A pilot study of IL-2Rα blockade during lymphopenia depletes regulatory T-cells and correlates with enhanced immunity in patients with glioblastoma

PLoS ONE

Volumn 7, Issue 2, 2012, Pages

  Sampson, John H ^a   Schmittling, Robert J ^a   Archer, Gary E ^a   Congdon, Kendra L ^a   Nair, Smita K ^a   Reap, Elizabeth A ^a   Desjardins, Annick ^a   Friedman, Allan H ^a   Friedman, Henry S ^a   Herndon II, James E ^a   Coan, April ^a   McLendon, Roger E ^a   Reardon, David A ^b   Vredenburgh, James J ^a   Bigner, Darell D ^a   Mitchell, Duane A ^a  

^a DUKE UNIVERSITY MEDICAL CENTER   (United States)

^b DANA FARBER CANCER INSTITUTE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CD4 ANTIGEN; CYTOKINE RECEPTOR ANTAGONIST; DACLIZUMAB; EPIDERMAL GROWTH FACTOR RECEPTOR 3; GAMMA INTERFERON; GRANULOCYTE MACROPHAGE COLONY STIMULATING FACTOR; INTERLEUKIN 15; INTERLEUKIN 2 RECEPTOR ALPHA BLOCKING AGENT; PLACEBO; RINDOPEPIMUT; SODIUM CHLORIDE; TEMOZOLOMIDE; TRANSCRIPTION FACTOR FOXP3; UNCLASSIFIED DRUG; IMMUNOGLOBULIN G; IMMUNOSUPPRESSIVE AGENT; INTERLEUKIN 2 RECEPTOR ALPHA; MONOCLONAL ANTIBODY;

ADULT; AGED; ARTICLE; AUTOIMMUNE DISEASE; CANCER RADIOTHERAPY; CD4+ T LYMPHOCYTE; CD8+ T LYMPHOCYTE; CLINICAL ARTICLE; CONTROLLED STUDY; CORRELATION ANALYSIS; CYTOKINE RELEASE; DOUBLE BLIND PROCEDURE; DRUG SAFETY; DRUG SELECTIVITY; DRUG TOLERABILITY; FEMALE; GLIOBLASTOMA; HUMAN; HUMAN CELL; HUMORAL IMMUNITY; IMMUNE RESPONSE; INJECTION SITE PRURITUS; INJECTION SITE SWELLING; LYMPHOCYTE COUNT; LYMPHOCYTE DEPLETION; LYMPHOCYTOPENIA; MALE; MULTIPLE CYCLE TREATMENT; PILOT STUDY; RANDOMIZED CONTROLLED TRIAL; RECEPTOR BLOCKING; REGULATORY T LYMPHOCYTE; SIGNAL TRANSDUCTION; SINGLE DRUG DOSE; SKIN REDNESS; TUMOR IMMUNITY; BRAIN TUMOR; CHEMISTRY; CLINICAL TRIAL; CONTROLLED CLINICAL TRIAL; CYTOLOGY; DRUG ANTAGONISM; IMMUNE SYSTEM; METABOLISM; MIDDLE AGED; T LYMPHOCYTE;

MUS;

ADULT; AGED; ANTIBODIES, MONOCLONAL, HUMANIZED; BRAIN NEOPLASMS; CD4-POSITIVE T-LYMPHOCYTES; CD8-POSITIVE T-LYMPHOCYTES; FEMALE; GLIOBLASTOMA; HUMANS; IMMUNE SYSTEM; IMMUNOGLOBULIN G; IMMUNOSUPPRESSIVE AGENTS; INTERLEUKIN-2 RECEPTOR ALPHA SUBUNIT; LYMPHOPENIA; MALE; MIDDLE AGED; PILOT PROJECTS; T-LYMPHOCYTES; T-LYMPHOCYTES, REGULATORY;

EID: 84857547272     PISSN: None     EISSN: 19326203     Source Type: Journal    
DOI: 10.1371/journal.pone.0031046     Document Type: Article

References (76)

1. Zou W, (2006) Regulatory T cells, tumour immunity and immunotherapy. Nat Rev Immunol 6: 295-307.
2. Thornton AM, Shevach EM, (1998) CD4+CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production. J Exp Med 188: 287-296.
3. Jonuleit H, Schmitt E, Stassen M, Tuettenberg A, Knop J, et al. (2001) Identification and functional characterization of human CD4(+)CD25(+) T cells with regulatory properties isolated from peripheral blood. J Exp Med 193: 1285-1294.
4. Dieckmann D, Plottner H, Berchtold S, Berger T, Schuler G, (2001) Ex vivo isolation and characterization of CD4(+)CD25(+) T cells with regulatory properties from human blood. J Exp Med 193: 1303-1310.
5. Fontenot JD, Gavin MA, Rudensky AY, (2003) Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol 4: 330-336.
6. Khattri R, Cox T, Yasayko SA, Ramsdell F, (2003) An essential role for Scurfin in CD4+CD25+ T regulatory cells. Nat Immunol 4: 337-342.
7. Green DR, Webb DR, (1993) Saying the 'S' word in public. Immunol Today 14: 523-525.
8. Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M, (1995) 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. J Immunol 155: 1151-1164.
9. Asano M, Toda M, Sakaguchi N, Sakaguchi S, (1996) Autoimmune disease as a consequence of developmental abnormality of a T cell subpopulation. J Exp Med 184: 387-396.
10. Salomon B, Lenschow DJ, Rhee L, Ashourian N, Singh B, et al. (2000) B7/CD28 costimulation is essential for the homeostasis of the CD4+CD25+ immunoregulatory T cells that control autoimmune diabetes. Immunity 12: 431-440.
11. Stephens LA, Mason D, (2000) CD25 is a marker for CD4+ thymocytes that prevent autoimmune diabetes in rats, but peripheral T cells with this function are found in both CD25+ and CD25- subpopulations. J Immunol 165: 3105-3110.
12. Taguchi O, Nishizuka Y, (1987) Self tolerance and localized autoimmunity. Mouse models of autoimmune disease that suggest tissue-specific suppressor T cells are involved in self tolerance. J Exp Med 165: 146-156.
13. Taguchi O, Kontani K, Ikeda H, Kezuka T, Takeuchi M, et al. (1994) Tissue-specific suppressor T cells involved in self-tolerance are activated extrathymically by self-antigens. Immunology 82: 365-369.
14. Seddon B, Mason D, (1999) Regulatory T cells in the control of autoimmunity: the essential role of transforming growth factor beta and interleukin 4 in the prevention of autoimmune thyroiditis in rats by peripheral CD4(+)CD45RC- cells and CD4(+)CD8(-) thymocytes. J Exp Med 189: 279-288.
15. Seddon B, Mason D, (1999) Peripheral autoantigen induces regulatory T cells that prevent autoimmunity. J Exp Med 189: 877-882.
16. Bagavant H, Thompson C, Ohno K, Setiady Y, Tung KSK, (2002) Differential effect of neonatal thymectomy on systemic and organ-specific autoimmune disease. Int Immunol 14: 1397-1406.
17. Somasundaram R, Jacob L, Swoboda R, Caputo L, Song H, et al. (2002) Inhibition of cytolytic T lymphocyte proliferation by autologous CD4+/CD25+ regulatory T cells in a colorectal carcinoma patient is mediated by transforming growth factor-beta. Cancer Res 62: 5267-5272.
18. Curiel TJ, Coukos G, Zou L, Alvarez X, Cheng P, et al. (2004) Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 10: 942-949.
19. Liyanage UK, Moore TT, Joo HG, Tanaka Y, Herrmann V, et al. (2002) Prevalence of regulatory T cells is increased in peripheral blood and tumor microenvironment of patients with pancreas or breast adenocarcinoma. J Immunol 169: 2756-2761.
20. Wolf AM, Wolf D, Steurer M, Gastl G, Gunsilius E, et al. (2003) Increase of regulatory T cells in the peripheral blood of cancer patients. Clin Cancer Res 9: 606-612.
21. Ichihara F, Kono K, Takahashi A, Kawaida H, Sugai H, et al. (2003) Increased populations of regulatory T cells in peripheral blood and tumor-infiltrating lymphocytes in patients with gastric and esophageal cancers. Clin Cancer Res 9: 4404-4408.
22. Woo EY, Chu CS, Goletz TJ, Schlienger K, Yeh H, et al. (2001) Regulatory CD4(+)CD25(+) T cells in tumors from patients with early-stage non-small cell lung cancer and late-stage ovarian cancer. Cancer Res 61: 4766-4772.
23. Fecci PE, Mitchell DA, Whitesides JF, Xie W, Friedman AH, et al. (2006) Increased regulatory T-cell fraction amidst a diminished CD4 compartment explains cellular immune defects in patients with malignant glioma. Cancer Res 66: 3294-3302.
24. Morse MA, Hobeika AC, Osada T, Serra D, Niedzwiecki D, et al. (2008) Depletion of human regulatory T cells specifically enhances antigen-specific immune responses to cancer vaccines. Blood 112: 610-618.
25. Dannull J, Su Z, Rizzieri D, Yang BK, Coleman D, et al. (2005) Enhancement of vaccine-mediated antitumor immunity in cancer patients after depletion of regulatory T cells. J Clin Invest 115: 3623-3633.
26. Attia P, Maker AV, Haworth LR, Rogers-Freezer L, Rosenberg SA, (2005) Inability of a fusion protein of IL-2 and diphtheria toxin (Denileukin Diftitox, DAB389IL-2, ONTAK) to eliminate regulatory T lymphocytes in patients with melanoma. J Immunother 28: 582-592.
27. Powell DJ Jr, Felipe-Silva A, Merino MJ, Ahmadzadeh M, Allen T, et al. (2007) Administration of a CD25-directed immunotoxin, LMB-2, to patients with metastatic melanoma induces a selective partial reduction in regulatory T cells in vivo. J Immunol 179: 4919-4928.
28. Curtin JF, Candolfi M, Fakhouri TM, Liu C, Alden A, et al. (2008) Treg depletion inhibits efficacy of cancer immunotherapy: implications for clinical trials. PLoS One 3: e1983.
29. Goebel J, Stevens E, Forrest K, Roszman TL, (2000) Daclizumab (Zenapax) inhibits early interleukin-2 receptor signal transduction events. Transpl Immunol 8: 153-159.
30. Fecci PE, Sweeney AE, Grossi PM, Nair SK, Learn CA, et al. (2006) Systemic anti-CD25 monoclonal antibody administration safely enhances immunity in murine glioma without eliminating regulatory T cells. Clin Cancer Res 12: 4294-4305.
31. Kohm AP, McMahon JS, Podojil JR, Begolka WS, DeGutes M, et al. (2006) Cutting Edge: Anti-CD25 monoclonal antibody injection results in the functional inactivation, not depletion, of CD4+CD25+ T regulatory cells. J Immunol 176: 3301-3305.
32. Jacobs JF, Punt CJ, Lesterhuis WJ, Sutmuller RP, Brouwer HM, et al. (2010) Dendritic Cell Vaccination in Combination with Anti-CD25 Monoclonal Antibody Treatment: A Phase I/II Study in Metastatic Melanoma Patients. Clin Cancer Res 16: 5067-5078.
33. Mitchell DA, Cui X, Schmittling RJ, Sanchez-Perez L, Snyder DJ, et al. (2011) Monoclonal antibody blockade of IL-2R{alpha} during lymphopenia selectively depletes regulatory T cells in mice and humans. Blood.
34. Humphrey PA, Wong AJ, Vogelstein B, Zalutsky MR, Fuller GN, et al. (1990) Anti-synthetic peptide antibody reacting at the fusion junction of deletion-mutant epidermal growth factor receptors in human glioblastoma. Proc Natl Acad Sci U S A 87: 4207-4211.
35. Wikstrand CJ, Hale LP, Batra SK, Hill ML, Humphrey PA, et al. (1995) Monoclonal antibodies against EGFRvIII are tumor specific and react with breast and lung carcinomas and malignant gliomas. Cancer Res 55: 3140-3148.
36. Purev E, Cai D, Miller E, Swoboda R, Mayer T, et al. (2004) Immune responses of breast cancer patients to mutated epidermal growth factor receptor (EGF-RvIII, Delta EGF-R, and de2-7 EGF-R). J Immunol 173: 6472-6480.
37. Sok JC, Coppelli FM, Thomas SM, Lango MN, Xi S, et al. (2006) Mutant epidermal growth factor receptor (EGFRvIII) contributes to head and neck cancer growth and resistance to EGFR targeting. Clin Cancer Res 12: 5064-5073.
38. Sampson JH, Aldape KD, Archer GE, Coan A, Desjardins A, et al. (2011) Greater chemotherapy-induced lymphopenia enhances tumor-specific immune responses that eliminate EGFRvIII-expressing tumor cells in patients with glioblastoma. Neuro Oncol 13: 324-333.
39. Sampson JH, Heimberger AB, Archer GE, Aldape KD, Friedman AH, et al. (2010) Immunologic escape after prolonged progression-free survival with epidermal growth factor receptor variant III peptide vaccination in patients with newly diagnosed glioblastoma. J Clin Oncol 28: 4722-4729.
40. Sampson JH, Archer GE, Mitchell DA, Heimberger AB, Herndon JE, 2nd, et al. (2009) An epidermal growth factor receptor variant III-targeted vaccine is safe and immunogenic in patients with glioblastoma multiforme. Mol Cancer Ther 8: 2773-2779.
41. Binder M, Vogtle FN, Michelfelder S, Muller F, Illerhaus G, et al. (2007) Identification of their epitope reveals the structural basis for the mechanism of action of the immunosuppressive antibodies basiliximab and daclizumab. Cancer Res 67: 3518-3523.
42. Bielekova B, Catalfamo M, Reichert-Scrivner S, Packer A, Cerna M, et al. (2006) Regulatory CD56(bright) natural killer cells mediate immunomodulatory effects of IL-2Ralpha-targeted therapy (daclizumab) in multiple sclerosis. Proc Natl Acad Sci U S A 103: 5941-5946.
43. Gattinoni L, Finkelstein SE, Klebanoff CA, Antony PA, Palmer DC, et al. (2005) Removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor-specific CD8+ T cells. J Exp Med 202: 907-912.
44. Phan GQ, Yang JC, Sherry RM, Hwu P, Topalian SL, et al. (2003) Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc Natl Acad Sci U S A 100: 8372-8377.
45. Attia P, Phan GQ, Maker AV, Robinson MR, Quezado MM, et al. (2005) Autoimmunity correlates with tumor regression in patients with metastatic melanoma treated with anti-cytotoxic T-lymphocyte antigen-4. J Clin Oncol 23: 6043-6053.
46. Jaber SH, Cowen EW, Haworth LR, Booher SL, Berman DM, et al. (2006) Skin reactions in a subset of patients with stage IV melanoma treated with anti-cytotoxic T-lymphocyte antigen 4 monoclonal antibody as a single agent. Arch Dermatol 142: 166-172.
47. Blansfield JA, Beck KE, Tran K, Yang JC, Hughes MS, et al. (2005) Cytotoxic T-lymphocyte-associated antigen-4 blockage can induce autoimmune hypophysitis in patients with metastatic melanoma and renal cancer. J Immunother 28: 593-598.
48. Setoguchi R, Hori S, Takahashi T, Sakaguchi S, (2005) Homeostatic maintenance of natural Foxp3(+) CD25(+) CD4(+) regulatory T cells by interleukin (IL)-2 and induction of autoimmune disease by IL-2 neutralization. J Exp Med 201: 723-735.
49. Neujahr DC, Chen C, Huang X, Markmann JF, Cobbold S, et al. (2006) Accelerated memory cell homeostasis during T cell depletion and approaches to overcome it. J Immunol 176: 4632-4639.
50. Quezada SA, Peggs KS, Simpson TR, Shen Y, Littman DR, et al. (2008) Limited tumor infiltration by activated T effector cells restricts the therapeutic activity of regulatory T cell depletion against established melanoma. J Exp Med 205: 2125-2138.
51. Wrzesinski C, Paulos CM, Gattinoni L, Palmer DC, Kaiser A, et al. (2007) Hematopoietic stem cells promote the expansion and function of adoptively transferred antitumor CD8 T cells. J Clin Invest 117: 492-501.
52. Sato E, Olson SH, Ahn J, Bundy B, Nishikawa H, et al. (2005) Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proc Natl Acad Sci U S A 102: 18538-18543.
53. Nair S, Boczkowski D, Fassnacht M, Pisetsky D, Gilboa E, (2007) Vaccination against the forkhead family transcription factor Foxp3 enhances tumor immunity. Cancer Res 67: 371-380.
54. Koyama K, Kagamu H, Miura S, Hiura T, Miyabayashi T, et al. (2008) Reciprocal CD4+ T-cell balance of effector CD62Llow CD4+ and CD62LhighCD25+ CD4+ regulatory T cells in small cell lung cancer reflects disease stage. Clin Cancer Res 14: 6770-6779.
55. Martin JF, Perry JS, Jakhete NR, Wang X, Bielekova B, An IL-2 paradox: blocking CD25 on T cells induces IL-2-driven activation of CD56(bright) NK cells. J Immunol 185: 1311-1320.
56. Vincenti F, Nashan B, Light S, (1998) Daclizumab: outcome of phase III trials and mechanism of action. Double Therapy and the Triple Therapy Study Groups. Transplant Proc 30: 2155-2158.
57. Van Assche G, Sandborn WJ, Feagan BG, Salzberg BA, Silvers D, et al. (2006) Daclizumab, a humanised monoclonal antibody to the interleukin 2 receptor (CD25), for the treatment of moderately to severely active ulcerative colitis: a randomised, double blind, placebo controlled, dose ranging trial. Gut 55: 1568-1574.
58. Boissonnas A, Scholer-Dahirel A, Simon-Blancal V, Pace L, Valet F, et al. (2010) Foxp3+ T cells induce perforin-dependent dendritic cell death in tumor-draining lymph nodes. Immunity 32: 266-278.
59. Powell DJ Jr, Attia P, Ghetie V, Schindler J, Vitetta ES, et al. (2008) Partial reduction of human FOXP3+ CD4 T cells in vivo after CD25-directed recombinant immunotoxin administration. J Immunother 31: 189-198.
60. Attia P, Powell DJ Jr, Maker AV, Kreitman RJ, Pastan I, et al. (2006) Selective elimination of human regulatory T lymphocytes in vitro with the recombinant immunotoxin LMB-2. J Immunother 29: 208-214.
61. Maloy KJ, Powrie F, (2005) Fueling regulation: IL-2 keeps CD4+ Treg cells fit.[comment]. Nat Immunol 6: 1071-1072.
62. D'Cruz LM, Klein L, (2005) Development and function of agonist-induced CD25+Foxp3+ regulatory T cells in the absence of interleukin 2 signaling. Nat Immunol 6: 1152-1159.
63. Fontenot JD, Rasmussen JP, Gavin MA, Rudensky AY, (2005) A function for interleukin 2 in Foxp3-expressing regulatory T cells. Nat Immunol 6: 1142-1151.
64. Malek TR, Bayer AL, (2004) Tolerance, not immunity, crucially depends on IL-2. Nat Rev Immunol 4: 665-674.
65. Onizuka S, Tawara I, Shimizu J, Sakaguchi S, Fujita T, et al. (1999) Tumor rejection by in vivo administration of anti-CD25 (interleukin-2 receptor alpha) monoclonal antibody. Cancer Res 59: 3128-3133.
66. Antony PA, Piccirillo CA, Akpinarli A, Finkelstein SE, Speiss PJ, et al. (2005) CD8+ T cell immunity against a tumor/self-antigen is augmented by CD4+ T helper cells and hindered by naturally occurring T regulatory cells. J Immunol 174: 2591-2601.
67. Turk MJ, Guevara-Patino JA, Rizzuto GA, Engelhorn ME, Sakaguchi S, et al. (2004) Concomitant tumor immunity to a poorly immunogenic melanoma is prevented by regulatory T cells. J Exp Med 200: 771-782.
68. Williams MA, Tyznik AJ, Bevan MJ, (2006) Interleukin-2 signals during priming are required for secondary expansion of CD8+ memory T cells. Nature 441: 890-893.
69. Wainwright DA, Sengupta S, Han Y, Lesniak MS, (2011) Thymus-derived rather than tumor-induced regulatory T cells predominate in brain tumors. Neuro Oncol 13: 1308-1323.
70. Mitchell DA, Xie W, Schmittling R, Learn C, Friedman A, et al. (2008) Sensitive detection of human cytomegalovirus in tumors and peripheral blood of patients diagnosed with glioblastoma. Neuro Oncol 10: 10-18.
71. Cobbs CS, Harkins L, Samanta M, Gillespie GY, Bharara S, et al. (2002) Human cytomegalovirus infection and expression in human malignant glioma. Cancer Res 62: 3347-3350.
72. Prins RM, Cloughesy TF, Liau LM, (2008) Cytomegalovirus immunity after vaccination with autologous glioblastoma lysate. N Engl J Med 359: 539-541.
73. Scheurer ME, Bondy ML, Aldape KD, Albrecht T, El-Zein R, et al. (2008) Detection of human cytomegalovirus in different histological types of gliomas. Acta Neuropathol 116: 79-86.
74. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, et al. (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352: 987-996.
75. Liau LM, Prins RM, Kiertscher SM, Odesa SK, Kremen TJ, et al. (2005) Dendritic cell vaccination in glioblastoma patients induces systemic and intracranial T-cell responses modulated by the local central nervous system tumor microenvironment. Clin Cancer Res 11: 5515-5525.
76. Schmittling RJ, Archer GE, Mitchell DA, Heimberger A, Pegram C, et al. (2008) Detection of humoral response in patients with glioblastoma receiving EGFRvIII-KLH vaccines. J Immunol Methods 339: 74-81.