Saber LT, Cunha FQ, Donadi EA. Interleukin-17 and kidney allograft outcome. Transplant Proc. 2009 Jun;41(5):1562-4. doi: 10.1016/j.transproceed.2009.01.092.
• Background da Silva AJ, Brickelmaier M, Majeau GR, Li Z, Su L, Hsu YM, Hochman PS. Alefacept, an immunomodulatory recombinant LFA-3/IgG1 fusion protein, induces CD16 signaling and CD2/CD16-dependent apoptosis of CD2(+) cells. J Immunol. 2002 May 1;168(9):4462-71. doi: 10.4049/jimmunol.168.9.4462.
• Background Dasgeb B, Holzman G, Phillips TJ. An extended 16-week course of alefacept in conjunction with reduced T-cell monitoring for the treatment of chronic plaque psoriasis. Poster P2720, American Academy of Dermatology 2005 Annual Meeting, New Orleans, Louisiana, February 2005.
• Background Dhanireddy KK, Bruno DA, Zhang X, Leopardi FV, Johnson LB, et al. Alefacept (LFA-3-Ig), portal venous donor specific transfusion, and sirolimus prolong renal allograft survival in non-human primates. Abstract 1627, American College of Surgeons 2006 Clinical Congress, Poster Session: Primate Models 2006 Jul 24.
• Background Di Pucchio T, Lapenta C, Santini SM, Logozzi M, Parlato S, Belardelli F. CD2+/CD14+ monocytes rapidly differentiate into CD83+ dendritic cells. Eur J Immunol. 2003 Feb;33(2):358-67. doi: 10.1002/immu.200310010.
• Background Dustin ML, Springer TA. Role of lymphocyte adhesion receptors in transient interactions and cell locomotion. Annu Rev Immunol. 1991;9:27-66. doi: 10.1146/annurev.iy.09.040191.000331.
• Background Eypasch E, Williams JI, Wood-Dauphinee S, Ure BM, Schmulling C, Neugebauer E, Troidl H. Gastrointestinal Quality of Life Index: development, validation and application of a new instrument. Br J Surg. 1995 Feb;82(2):216-22. doi: 10.1002/bjs.1800820229.
• Background Ellis CN, Krueger GG; Alefacept Clinical Study Group. Treatment of chronic plaque psoriasis by selective targeting of memory effector T lymphocytes. N Engl J Med. 2001 Jul 26;345(4):248-55. doi: 10.1056/NEJM200107263450403.
• Background Evans HG, Suddason T, Jackson I, Taams LS, Lord GM. Optimal induction of T helper 17 cells in humans requires T cell receptor ligation in the context of Toll-like receptor-activated monocytes. Proc Natl Acad Sci U S A. 2007 Oct 23;104(43):17034-9. doi: 10.1073/pnas.0708426104. Epub 2007 Oct 17.
• Background Fabrega E, Lopez-Hoyos M, San Segundo D, Casafont F, Pons-Romero F. Changes in the serum levels of interleukin-17/interleukin-23 during acute rejection in liver transplantation. Liver Transpl. 2009 Jun;15(6):629-33. doi: 10.1002/lt.21724.
• Background Gamadia LE, Remmerswaal EB, Weel JF, Bemelman F, van Lier RA, Ten Berge IJ. Primary immune responses to human CMV: a critical role for IFN-gamma-producing CD4+ T cells in protection against CMV disease. Blood. 2003 Apr 1;101(7):2686-92. doi: 10.1182/blood-2002-08-2502. Epub 2002 Oct 31.
• Background Gandhi MK, Khanna R. Human cytomegalovirus: clinical aspects, immune regulation, and emerging treatments. Lancet Infect Dis. 2004 Dec;4(12):725-38. doi: 10.1016/S1473-3099(04)01202-2.
• Background Gold MH, Hamilton TK, Rynearson A, Mathes B. An open-label community-based study of an extended course of alefacept in the treatment of chronic plaque psoriasis. Poster P2722, American Academy of Dermatology 2005 Annual Meeting, New Orleans, Louisiana, February 2005.
• Background Gonwa T, Mendez R, Yang HC, Weinstein S, Jensik S, Steinberg S; Prograf Study Group. Randomized trial of tacrolimus in combination with sirolimus or mycophenolate mofetil in kidney transplantation: results at 6 months. Transplantation. 2003 Apr 27;75(8):1213-20. doi: 10.1097/01.TP.0000062837.99400.60.
• Background Gribetz CH, Blum R, Brady C, Cohen S, Lebwohl M. An extended 16-week course of alefacept in the treatment of chronic plaque psoriasis. J Am Acad Dermatol. 2005 Jul;53(1):73-5. doi: 10.1016/j.jaad.2005.03.053.
• Background Humar A, Michaels M; AST ID Working Group on Infectious Disease Monitoring. American Society of Transplantation recommendations for screening, monitoring and reporting of infectious complications in immunosuppression trials in recipients of organ transplantation. Am J Transplant. 2006 Feb;6(2):262-74. doi: 10.1111/j.1600-6143.2005.01207.x.
• Background Ibrahim S, Dawson DV, Sanfilippo F. Predominant infiltration of rejecting human renal allografts with T cells expressing CD8 and CD45RO. Transplantation. 1995 Mar 15;59(5):724-8. doi: 10.1097/00007890-199503150-00015.
• Background Jeong H, Kaplan B. Therapeutic monitoring of mycophenolate mofetil. Clin J Am Soc Nephrol. 2007 Jan;2(1):184-91. doi: 10.2215/CJN.02860806. Epub 2006 Nov 8. No abstract available.
• Background Johnson C, Ahsan N, Gonwa T, Halloran P, Stegall M, Hardy M, Metzger R, Shield C 3rd, Rocher L, Scandling J, Sorensen J, Mulloy L, Light J, Corwin C, Danovitch G, Wachs M, van Veldhuisen P, Salm K, Tolzman D, Fitzsimmons WE. Randomized trial of tacrolimus (Prograf) in combination with azathioprine or mycophenolate mofetil versus cyclosporine (Neoral) with mycophenolate mofetil after cadaveric kidney transplantation. Transplantation. 2000 Mar 15;69(5):834-41. doi: 10.1097/00007890-200003150-00028.
• Background Jones ND, Van Maurik A, Hara M, Spriewald BM, Witzke O, Morris PJ, Wood KJ. CD40-CD40 ligand-independent activation of CD8+ T cells can trigger allograft rejection. J Immunol. 2000 Jul 15;165(2):1111-8. doi: 10.4049/jimmunol.165.2.1111.
• Background Kaplon RJ, Hochman PS, Michler RE, Kwiatkowski PA, Edwards NM, Berger CL, Xu H, Meier W, Wallner BP, Chisholm P, Marboe CC. Short course single agent therapy with an LFA-3-IgG1 fusion protein prolongs primate cardiac allograft survival. Transplantation. 1996 Feb 15;61(3):356-63. doi: 10.1097/00007890-199602150-00004.
• Background Kondo T, Takata H, Matsuki F, Takiguchi M. Cutting edge: Phenotypic characterization and differentiation of human CD8+ T cells producing IL-17. J Immunol. 2009 Feb 15;182(4):1794-8. doi: 10.4049/jimmunol.0801347.
• Background Krueger GG, Papp KA, Stough DB, Loven KH, Gulliver WP, Ellis CN; Alefacept Clinical Study Group. A randomized, double-blind, placebo-controlled phase III study evaluating efficacy and tolerability of 2 courses of alefacept in patients with chronic plaque psoriasis. J Am Acad Dermatol. 2002 Dec;47(6):821-33. doi: 10.1067/mjd.2002.127247.
• Background Lerut J, Van Thuyne V, Mathijs J, Lemaire J, Talpe S, Roggen F, Ciccarelli O, Zuckermann M, Goffette P, Hope J, Gianello P, Bazin H, Cornet A, Rahier J, Latinne D. Anti-CD2 monoclonal antibody and tacrolimus in adult liver transplantation. Transplantation. 2005 Nov 15;80(9):1186-93. doi: 10.1097/01.tp.0000173996.81192.f9.
• Background Loong CC, Hsieh HG, Lui WY, Chen A, Lin CY. Evidence for the early involvement of interleukin 17 in human and experimental renal allograft rejection. J Pathol. 2002 Jul;197(3):322-32. doi: 10.1002/path.1117.
• Background Majeau GR, Meier W, Jimmo B, Kioussis D, Hochman PS. Mechanism of lymphocyte function-associated molecule 3-Ig fusion proteins inhibition of T cell responses. Structure/function analysis in vitro and in human CD2 transgenic mice. J Immunol. 1994 Mar 15;152(6):2753-67.
• Background Mendez R, Gonwa T, Yang HC, Weinstein S, Jensik S, Steinberg S; Prograf Study Group. A prospective, randomized trial of tacrolimus in combination with sirolimus or mycophenolate mofetil in kidney transplantation: results at 1 year. Transplantation. 2005 Aug 15;80(3):303-9. doi: 10.1097/01.tp.0000167757.63922.42.
• Background Miller GT, Hochman PS, Meier W, Tizard R, Bixler SA, Rosa MD, Wallner BP. Specific interaction of lymphocyte function-associated antigen 3 with CD2 can inhibit T cell responses. J Exp Med. 1993 Jul 1;178(1):211-22. doi: 10.1084/jem.178.1.211.
• Background Miller J, Mendez R, Pirsch JD, Jensik SC. Safety and efficacy of tacrolimus in combination with mycophenolate mofetil (MMF) in cadaveric renal transplant recipients. FK506/MMF Dose-Ranging Kidney Transplant Study Group. Transplantation. 2000 Mar 15;69(5):875-80. doi: 10.1097/00007890-200003150-00035.
• Background Mourad M, Besse T, Malaise J, Baldi A, Latinne D, Bazin H, Pirson Y, Hope J, Squifflet JP. BTI-322 for acute rejection after renal transplantation. Transplant Proc. 1997 Aug;29(5):2353. doi: 10.1016/s0041-1345(97)00398-9. No abstract available.
• Background Newell KA, He G, Guo Z, Kim O, Szot GL, Rulifson I, Zhou P, Hart J, Thistlethwaite JR, Bluestone JA. Cutting edge: blockade of the CD28/B7 costimulatory pathway inhibits intestinal allograft rejection mediated by CD4+ but not CD8+ T cells. J Immunol. 1999 Sep 1;163(5):2358-62.
• Background Olson DP, Dombkowski DM, Kelliher AS, Pontillo C, Anderson DC, Preffer FI. Differential expression of cell surface antigens on subsets of CD4+ and CD8+ T cells. Med Sci Monit. 2004 Sep;10(9):BR339-45. Epub 2004 Aug 20.
• Background Park H, Li Z, Yang XO, Chang SH, Nurieva R, Wang YH, Wang Y, Hood L, Zhu Z, Tian Q, Dong C. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol. 2005 Nov;6(11):1133-41. doi: 10.1038/ni1261. Epub 2005 Oct 2.
• Background Preston EH, Xu H, Dhanireddy KK, Pearl JP, Leopardi FV, Starost MF, Hale DA, Kirk AD. IDEC-131 (anti-CD154), sirolimus and donor-specific transfusion facilitate operational tolerance in non-human primates. Am J Transplant. 2005 May;5(5):1032-41. doi: 10.1111/j.1600-6143.2005.00796.x.
• Background Putnam Associates, from the results of a survey (funded by Astellas Pharma US, Inc.) conducted at the 2004 American Transplant Congress July 14, 2004.
• Background Valujskikh A, Pantenburg B, Heeger PS. Primed allospecific T cells prevent the effects of costimulatory blockade on prolonged cardiac allograft survival in mice. Am J Transplant. 2002 Jul;2(6):501-9. doi: 10.1034/j.1600-6143.2002.20603.x.
• Background Van Kooten C, Boonstra JG, Paape ME, Fossiez F, Banchereau J, Lebecque S, Bruijn JA, De Fijter JW, Van Es LA, Daha MR. Interleukin-17 activates human renal epithelial cells in vitro and is expressed during renal allograft rejection. J Am Soc Nephrol. 1998 Aug;9(8):1526-34. doi: 10.1681/ASN.V981526.
• Background Vanaudenaerde BM, Dupont LJ, Wuyts WA, Verbeken EK, Meyts I, Bullens DM, Dilissen E, Luyts L, Van Raemdonck DE, Verleden GM. The role of interleukin-17 during acute rejection after lung transplantation. Eur Respir J. 2006 Apr;27(4):779-87. doi: 10.1183/09031936.06.00019405.
• Background Sester M, Sester U, Gartner BC, Girndt M, Meyerhans A, Kohler H. Dominance of virus-specific CD8 T cells in human primary cytomegalovirus infection. J Am Soc Nephrol. 2002 Oct;13(10):2577-84. doi: 10.1097/01.asn.0000030141.41726.52.
• Background Sester M, Sester U, Gartner B, Heine G, Girndt M, Mueller-Lantzsch N, Meyerhans A, Kohler H. Levels of virus-specific CD4 T cells correlate with cytomegalovirus control and predict virus-induced disease after renal transplantation. Transplantation. 2001 May 15;71(9):1287-94. doi: 10.1097/00007890-200105150-00018.
• Background Solez K, Colvin RB, Racusen LC, Sis B, Halloran PF, Birk PE, Campbell PM, Cascalho M, Collins AB, Demetris AJ, Drachenberg CB, Gibson IW, Grimm PC, Haas M, Lerut E, Liapis H, Mannon RB, Marcus PB, Mengel M, Mihatsch MJ, Nankivell BJ, Nickeleit V, Papadimitriou JC, Platt JL, Randhawa P, Roberts I, Salinas-Madriga L, Salomon DR, Seron D, Sheaff M, Weening JJ. Banff '05 Meeting Report: differential diagnosis of chronic allograft injury and elimination of chronic allograft nephropathy ('CAN'). Am J Transplant. 2007 Mar;7(3):518-26. doi: 10.1111/j.1600-6143.2006.01688.x.
• Background Squifflet JP, Backman L, Claesson K, Dietl KH, Ekberg H, Forsythe JL, Kunzendorf U, Heemann U, Land W, Morales JM, Muhlbacher F, Talbot D, Taube D, Tyden G, van Hooff J, Schleibner S, Vanrenterghem Y; European Tacrolimus-MMF Renal Study Group. Dose optimization of mycophenolate mofetil when administered with a low dose of tacrolimus in cadaveric renal transplant recipients. Transplantation. 2001 Jul 15;72(1):63-9. doi: 10.1097/00007890-200107150-00014.
• Background Squifflet JP, Besse T, Malaise J, Mourad M, Delcorde C, Hope JA, Pirson Y. BTI-322 for induction therapy after renal transplantation: a randomized study. Transplant Proc. 1997 Feb-Mar;29(1-2):317-9. doi: 10.1016/s0041-1345(96)00282-5. No abstract available.
• Background Sultan P, Schechner JS, McNiff JM, Hochman PS, Hughes CC, Lorber MI, Askenase PW, Pober JS. Blockade of CD2-LFA-3 interactions protects human skin allografts in immunodeficient mouse/human chimeras. Nat Biotechnol. 1997 Aug;15(8):759-62. doi: 10.1038/nbt0897-759.
• Background Walter EA, Greenberg PD, Gilbert MJ, Finch RJ, Watanabe KS, Thomas ED, Riddell SR. Reconstitution of cellular immunity against cytomegalovirus in recipients of allogeneic bone marrow by transfer of T-cell clones from the donor. N Engl J Med. 1995 Oct 19;333(16):1038-44. doi: 10.1056/NEJM199510193331603.
• Background Wu Z, Bensinger SJ, Zhang J, Chen C, Yuan X, Huang X, Markmann JF, Kassaee A, Rosengard BR, Hancock WW, Sayegh MH, Turka LA. Homeostatic proliferation is a barrier to transplantation tolerance. Nat Med. 2004 Jan;10(1):87-92. doi: 10.1038/nm965. Epub 2003 Nov 30.
• Background Yuan X, Ansari MJ, D'Addio F, Paez-Cortez J, Schmitt I, Donnarumma M, Boenisch O, Zhao X, Popoola J, Clarkson MR, Yagita H, Akiba H, Freeman GJ, Iacomini J, Turka LA, Glimcher LH, Sayegh MH. Targeting Tim-1 to overcome resistance to transplantation tolerance mediated by CD8 T17 cells. Proc Natl Acad Sci U S A. 2009 Jun 30;106(26):10734-9. doi: 10.1073/pnas.0812538106. Epub 2009 Jun 15.
• Background Yuan X, Paez-Cortez J, Schmitt-Knosalla I, D'Addio F, Mfarrej B, Donnarumma M, Habicht A, Clarkson MR, Iacomini J, Glimcher LH, Sayegh MH, Ansari MJ. A novel role of CD4 Th17 cells in mediating cardiac allograft rejection and vasculopathy. J Exp Med. 2008 Dec 22;205(13):3133-44. doi: 10.1084/jem.20081937. Epub 2008 Dec 1.
• Background Zhai Y, Meng L, Gao F, Busuttil RW, Kupiec-Weglinski JW. Allograft rejection by primed/memory CD8+ T cells is CD154 blockade resistant: therapeutic implications for sensitized transplant recipients. J Immunol. 2002 Oct 15;169(8):4667-73. doi: 10.4049/jimmunol.169.8.4667.

Drugs

Indications

No indication recorded.