Skip to main content
SpringerLink
Log in

Overcoming Cancer Tolerance with Immune Checkpoint Blockade

  • Chapter
  • First Online:
Cancer Immunology

  • 3181 Accesses

Abstract

Cancer immunotherapy has largely been hindered by the ability of tumors to induce tolerance and escape the immune system. By targeting coinhibitory and costimulatory receptors in the immune system, it is possible to counteract the pathways that tumors utilize to avoid immune destruction. Ipilimumab, the first approved drug of this class, blocks the coinhibitory receptor CTLA-4 and has been shown to improve survival in advanced melanoma. Research into expanding the uses of CTLA-4 blockade as well as targeting alternative coinhibitory and costimulatory checkpoints is ongoing. Checkpoint blockade, particularly when combined with conventional therapies and cancer vaccines, has the potential to revolutionize cancer immunotherapy and provide new therapeutic options to a broad range of malignancies. This chapter will review the rationale for targeting immune checkpoints, the pathways of particular interest, and the research being conducted to bring checkpoint blockade to clinical use.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 109.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 139.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Burnet M. Cancer: a biological approach. III. Viruses associated with neoplastic conditions. IV. Practical applications. Br Med J. 1957;1:841–7.

    CAS  PubMed Central  PubMed  Google Scholar 

  2. Ichim CV. Revisiting immunosurveillance and immunostimulation: implications for cancer immunotherapy. J Transl Med. 2005;3:8.

    PubMed Central  PubMed  Google Scholar 

  3. Manjili MH. Revisiting cancer immunoediting by understanding cancer immune complexity. J Pathol. 2011;224:5–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  4. Rosenberg SA, Yang JC, Restifo NP. Cancer immunotherapy: moving beyond current vaccines. Nat Med. 2004;10:909–15.

    CAS  PubMed Central  PubMed  Google Scholar 

  5. Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363:411–22.

    CAS  PubMed  Google Scholar 

  6. Small EJ. Placebo-controlled phase III trial of immunologic therapy with sipuleucel-T (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer. J Clin Oncol. 2006;24:3089–94.

    CAS  PubMed  Google Scholar 

  7. Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science. 2011;331:1565–70.

    CAS  PubMed  Google Scholar 

  8. Yamazaki K, Spruill G, Rhoderick J, Spielman J, Savaraj N, Podack ER. Small cell lung carcinomas express shared and private tumor antigens presented by HLA-A1 or HLA-A2. Cancer Res. 1999;59:4642–50.

    CAS  PubMed  Google Scholar 

  9. Redondo M, Concha A, Oldiviela R, Cueto A, Gonzalez A, Garrido F, Ruiz-Cabello F. Expression of HLA class I and II antigens in bronchogenic carcinomas: its relationship to cellular DNA content and clinical-pathological parameters. Cancer Res. 1991;51:4948–54.

    CAS  PubMed  Google Scholar 

  10. Bronte V, Mocellin S. Suppressive influences in the immune response to cancer. J Immunother. 2009;32:1–11.

    PubMed  Google Scholar 

  11. Smyth MJ, Dunn GP, Schreiber RD. Cancer immunosurveillance and immunoediting: the roles of immunity in suppressing tumor development and shaping tumor immunogenicity. Adv Immunol. 2006;90:1–50.

    CAS  PubMed  Google Scholar 

  12. Brunet JF, Denizot F, Luciani MF, Roux-Dosseto M, Suzan M, Mattei MG, Golstein P. A new member of the immunoglobulin superfamily – CTLA-4. Nature. 1987;328:267–70.

    CAS  PubMed  Google Scholar 

  13. Mocellin S, Benna C, Pilati P. Coinhibitory molecules in cancer biology and therapy. Cytokine Growth Factor Rev. 2013;24:1–15.

    Google Scholar 

  14. Waterhouse P, Penninger JM, Timms E, Wakeham A, Shahinian A, Lee KP, et al. Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science. 1995;270:985–8.

    CAS  PubMed  Google Scholar 

  15. Diehn M, Alizadeh AA, Rando OJ, Liu CL, Stankunas K, Botstein D, et al. Genomic expression programs and the integration of the CD28 costimulatory signal in T cell activation. Proc Natl Acad Sci U S A. 2002;99:11796–801.

    CAS  PubMed Central  PubMed  Google Scholar 

  16. Walker LSK, Sansom DM. The emerging role of CTLA4 as a cell-extrinsic regulator of T cell responses. Nat Rev Immunol. 2011;11:852–63.

    CAS  PubMed  Google Scholar 

  17. Sansom DM, Walker LSK. The role of CD28 and cytotoxic T-lymphocyte antigen-4 (CTLA-4) in regulatory T-cell biology. Immunol Rev. 2006;212:131–48.

    CAS  PubMed  Google Scholar 

  18. Grosso JF, Jure-Kunkel MN. CTLA-4 blockade in tumor models: an overview of preclinical and translational research. Cancer Immun. 2013;13:5.

    PubMed Central  PubMed  Google Scholar 

  19. Collins AV, Brodie DW, Gilbert RJC, Iaboni A, Manso-Sancho R, Walse B, et al. The interaction properties of costimulatory molecules revisited. Immunity. 2002;17:201–10.

    CAS  PubMed  Google Scholar 

  20. Thompson CB, Allison JP. The emerging role of CTLA-4 as an immune attenuator. Immunity. 1997;7:445–50.

    CAS  PubMed  Google Scholar 

  21. Doyle AM, Mullen AC, Villarino AV, Hutchins AS, High FA, Lee HW, et al. Induction of cytotoxic T lymphocyte antigen 4 (CTLA-4) restricts clonal expansion of helper T cells. J Exp Med. 2001;194:893–902.

    CAS  PubMed Central  PubMed  Google Scholar 

  22. Tivol EA, Boyd SD, McKeon S, Borriello F, Nickerson P, Strom TB, et al. CTLA4Ig prevents lymphoproliferation and fatal multiorgan tissue destruction in CTLA-4-deficient mice. J Immunol. 1997;158:5091–4.

    CAS  PubMed  Google Scholar 

  23. Mandelbrot DA, McAdam AJ, Sharpe AH. B7-1 or B7-2 is required to produce the lymphoproliferative phenotype in mice lacking cytotoxic T lymphocyte-associated antigen 4 (CTLA-4). J Exp Med. 1999;189:435–40.

    CAS  PubMed Central  PubMed  Google Scholar 

  24. Peggs KS, Quezada SA, Allison JP. Cell intrinsic mechanisms of T-cell inhibition and application to cancer therapy. Immunol Rev. 2008;224:141–65.

    CAS  PubMed  Google Scholar 

  25. Khan S, Burt DJ, Ralph C, Thistlethwaite FC, Hawkins RE, Elkord E. Tremelimumab (anti-CTLA4) mediates immune responses mainly by direct activation of T effector cells rather than by affecting T regulatory cells. Clin Immunol. 2011;138:85–96.

    CAS  PubMed  Google Scholar 

  26. Selby MJ, Engelhardt JJ, Quigley M, Henning KA, Chen T, Srinivasan M, Korman AJ. Anti-CTLA-4 antibodies of IgG2a isotype enhance antitumor activity through reduction of intratumoral regulatory T cells. Cancer Immunol Res. 2013.

    Google Scholar 

  27. Wing K, Onishi Y, Prieto-Martin P, Yamaguchi T, Miyara M, Fehervari Z, et al. CTLA-4 control over Foxp3+ regulatory T cell function. Science. 2008;322:271–5.

    CAS  PubMed  Google Scholar 

  28. Tang AL, Teijaro JR, Njau MN, Chandran SS, Azimzadeh A, Nadler SG, et al. CTLA4 expression is an indicator and regulator of steady-state CD4+ FoxP3+ T cell homeostasis. J Immunol. 2008;181:1806–13.

    CAS  PubMed Central  PubMed  Google Scholar 

  29. Quezada SA, Peggs KS, Curran MA, Allison JP. CTLA4 blockade and GM-CSF combination immunotherapy alters the intratumor balance of effector and regulatory T cells. J Clin Invest. 2006;116:1935–45.

    CAS  PubMed Central  PubMed  Google Scholar 

  30. Kavanagh B, O’Brien S, Lee D, Hou Y, Weinberg V, Rini B, et al. CTLA4 blockade expands FoxP3+ regulatory and activated effector CD4+ T cells in a dose-dependent fashion. Blood. 2008;112:1175–83.

    CAS  PubMed Central  PubMed  Google Scholar 

  31. Riella LV, Liu T, Yang J, Chock S, Shimizu T, Mfarrej B, Batal I, Xiao X, Sayegh MH, Chandraker A. Deleterious effect of CTLA4-Ig on a treg-dependent transplant model. Am J Transplant. 2012;12:846–55.

    CAS  PubMed  Google Scholar 

  32. Ueda H, Howson JMM, Esposito L, et al. Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature. 2003;423:506–11.

    CAS  PubMed  Google Scholar 

  33. Awata T, Kurihara S, Iitaka M, et al. Association of CTLA-4 gene a-G polymorphism (IDDM12 locus) with acute-onset and insulin-depleted IDDM as well as autoimmune thyroid disease (graves “disease and Hashimotos” thyroiditis) in the Japanese population. Diabetes. 1998;47:128–9.

    CAS  PubMed  Google Scholar 

  34. Araki M, Chung D, Liu S, et al. Genetic evidence that the differential expression of the ligand-independent isoform of CTLA-4 is the molecular basis of the Idd5.1 type 1 diabetes region in nonobese diabetic mice. J Immunol. 2009;183:5146–57.

    CAS  PubMed Central  PubMed  Google Scholar 

  35. Marron MP, Zeidler A, Raffel LJ, et al. Genetic and physical mapping of a type 1 diabetes susceptibility gene (IDDM12) to a 100-kb phagemid artificial chromosome clone containing D2S72-CTLA4-D2S105 on chromosome 2q33. Diabetes. 2000;49:492–9.

    CAS  PubMed  Google Scholar 

  36. Lenschow DJ, Zeng Y, Thistlethwaite JR, Montag A, Brady W, Gibson MG, et al. Long-term survival of xenogeneic pancreatic islet grafts induced by CTLA4lg. Science. 1992;257:789–92.

    CAS  PubMed  Google Scholar 

  37. Turka LA, Linsley PS, Lin H, Brady W, Leiden JM, Wei RQ, et al. T-cell activation by the CD28 ligand B7 is required for cardiac allograft rejection in vivo. Proc Natl Acad Sci U S A. 1992;89:11102–5.

    CAS  PubMed Central  PubMed  Google Scholar 

  38. Linsley PS, Brady W, Urnes M, Grosmaire LS, Damle NK, Ledbetter JA. CTLA-4 is a second receptor for the B cell activation antigen B7. J Exp Med. 1991;174:561–9.

    CAS  PubMed  Google Scholar 

  39. Lenschow DJ, Su GH, Zuckerman LA, Nabavi N, Jellis CL, Gray GS, et al. Expression and functional significance of an additional ligand for CTLA-4. Proc Natl Acad Sci U S A. 1993;90:11054–8.

    CAS  PubMed Central  PubMed  Google Scholar 

  40. Lin H, Bolling SF, Linsley PS, Wei RQ, Gordon D, Thompson CB, Turka LA. Long-term acceptance of major histocompatibility complex mismatched cardiac allografts induced by CTLA4Ig plus donor-specific transfusion. J Exp Med. 1993;178:1801–6.

    CAS  PubMed  Google Scholar 

  41. Cross AH, Girard TJ, Giacoletto KS, Evans RJ, Keeling RM, Lin RF, Trotter JL, Karr RW. Long-term inhibition of murine experimental autoimmune encephalomyelitis using CTLA-4-Fc supports a key role for CD28 costimulation. J Clin Invest. 1995;95:2783–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  42. Chen L, Ashe S, Brady WA, Hellström I, Hellström KE, Ledbetter JA, et al. Costimulation of antitumor immunity by the B7 counterreceptor for the T lymphocyte molecules CD28 and CTLA-4. Cell. 1992;71:1093–02.

    CAS  PubMed  Google Scholar 

  43. Hoos A, Ibrahim R, Korman A, Abdallah K, Berman D, Shahabi V, Chin K, Canetta R, Humphrey R. Development of ipilimumab: contribution to a new paradigm for cancer immunotherapy. Semin Oncol. 2010;37:533–46. YSONC.

    CAS  PubMed  Google Scholar 

  44. Vincenti F, Larsen C, Durrbach A, et al. Costimulation blockade with belatacept in renal transplantation. N Engl J Med. 2005;353:770–81.

    CAS  PubMed  Google Scholar 

  45. Genovese MC, Becker J-C, Schiff M, et al. Abatacept for rheumatoid arthritis refractory to tumor necrosis factor alpha inhibition. N Engl J Med. 2005;353:1114–23.

    CAS  PubMed  Google Scholar 

  46. Walunas TL, Lenschow DJ, Bakker CY, Linsley PS, Freeman GJ, Green JM, Thompson CB, Bluestone JA. CTLA-4 can function as a negative regulator of T cell activation. Immunity. 1994;1:405–13.

    CAS  PubMed  Google Scholar 

  47. Kearney ER, Walunas TL, Karr RW, Morton PA, Loh DY, Bluestone JA, et al. Antigen-dependent clonal expansion of a trace population of antigen-specific CD4+ T cells in vivo is dependent on CD28 costimulation and inhibited by CTLA-4. J Immunol. 1995;155:1032–6.

    CAS  PubMed  Google Scholar 

  48. Leach DR, Krummel MF, Allison JP. Enhancement of antitumor immunity by CTLA-4 blockade. Science. 1996;271:1734–6.

    CAS  PubMed  Google Scholar 

  49. Yang YF, Zou JP, Mu J, Wijesuriya R, Ono S, Walunas T, Bluestone J, Fujiwara H, Hamaoka T. Enhanced induction of antitumor T-cell responses by cytotoxic T lymphocyte-associated molecule-4 blockade: the effect is manifested only at the restricted tumor-bearing stages. Cancer Res. 1997;57:4036–41.

    CAS  PubMed  Google Scholar 

  50. Fecci PE, Ochiai H, Mitchell DA, Grossi PM, Sweeney AE, Archer GE, et al. Systemic CTLA-4 blockade ameliorates glioma-induced changes to the CD4+ T cell compartment without affecting regulatory T-cell function. Clin Cancer Res. 2007;13:2158–67.

    CAS  PubMed  Google Scholar 

  51. Grauer OM, Grauer OM, Nierkens S, et al. CD4+FoxP3+ regulatory T cells gradually accumulate in gliomas during tumor growth and efficiently suppress antiglioma immune responses in vivo. Int J Cancer. 2007;121:95–05.

    CAS  PubMed  Google Scholar 

  52. Espenschied J, Lamont J, Longmate J, Pendas S, Wang Z, Diamond DJ, et al. CTLA-4 blockade enhances the therapeutic effect of an attenuated poxvirus vaccine targeting p53 in an established murine tumor model. J Immunol. 2003;170:3401–7.

    CAS  PubMed  Google Scholar 

  53. Kwon ED, Hurwitz AA, Foster BA, Madias C, Feldhaus AL, Greenberg NM, Burg MB, Allison JP. Manipulation of T cell costimulatory and inhibitory signals for immunotherapy of prostate cancer. Proc Natl Acad Sci U S A. 1997;94:8099–03.

    CAS  PubMed Central  PubMed  Google Scholar 

  54. Pedersen AE, Buus S, Claesson MH. Treatment of transplanted CT26 tumour with dendritic cell vaccine in combination with blockade of vascular endothelial growth factor receptor 2 and CTLA-4. Cancer Lett. 2006;235:229–38.

    CAS  PubMed  Google Scholar 

  55. Dewan MZ, Galloway AE, Kawashima N, Dewyngaert JK, Babb JS, Formenti SC, et al. Fractionated but not single-dose radiotherapy induces an immune-mediated abscopal effect when combined with anti-CTLA-4 antibody. Clin Cancer Res. 2009;15:5379–88.

    CAS  PubMed Central  PubMed  Google Scholar 

  56. Pilones KA, Kawashima N, Yang AM, Babb JS, Formenti SC, Demaria S. Invariant natural killer T cells regulate breast cancer response to radiation and CTLA-4 blockade. Clin Cancer Res. 2009;15(2):597–606.

    CAS  PubMed Central  PubMed  Google Scholar 

  57. Demaria S, Kawashima N, Yang AM, Devitt ML, Babb JS, Allison JP, et al. Immune-mediated inhibition of metastases after treatment with local radiation and CTLA-4 blockade in a mouse model of breast cancer. Clin Cancer Res. 2005;11:728–34.

    CAS  PubMed  Google Scholar 

  58. Takeda K, Kojima Y, Uno T, Hayakawa Y, Teng MWL, Yoshizawa H, et al. Combination therapy of established tumors by antibodies targeting immune activating and suppressing molecules. J Immunol. 2010;184:5493–01.

    CAS  PubMed  Google Scholar 

  59. Hurwitz AA, Yu TF, Leach DR, Allison JP. CTLA-4 blockade synergizes with tumor-derived granulocyte-macrophage colony-stimulating factor for treatment of an experimental mammary carcinoma. Proc Natl Acad Sci U S A. 1998;95:10067–71.

    CAS  PubMed Central  PubMed  Google Scholar 

  60. Saha A, Chatterjee SK. Combination of CTL-associated antigen-4 blockade and depletion of CD25 regulatory T cells enhance tumour immunity of dendritic cell-based vaccine in a mouse model of colon cancer. Scand J Immunol. 2010;71:70–82.

    CAS  PubMed  Google Scholar 

  61. Met Ö, Wang M, Pedersen AE, Nissen MH, Buus S, Claesson MH. The effect of a therapeutic dendritic cell-based cancer vaccination depends on the blockage of CTLA-4 signaling. Cancer Lett. 2006;231:247–56.

    CAS  PubMed  Google Scholar 

  62. Waitz R, Solomon SB, Petre EN, Trumble AE, Fassò M, Norton L, Allison JP. Potent induction of tumor immunity by combining tumor cryoablation with anti-CTLA-4 therapy. Cancer Res. 2012;72:430–9.

    CAS  PubMed  Google Scholar 

  63. Sorensen MR, Holst PJ, Steffensen MA, Christensen JP, Thomsen AR. Adenoviral vaccination combined with CD40 stimulation and CTLA-4 blockage can lead to complete tumor regression in a murine melanoma model. Vaccine. 2010;28:6757–64.

    CAS  PubMed  Google Scholar 

  64. Mokyr MB, Kalinichenko T, Gorelik L, Bluestone JA. Realization of the therapeutic potential of CTLA-4 blockade in low-dose chemotherapy-treated tumor-bearing mice. Cancer Res. 1998;58:5301–4.

    CAS  PubMed  Google Scholar 

  65. Fishwild DM, O’Donnell SL, Bengoechea T, et al. High-avidity human IgG kappa monoclonal antibodies from a novel strain of minilocus transgenic mice. Nat Biotechnol. 1996;14:845–51.

    CAS  PubMed  Google Scholar 

  66. Keler T, Halk E, Vitale L, et al. Activity and safety of CTLA-4 blockade combined with vaccines in cynomolgus macaques. J Immunol. 2003;171:6251–9.

    CAS  PubMed  Google Scholar 

  67. Morse MA. Technology evaluation: ipilimumab, Medarex/Bristol-Myers Squibb. Curr Opin Mol Ther. 2005;7:588–97.

    CAS  PubMed  Google Scholar 

  68. Hodi FS, Mihm MC, Soiffer RJ, et al. Biologic activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade in previously vaccinated metastatic melanoma and ovarian carcinoma patients. Proc Natl Acad Sci U S A. 2003;100:4712–7.

    CAS  PubMed Central  PubMed  Google Scholar 

  69. O’mahony D, Morris JC, Quinn C, et al. A pilot study of CTLA-4 blockade after cancer vaccine failure in patients with advanced malignancy. Clin Cancer Res. 2007;13:958–64.

    PubMed  Google Scholar 

  70. Weber JS, O’Day S, Urba W, Powderly J, Nichol G, Yellin M, et al. Phase I/II study of ipilimumab for patients with metastatic melanoma. J Clin Oncol. 2008;26:5950–6.

    CAS  PubMed  Google Scholar 

  71. Downey SG, Klapper JA, Smith FO, et al. Prognostic factors related to clinical response in patients with metastatic melanoma treated by CTL-associated antigen-4 blockade. Clin Cancer Res. 2007;13:6681–8.

    CAS  PubMed Central  PubMed  Google Scholar 

  72. O’Day SJ, Maio M, Chiarion-Sileni V, et al. Efficacy and safety of ipilimumab monotherapy in patients with pretreated advanced melanoma: a multicenter single-arm phase II study. Ann Oncol. 2010;21:1712–7.

    PubMed  Google Scholar 

  73. Wolchok JD, Neyns B, Linette G, et al. Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. Lancet Oncol. 2010;11:155–64.

    CAS  PubMed  Google Scholar 

  74. Weber J, Thompson JA, Hamid O, et al. A randomized, double-blind, placebo-controlled, phase II study comparing the tolerability and efficacy of ipilimumab administered with or without prophylactic budesonide in patients with unresectable stage III or IV melanoma. Clin Cancer Res. 2009;15:5591–8.

    CAS  PubMed  Google Scholar 

  75. Thompson JA, Hamid O, Minor D, Amin A, Ron IG, Ridolfi R, et al. Ipilimumab in treatment-naive and previously treated patients with metastatic melanoma: retrospective analysis of efficacy and safety data from a phase II trial. J Immunother. 2013;35:73–7.

    Google Scholar 

  76. Margolin K, Ernstoff MS, Hamid O, et al. Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. Lancet Oncol. 2012;13:459–65.

    CAS  PubMed  Google Scholar 

  77. Rosenberg SA, Yang JC, Schwartzentruber DJ, et al. Immunologic and therapeutic evaluation of a synthetic peptide vaccine for the treatment of patients with metastatic melanoma. Nat Med. 1998;4:321–7.

    CAS  PubMed Central  PubMed  Google Scholar 

  78. Attia P, Phan GQ, Maker AV, et al. Autoimmunity correlates with tumor regression in patients with metastatic melanoma treated with anti-cytotoxic T-lymphocyte antigen-4. J Clin Oncol. 2005;23:6043–53.

    CAS  PubMed Central  PubMed  Google Scholar 

  79. Phan GQ, Yang JC, Sherry RM, et al. 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. 2003;100:8372–7.

    CAS  PubMed Central  PubMed  Google Scholar 

  80. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711–23.

    CAS  PubMed Central  PubMed  Google Scholar 

  81. Robert C, Schadendorf D, Messina M, Hodi FS, O’Day S, MDX010-20 Investigators. Efficacy and safety of retreatment with ipilimumab in patients with pretreated advanced melanoma who progressed after initially achieving disease control. Clin Cancer Res. 2013;19:2232–9.

    CAS  PubMed  Google Scholar 

  82. Agarwala SS. Current systemic therapy for metastatic melanoma. Expert Rev Anticancer Ther. 2009;9:587–95.

    CAS  PubMed  Google Scholar 

  83. Margolin KA, Di Giacomo AM, Maio M. Brain metastasis in melanoma: clinical activity of CTLA-4 antibody therapy. Semin Oncol. 2010;37:468–72. YSONC.

    CAS  PubMed  Google Scholar 

  84. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364:2507–16.

    CAS  PubMed Central  PubMed  Google Scholar 

  85. Shahabi V, Whitney G, Hamid O, Schmidt H, Chasalow SD, Alaparthy S. Assessment of association between BRAF-V600E mutation status in melanomas and clinical response to ipilimumab. Cancer Immunol Immunother. 2012;61:733–7.

    CAS  PubMed  Google Scholar 

  86. Callahan MK, Postow MA, Wolchok JD. Immunomodulatory therapy for melanoma: ipilimumab and beyond. Clin Dermatol. 2013;31:191–9.

    PubMed Central  PubMed  Google Scholar 

  87. Ribas A, Camacho LH, Lopez-Berestein G, et al. Antitumor activity in melanoma and anti-self responses in a phase I trial with the anti-cytotoxic T lymphocyte-associated antigen 4 monoclonal antibody CP-675,206. J Clin Oncol. 2005;23:8968–77.

    CAS  PubMed  Google Scholar 

  88. Camacho LH, Antonia S, Sosman J, et al. Phase I/II trial of tremelimumab in patients with metastatic melanoma. J Clin Oncol. 2009;27:1075–81.

    CAS  PubMed  Google Scholar 

  89. Kirkwood JM, Lorigan P, Hersey P, Hauschild A, Robert C, McDermott D, et al. Phase II trial of tremelimumab (CP-675,206) in patients with advanced refractory or relapsed melanoma. Clin Cancer Res. 2010;16:1042–8.

    CAS  PubMed  Google Scholar 

  90. Ribas A. Clinical development of the anti–CTLA-4 antibody tremelimumab. Semin Oncol. 2010;37:450–4. YSONC.

    CAS  PubMed  Google Scholar 

  91. Ribas A, Kefford R, Marshall MA, et al. Phase III randomized clinical trial comparing tremelimumab with standard-of-care chemotherapy in patients with advanced melanoma. J Clin Oncol. 2013;31(5):616–22.

    CAS  PubMed  Google Scholar 

  92. Weber JS, Kähler KC, Hauschild A. Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol. 2012;30:2691–7.

    CAS  PubMed  Google Scholar 

  93. Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011;364:2517–26.

    CAS  PubMed  Google Scholar 

  94. Corsello SM, Barnabei A, Marchetti P, De Vecchis L, Salvatori R, Torino F. Endocrine side effects induced by immune checkpoint inhibitors. J Clin Endocrinol Metab. 2013;98(4):1361–75.

    CAS  PubMed  Google Scholar 

  95. Coit DG, Andtbacka R, Anker CJ, et al. Melanoma, version 2.2013: featured updates to the NCCN guidelines. J Natl Compr Canc Netw. 2013;11:395–407.

    CAS  PubMed  Google Scholar 

  96. van den Eertwegh AJM, Versluis J, van den Berg HP, et al. Combined immunotherapy with granulocyte-macrophage colony-stimulating factor-transduced allogeneic prostate cancer cells and ipilimumab in patients with metastatic castration-resistant prostate cancer: a phase 1 dose-escalation trial. Lancet Oncol. 2012;13:509–17.

    PubMed  Google Scholar 

  97. Yang JC, Hughes M, Kammula U, et al. Ipilimumab (anti-CTLA4 antibody) causes regression of metastatic renal cell cancer associated with enteritis and hypophysitis. J Immunother. 2007;30:825–30.

    CAS  PubMed Central  PubMed  Google Scholar 

  98. Maker AV, Yang JC, Sherry RM, et al. Intrapatient dose escalation of anti-CTLA-4 antibody in patients with metastatic melanoma. J Immunother. 2006;29:455–63.

    CAS  PubMed Central  PubMed  Google Scholar 

  99. Sanderson K, Scotland R, Lee P, et al. Autoimmunity in a phase I trial of a fully human anti-cytotoxic T-lymphocyte antigen-4 monoclonal antibody with multiple melanoma peptides and Montanide ISA 51 for patients with resected stages III and IV melanoma. J Clin Oncol. 2005;23:741–50.

    CAS  PubMed  Google Scholar 

  100. Oxnard GR, Morris MJ, Hodi FS, Baker LH, Kris MG, Venook AP, et al. When progressive disease does not mean treatment failure: reconsidering the criteria for progression. J Natl Cancer Inst. 2012;104:1534–41.

    PubMed Central  PubMed  Google Scholar 

  101. Wolchok JD, Hoos A, O’Day S, et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res. 2009;15:7412–20.

    CAS  PubMed  Google Scholar 

  102. Lynch TJ, Bondarenko I, Luft A, et al. Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non-small-cell lung cancer: results from a randomized, double-blind, multicenter phase II study. J Clin Oncol. 2012;30:2046–54.

    CAS  PubMed  Google Scholar 

  103. Zikich D, Schachter J, Besser MJ. Immunotherapy for the management of advanced melanoma: the next steps. Am J Clin Dermatol. 2013;14(4):261–72.

    PubMed  Google Scholar 

  104. Yonekawa Y, Kim IK. Epidemiology and management of uveal melanoma. Hematol Oncol Clin North Am. 2012;26:1169–84.

    PubMed  Google Scholar 

  105. Danielli R, Queirolo P, Testori A, Plummer R, Razis E, Sileni VC, Calabro L, Giacomo AM, Ridolfi R, Maio M. Ipilimumab in pretreated metastatic uveal melanoma patients: safety and clinical efficacy. Ann Oncol. 2009;20:viii70–8.

    Google Scholar 

  106. Small EJ, Tchekmedyian NS, Rini BI, Fong L, Lowy I, Allison JP. A pilot trial of CTLA-4 blockade with human anti-CTLA-4 in patients with hormone-refractory prostate cancer. Clin Cancer Res. 2007;13:1810–5.

    CAS  PubMed  Google Scholar 

  107. McNeel DG, Smith HA, Eickhoff JC, Lang JM, Staab MJ, Wilding G, Liu G. Phase I trial of tremelimumab in combination with short-term androgen deprivation in patients with PSA-recurrent prostate cancer. Cancer Immunol Immunother. 2012;61:1137–47.

    CAS  PubMed Central  PubMed  Google Scholar 

  108. Home – ClinicalTrials.gov. In: clinicaltrials.gov. http://www.clinicaltrials.gov. Accessed 20 Apr 2013.

  109. Small EJ, Higano CS, Tchekmedyian NS, Sartor O, Stein B, Young R, et al. Randomized phase II study comparing 4 monthly doses of ipilimumab (MDX-010) as a single agent or incombination with a single dose of docetaxel in patients with hormone-refractory prostate cancer. J Clin Oncol. 2006;24:4609.

    Google Scholar 

  110. Slovin SF, Higano CS, Hamid O, et al. Ipilimumab alone or in combination with radiotherapy in metastatic castration-resistant prostate cancer: results from an open-label, multicenter phase I/II study. Ann Oncol. 2013;24(7):1813–21.

    CAS  PubMed Central  PubMed  Google Scholar 

  111. Kwek SS, Cha E, Fong L. Unmasking the immune recognition of prostate cancer with CTLA4 blockade. Nat Rev Cancer. 2012;12:289–97.

    CAS  PubMed Central  PubMed  Google Scholar 

  112. Aragon-Ching JB, Williams KM, Gulley JL. Impact of androgen-deprivation therapy on the immune system: implications for combination therapy of prostate cancer. Front Biosci. 2007;12:4957–71.

    CAS  PubMed  Google Scholar 

  113. Tollefson MK, Karnes RJ, Thompson RH, Granberg CF, Hillman DW, Breau RH, et al. A randomized phase II study of ipilimumab with androgen ablation compared with androgen ablation alone in patients with advanced prostate cancer. Abstract 168. Presented at 2010 genitourinary cancers symposium, San Francisco; 5–7 Mar 2010.

    Google Scholar 

  114. Vonderheide RH, LoRusso PM, Khalil M, et al. Tremelimumab in combination with exemestane in patients with advanced breast cancer and treatment-associated modulation of inducible costimulator expression on patient T cells. Clin Cancer Res. 2010;16:3485–94.

    CAS  PubMed  Google Scholar 

  115. Ralph C, Elkord E, Burt DJ, O’Dwyer JF, Austin EB, Stern PL, et al. Modulation of lymphocyte regulation for cancer therapy: a phase II trial of tremelimumab in advanced gastric and esophageal adenocarcinoma. Clin Cancer Res. 2010;16:1662–72.

    CAS  PubMed  Google Scholar 

  116. Royal RE, Levy C, Turner K, et al. Phase 2 trial of single agent ipilimumab (anti-CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma. J Immunother. 2010;33:828–33.

    CAS  PubMed  Google Scholar 

  117. Chung KY, Gore I, Fong L, et al. Phase II study of the anti-cytotoxic T-lymphocyte-associated antigen 4 monoclonal antibody, tremelimumab, in patients with refractory metastatic colorectal cancer. J Clin Oncol. 2010;28:3485–90.

    CAS  PubMed  Google Scholar 

  118. Oquiñena S, Iñarrairaegui M, Vila JJ, Alegre F, Zozaya JM, Sangro B. Spontaneous regression of hepatocellular carcinoma: three case reports and a categorized review of the literature. Dig Dis Sci. 2009;54:1147–53.

    PubMed  Google Scholar 

  119. Sangro B, Gomez-Martin C, la Mata de M, et al. A clinical trial of CTLA-4 blockade with tremelimumab in patients with hepatocellular carcinoma and chronic hepatitis C. J Hepatol. 2013;59(1):81–8.

    CAS  PubMed  Google Scholar 

  120. Calabrò L, Danielli R, Sigalotti L, Maio M. Clinical studies with anti–CTLA-4 antibodies in non-melanoma indications. Semin Oncol. 2010;37:460–7. YSONC.

    PubMed  Google Scholar 

  121. Carthon BC, Wolchok JD, Yuan J, et al. Preoperative CTLA-4 blockade: tolerability and immune monitoring in the setting of a presurgical clinical trial. Clin Cancer Res. 2010;16:2861–71.

    CAS  PubMed Central  PubMed  Google Scholar 

  122. Ansell SM, Hurvitz SA, Koenig PA, et al. Phase I study of ipilimumab, an anti-CTLA-4 monoclonal antibody, in patients with relapsed and refractory B-cell non-Hodgkin lymphoma. Clin Cancer Res. 2009;15:6446–53.

    CAS  PubMed Central  PubMed  Google Scholar 

  123. Zitvogel L, Apetoh L, Ghiringhelli F, André F, Tesniere A, Kroemer G. The anticancer immune response: indispensable for therapeutic success? J Clin Invest. 2008;118:1991–2001.

    CAS  PubMed Central  PubMed  Google Scholar 

  124. Zielinski C, Knapp S, Mascaux C, Hirsch F. Rationale for targeting the immune system through checkpoint molecule blockade in the treatment of non-small-cell lung cancer. Ann Oncol. 2013;24(5):1170–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  125. Wu L, Yun Z, Tagawa T, Rey-McIntyre K, de Perrot M. CTLA-4 blockade expands infiltrating T cells and inhibits cancer cell repopulation during the intervals of chemotherapy in murine mesothelioma. Mol Cancer Ther. 2012;11:1809–19.

    CAS  PubMed  Google Scholar 

  126. Lee F, Jure-Kunkel MN, Salvati ME. Synergistic activity of ixabepilone plus other anticancer agents: preclinical and clinical evidence. Ther Adv Med Oncol. 2011;3:11–25.

    CAS  PubMed Central  PubMed  Google Scholar 

  127. Kang TH, Mao C-P, Lee SY, et al. Chemotherapy acts as an adjuvant to convert the tumor microenvironment into a highly permissive state for vaccination-induced antitumor immunity. Cancer Res. 2013;73:2493–04.

    CAS  PubMed Central  PubMed  Google Scholar 

  128. Liu WM, Dalgleish AG. The potential beneficial effects of drugs on the immune response to vaccination. Semin Oncol. 2012;39:340–7.

    CAS  PubMed  Google Scholar 

  129. Correale P, Del Vecchio MT, La Placa M, et al. Chemotherapeutic drugs may be used to enhance the killing efficacy of human tumor antigen peptide-specific CTLs. J Immunother. 2008;31:132–47.

    CAS  PubMed  Google Scholar 

  130. Kroemer G, Galluzzi L, Kepp O, Zitvogel L. Immunogenic cell death in cancer therapy. Annu Rev Immunol. 2013;31:51–72.

    CAS  PubMed  Google Scholar 

  131. Hersh EM, O’Day SJ, Powderly J, Khan KD, Pavlick AC, Cranmer LD, et al. A phase II multicenter study of ipilimumab with or without dacarbazine in chemotherapy-naïve patients with advanced melanoma. Invest New Drugs. 2011;29:489–98.

    CAS  PubMed  Google Scholar 

  132. Hoos A, Eggermont AMM, Janetzki S, Hodi FS, Ibrahim R, Anderson A, Humphrey R, Blumenstein B, Old L, Wolchok J. Improved endpoints for cancer immunotherapy trials. J Natl Cancer Inst. 2010;102:1388–97.

    CAS  PubMed Central  PubMed  Google Scholar 

  133. Ribas A, Hodi FS, Callahan M, Konto C, Wolchok J. Hepatotoxicity with combination of vemurafenib and ipilimumab. N Engl J Med. 2013;368:1365–6.

    CAS  PubMed  Google Scholar 

  134. Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med. 2002;346:92–8.

    CAS  PubMed  Google Scholar 

  135. Oze I, Hotta K, Kiura K, Ochi N, Takigawa N, Fujiwara Y, et al. Twenty-seven years of phase III trials for patients with extensive disease small-cell lung cancer: disappointing results. PLoS One. 2009;4:e7835.

    PubMed Central  PubMed  Google Scholar 

  136. Rini BI, Stein M, Shannon P, Eddy S, Tyler A, Stephenson JJ, Catlett L, Huang B, Healey D, Gordon M. Phase 1 dose-escalation trial of tremelimumab plus sunitinib in patients with metastatic renal cell carcinoma. Cancer. 2011;117:758–67.

    CAS  PubMed  Google Scholar 

  137. Drake CG. Combination immunotherapy approaches. Ann Oncol. 2012;23 Suppl 8:viii41–6.

    PubMed  Google Scholar 

  138. Chakraborty M, Abrams SI, Camphausen K, Liu K, Scott T, Coleman CN, et al. Irradiation of tumor cells up-regulates Fas and enhances CTL lytic activity and CTL adoptive immunotherapy. J Immunol. 2003;170:6338–47.

    CAS  PubMed  Google Scholar 

  139. Chakraborty M, Abrams SI, Coleman CN, Camphausen K, Schlom J, Hodge JW. External beam radiation of tumors alters phenotype of tumor cells to render them susceptible to vaccine-mediated T-cell killing. Cancer Res. 2004;64:4328–37.

    CAS  PubMed  Google Scholar 

  140. Reits EA, Hodge JW, Herberts CA, et al. Radiation modulates the peptide repertoire, enhances MHC class I expression, and induces successful antitumor immunotherapy. J Exp Med. 2006;203:1259–71.

    CAS  PubMed Central  PubMed  Google Scholar 

  141. Demaria S, Bhardwaj N, McBride WH, Formenti SC. Combining radiotherapy and immunotherapy: a revived partnership. Int J Radiat Oncol Biol Phys. 2005;63:655–66.

    PubMed Central  PubMed  Google Scholar 

  142. Kingsley DP. An interesting case of possible abscopal effect in malignant melanoma. Br J Radiol. 1975;48:863–6.

    CAS  PubMed  Google Scholar 

  143. Wersäll PJ, Blomgren H, Pisa P, Lax I, Kälkner K-M, Svedman C. Regression of non-irradiated metastases after extracranial stereotactic radiotherapy in metastatic renal cell carcinoma. Acta Oncol. 2006;45:493–7.

    PubMed  Google Scholar 

  144. Robin HI, AuBuchon J, Varanasi VR, Weinstein AB. The abscopal effect: demonstration in lymphomatous involvement of kidneys. Med Pediatr Oncol. 1981;9:473–6.

    CAS  PubMed  Google Scholar 

  145. Postow MA, Callahan MK, Barker CA, et al. Immunologic correlates of the abscopal effect in a patient with melanoma. N Engl J Med. 2012;366:925–31.

    CAS  PubMed Central  PubMed  Google Scholar 

  146. Hiniker SM, Chen DS, Knox SJ. Abscopal effect in a patient with melanoma. N Engl J Med. 2012;366:2035; author reply 2035–6.

    CAS  PubMed  Google Scholar 

  147. Ishida Y, Agata Y, Shibahara K, Honjo T. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J. 1992;11:3887–95.

    CAS  PubMed Central  PubMed  Google Scholar 

  148. Nishimura H, Nose M, Hiai H, Minato N, Honjo T. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity. 1999;11:141–51.

    CAS  PubMed  Google Scholar 

  149. Okazaki T, Honjo T. PD-1 and PD-1 ligands: from discovery to clinical application. Int Immunol. 2007;19:813–24.

    CAS  PubMed  Google Scholar 

  150. Weber J. Immune checkpoint proteins: a new therapeutic paradigm for cancer—preclinical background: CTLA-4 and PD-1 blockade. Semin Oncol. 2010;37:430–9. YSONC.

    CAS  PubMed  Google Scholar 

  151. Terme M, Ullrich E, Aymeric L, et al. IL-18 induces PD-1-dependent immunosuppression in cancer. Cancer Res. 2011;71:5393–9.

    CAS  PubMed  Google Scholar 

  152. Fanoni D, Tavecchio S, Recalcati S, Balice Y, Venegoni L, Fiorani R, et al. New monoclonal antibodies against B-cell antigens: possible new strategies for diagnosis of primary cutaneous B-cell lymphomas. Immunol Lett. 2011;134:157–60.

    CAS  PubMed  Google Scholar 

  153. Nishimura H, Agata Y, Kawasaki A, Sato M, Imamura S, Minato N, Yagita H, et al. Developmentally regulated expression of the PD-1 protein on the surface of double-negative (CD4-CD8-) thymocytes. Int Immunol. 1996;8:773–80.

    CAS  PubMed  Google Scholar 

  154. Pentcheva-Hoang T, Chen L, Pardoll DM, Allison JP. Programmed death-1 concentration at the immunological synapse is determined by ligand affinity and availability. Proc Natl Acad Sci U S A. 2007;104:17765–70.

    CAS  PubMed Central  PubMed  Google Scholar 

  155. Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol. 2008;26:677–704.

    CAS  PubMed  Google Scholar 

  156. Petroff MG, Chen L, Phillips TA, Azzola D, Sedlmayr P, Hunt JS. B7 family molecules are favorably positioned at the human maternal-fetal interface. Biol Reprod. 2003;68:1496–04.

    CAS  PubMed  Google Scholar 

  157. Guleria I, Khosroshahi A, Ansari MJ, et al. A critical role for the programmed death ligand 1 in fetomaternal tolerance. J Exp Med. 2005;202:231–7.

    CAS  PubMed Central  PubMed  Google Scholar 

  158. Wilke CM, Wei S, Wang L, Kryczek I, Kao J, Zou W. Dual biological effects of the cytokines interleukin-10 and interferon-γ. Cancer Immunol Immunother. 2011;60:1529–41.

    CAS  PubMed  Google Scholar 

  159. Freeman GJ, Long AJ, Iwai Y, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med. 2000;192:1027–34.

    CAS  PubMed Central  PubMed  Google Scholar 

  160. Latchman Y, Wood CR, Chernova T, et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol. 2001;2:261–8.

    CAS  PubMed  Google Scholar 

  161. Sznol M, Chen L. Antagonist antibodies to PD-1 and B7-H1 (PD-L1) in the treatment of advanced human cancer. Clin Cancer Res. 2013;19:1021–34.

    CAS  PubMed Central  PubMed  Google Scholar 

  162. Topalian SL, Drake CG, Pardoll DM. Targeting the PD-1/B7-H1(PD-L1) pathway to activate anti-tumor immunity. Curr Opin Immunol. 2012;24:207–12.

    CAS  PubMed Central  PubMed  Google Scholar 

  163. Nishimura H, Okazaki T, Tanaka Y, et al. Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science. 2001;291:319–22.

    CAS  PubMed  Google Scholar 

  164. Wang J, Okazaki I-M, Yoshida T, Chikuma S, Kato Y, Nakaki F, et al. PD-1 deficiency results in the development of fatal myocarditis in MRL mice. Int Immunol. 2010;22:443–52.

    CAS  PubMed  Google Scholar 

  165. Dong H, Zhu G, Tamada K, Flies DB, van Deursen JMA. B7-H1 determines accumulation and deletion of intrahepatic CD8(+) T lymphocytes. Immunity. 2004;20:327–36.

    CAS  PubMed  Google Scholar 

  166. Sheppard K-A, Fitz LJ, Lee JM, et al. PD-1 inhibits T-cell receptor induced phosphorylation of the ZAP70/CD3zeta signalosome and downstream signaling to PKCtheta. FEBS Lett. 2004;574:37–41.

    CAS  PubMed  Google Scholar 

  167. Okazaki T, Maeda A, Nishimura H, Kurosaki T, Honjo T. PD-1 immunoreceptor inhibits B cell receptor-mediated signaling by recruiting src homology 2-domain-containing tyrosine phosphatase 2 to phosphotyrosine. Proc Natl Acad Sci U S A. 2001;98:13866–71.

    CAS  PubMed Central  PubMed  Google Scholar 

  168. Chemnitz JM, Parry RV, Nichols KE, June CH, Riley JL. SHP-1 and SHP-2 associate with immunoreceptor tyrosine-based switch motif of programmed death 1 upon primary human T cell stimulation, but only receptor ligation prevents T cell activation. J Immunol. 2004;173:945–54.

    CAS  PubMed  Google Scholar 

  169. Carter L, Fouser LA, Jussif J, Fitz L, Deng B, Wood CR, et al. PD-1:PD-L inhibitory pathway affects both CD4(+) and CD8(+) T cells and is overcome by IL-2. Eur J Immunol. 2002;32:634–43.

    CAS  PubMed  Google Scholar 

  170. Nurieva R, Thomas S, Nguyen T, Martin-Orozco N, Wang Y, Kaja M-K, et al. T-cell tolerance or function is determined by combinatorial costimulatory signals. EMBO J. 2006;25:2623–33.

    CAS  PubMed Central  PubMed  Google Scholar 

  171. Park J-J, Omiya R, Matsumura Y, et al. B7-H1/CD80 interaction is required for the induction and maintenance of peripheral T-cell tolerance. Blood. 2012;116:1291–8.

    Google Scholar 

  172. Butte MJ, Keir ME, Phamduy TB, Sharpe AH, Freeman GJ. Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses. Immunity. 2007;27:111–22.

    CAS  PubMed Central  PubMed  Google Scholar 

  173. Iwai Y, Terawaki S, Ikegawa M, Okazaki T, Honjo T. PD-1 inhibits antiviral immunity at the effector phase in the liver. J Exp Med. 2003;198:39–50.

    CAS  PubMed Central  PubMed  Google Scholar 

  174. Hino R, Kabashima K, Kato Y, Yagi H, Nakamura M, Honjo T, Okazaki T, Tokura Y. Tumor cell expression of programmed cell death-1 ligand 1 is a prognostic factor for malignant melanoma. Cancer. 2010;116:1757–66.

    PubMed  Google Scholar 

  175. Geng L, Huang D, Liu J, Qian Y, Deng J, Li D, et al. B7-H1 up-regulated expression in human pancreatic carcinoma tissue associates with tumor progression. J Cancer Res Clin Oncol. 2008;134:1021–7.

    CAS  PubMed  Google Scholar 

  176. Parsa AT, Waldron JS, Panner A, et al. Loss of tumor suppressor PTEN function increases B7-H1 expression and immunoresistance in glioma. Nat Med. 2007;13:84–8.

    CAS  PubMed  Google Scholar 

  177. Ghebeh H, Mohammed S, Al-Omair A, et al. The B7-H1 (PD-L1) T lymphocyte-inhibitory molecule is expressed in breast cancer patients with infiltrating ductal carcinoma: correlation with important high-risk prognostic factors. Neoplasia. 2006;8:190–8.

    CAS  PubMed Central  PubMed  Google Scholar 

  178. Wu C, Zhu Y, Jiang J, Zhao J, Zhang X-G, Xu N. Immunohistochemical localization of programmed death-1 ligand-1 (PD-L1) in gastric carcinoma and its clinical significance. Acta Histochem. 2006;108:19–24.

    PubMed  Google Scholar 

  179. Ohigashi Y, Sho M, Yamada Y, et al. Clinical significance of programmed death-1 ligand-1 and programmed death-1 ligand-2 expression in human esophageal cancer. Clin Cancer Res. 2005;11:2947–53.

    CAS  PubMed  Google Scholar 

  180. Strome SE, Dong H, Tamura H, et al. B7-H1 blockade augments adoptive T-cell immunotherapy for squamous cell carcinoma. Cancer Res. 2003;63:6501–5.

    CAS  PubMed  Google Scholar 

  181. Hamanishi J, Mandai M, Iwasaki M, et al. Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer. Proc Natl Acad Sci U S A. 2007;104:3360–5.

    CAS  PubMed Central  PubMed  Google Scholar 

  182. Thompson RH, Gillett MD, Cheville JC, et al. Costimulatory molecule B7-H1 in primary and metastatic clear cell renal cell carcinoma. Cancer. 2005;104:2084–91.

    CAS  PubMed  Google Scholar 

  183. Rosenwald A, Wright G, Leroy K, et al. Molecular diagnosis of primary mediastinal B cell lymphoma identifies a clinically favorable subgroup of diffuse large B cell lymphoma related to Hodgkin lymphoma. J Exp Med. 2003;198:851–62.

    CAS  PubMed Central  PubMed  Google Scholar 

  184. Zhou Q, Munger ME, Highfill SL, et al. Program death-1 signaling and regulatory T cells collaborate to resist the function of adoptively transferred cytotoxic T lymphocytes in advanced acute myeloid leukemia. Blood. 2010;116:2484–93.

    CAS  PubMed Central  PubMed  Google Scholar 

  185. Zou W, Chen L. Inhibitory B7-family molecules in the tumour microenvironment. Nat Rev Immunol. 2008;8:467–77.

    CAS  PubMed  Google Scholar 

  186. Konishi J, Yamazaki K, Azuma M, Kinoshita I, Dosaka-Akita H, Nishimura. B7-H1 expression on non-small cell lung cancer cells and its relationship with tumor-infiltrating lymphocytes and their PD-1 expression. Clin Cancer Res. 2004;10:5094–100.

    CAS  PubMed  Google Scholar 

  187. Droeser RA, Hirt C, Viehl CT, et al. Clinical impact of programmed cell death ligand 1 expression in colorectal cancer. Eur J Cancer. 2013;49(9):2233–42.

    CAS  PubMed  Google Scholar 

  188. Badoual C, Hans S, Merillon N, et al. PD-1-expressing tumor-infiltrating T cells are a favorable prognostic biomarker in HPV-associated head and neck cancer. Cancer Res. 2013;73:128–38.

    CAS  PubMed  Google Scholar 

  189. Sfanos KS, Bruno TC, Meeker AK, De Marzo AM, Isaacs WB, Drake CG. Human prostate-infiltrating CD8+ T lymphocytes are oligoclonal and PD-1+. Prostate. 2009;69:1694–703.

    CAS  PubMed Central  PubMed  Google Scholar 

  190. Benson DM, Bakan CE, Mishra A, et al. The PD-1/PD-L1 axis modulates the natural killer cell versus multiple myeloma effect: a therapeutic target for CT-011, a novel monoclonal anti-PD-1 antibody. Blood. 2010;116:2286–94.

    CAS  PubMed Central  PubMed  Google Scholar 

  191. Dong H, Strome SE, Salomao DR, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med. 2002;8:793–800.

    CAS  PubMed  Google Scholar 

  192. Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N. Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc Natl Acad Sci U S A. 2002;99:12293–7.

    CAS  PubMed Central  PubMed  Google Scholar 

  193. Azuma T, Yao S, Zhu G, Flies AS, Flies SJ, Chen L. B7-H1 is a ubiquitous antiapoptotic receptor on cancer cells. Blood. 2008;111:3635–43.

    CAS  PubMed Central  PubMed  Google Scholar 

  194. Hirano F, Kaneko K, Tamura H, et al. Blockade of B7-H1 and PD-1 by monoclonal antibodies potentiates cancer therapeutic immunity. Cancer Res. 2005;65:1089–96.

    CAS  PubMed  Google Scholar 

  195. Taube JM, Anders RA, Young GD, et al. Colocalization of inflammatory response with B7-h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Sci Transl Med. 2012;4:127ra37.

    PubMed Central  PubMed  Google Scholar 

  196. Kim J, Myers AC, Chen L, Pardoll DM, Truong-Tran Q-A, Lane AP, et al. Constitutive and inducible expression of b7 family of ligands by human airway epithelial cells. Am J Respir Cell Mol Biol. 2005;33:280–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  197. Lee S-K, Seo S-H, Kim B-S, Kim C-D, Lee J-H, Kang J-S, Maeng PJ, Lim J-S. IFN-gamma regulates the expression of B7-H1 in dermal fibroblast cells. J Dermatol Sci. 2005;40:95–103.

    CAS  PubMed  Google Scholar 

  198. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12:252–64.

    CAS  PubMed  Google Scholar 

  199. Okudaira K, Hokari R, Tsuzuki Y, et al. Blockade of B7-H1 or B7-DC induces an anti-tumor effect in a mouse pancreatic cancer model. Int J Oncol. 2009;35:741–9.

    CAS  PubMed  Google Scholar 

  200. Blank C, Brown I, Peterson AC, Spiotto M, Iwai Y, Honjo T, Gajewski TF. PD-L1/B7H-1 inhibits the effector phase of tumor rejection by T cell receptor (TCR) transgenic CD8+ T cells. Cancer Res. 2004;64:1140–5.

    CAS  PubMed  Google Scholar 

  201. Webster WS, Thompson RH, Harris KJ, Frigola X, Kuntz S, Inman BA, Dong H. Targeting molecular and cellular inhibitory mechanisms for improvement of antitumor memory responses reactivated by tumor cell vaccine. J Immunol. 2007;179:2860–9.

    CAS  PubMed  Google Scholar 

  202. Li B, VanRoey M, Wang C, Chen T-HT, Korman A, Jooss K. Anti-programmed death-1 synergizes with granulocyte macrophage colony-stimulating factor–secreting tumor cell immunotherapy providing therapeutic benefit to mice with established tumors. Clin Cancer Res. 2009;15:1623–34.

    CAS  PubMed  Google Scholar 

  203. Mkrtichyan M, Najjar YG, Raulfs EC, Abdalla MY, Samara R, Rotem-Yehudar R, et al. Anti-PD-1 synergizes with cyclophosphamide to induce potent anti-tumor vaccine effects through novel mechanisms. Eur J Immunol. 2011;41:2977–86.

    CAS  PubMed  Google Scholar 

  204. Zhou Q, Xiao H, Liu Y, et al. Blockade of programmed death-1 pathway rescues the effector function of tumor-infiltrating T cells and enhances the antitumor efficacy of lentivector immunization. J Immunol. 2010;185:5082–92.

    CAS  PubMed Central  PubMed  Google Scholar 

  205. Blank C, Kuball J, Voelkl S, et al. Blockade of PD-L1 (B7-H1) augments human tumor-specific T cell responses in vitro. Int J Cancer. 2006;119:317–27.

    CAS  PubMed  Google Scholar 

  206. Wong RM, Scotland RR, Lau RL, Wang C, Korman AJ, Kast WM, Weber JS. Programmed death-1 blockade enhances expansion and functional capacity of human melanoma antigen-specific CTLs. Int Immunol. 2007;19:1223–34.

    CAS  PubMed  Google Scholar 

  207. Zhang Y, Huang S, Gong D, Qin Y, Shen Q. Programmed death-1 upregulation is correlated with dysfunction of tumor-infiltrating CD8+ T lymphocytes in human non-small cell lung cancer. Cell Mol Immunol. 2010;7:389–95.

    PubMed Central  PubMed  Google Scholar 

  208. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti–PD-1 antibody in cancer. N Engl J Med. 2012;366:2443–54.

    CAS  PubMed Central  PubMed  Google Scholar 

  209. Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013;369(2):122–33.

    CAS  PubMed  Google Scholar 

  210. Patnaik A, Kang SP, Tolcher D, et al. Phase I study of MK-3475 (anti-PD-1 monoclonal antibody) in patients with advanced solid tumors. J Clin Oncol. 2012;30:abst 2512.

    Google Scholar 

  211. Rosenblatt J, Glotzbecker B, Mills H, et al. PD-1 blockade by CT-011, anti-PD-1 antibody, enhances ex vivo T-cell responses to autologous dendritic cell/myeloma fusion vaccine. J Immunother. 2011;34:409–18.

    CAS  PubMed Central  PubMed  Google Scholar 

  212. Brahmer JR, Tykodi SS, Chow LQM, et al. Safety and activity of anti–PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366:2455–65.

    CAS  PubMed Central  PubMed  Google Scholar 

  213. Zeng J, See AP, Phallen J, et al. Anti-PD-1 blockade and stereotactic radiation produce long-term survival in mice with intracranial gliomas. Int J Radiat Oncol Biol Phys. 2013;86:343–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  214. van Elsas A, Hurwitz AA, Allison JP. Combination immunotherapy of B16 melanoma using anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and granulocyte/macrophage colony-stimulating factor (GM-CSF)-producing vaccines induces rejection of subcutaneous and metastatic tumors accompanied by autoimmune depigmentation. J Exp Med. 1999;190:355–66.

    PubMed Central  PubMed  Google Scholar 

  215. Hurwitz AA, Foster BA, Kwon ED, Truong T, Choi EM, Greenberg NM, Burg MB, Allison JP. Combination immunotherapy of primary prostate cancer in a transgenic mouse model using CTLA-4 blockade. Cancer Res. 2000;60:2444–8.

    CAS  PubMed  Google Scholar 

  216. van Elsas A, Sutmuller RP, Hurwitz AA, et al. Elucidating the autoimmune and antitumor effector mechanisms of a treatment based on cytotoxic T lymphocyte antigen-4 blockade in combination with a B16 melanoma vaccine: comparison of prophylaxis and therapy. J Exp Med. 2001;194:481–9.

    PubMed Central  PubMed  Google Scholar 

  217. Davila E, Kennedy R, Celis E. Generation of antitumor immunity by cytotoxic T lymphocyte epitope peptide vaccination, CpG-oligodeoxynucleotide adjuvant, and CTLA-4 blockade. Cancer Res. 2003;63:3281–8.

    CAS  PubMed  Google Scholar 

  218. Daftarian P, Song G-Y, Ali S, Faynsod M, Longmate J, Diamond DJ, Ellenhorn JD. Two distinct pathways of immuno-modulation improve potency of p53 immunization in rejecting established tumors. Cancer Res. 2004;64:5407–14.

    CAS  PubMed  Google Scholar 

  219. Peggs KS, Quezada SA, Chambers CA, Korman AJ, Allison JP. Blockade of CTLA-4 on both effector and regulatory T cell compartments contributes to the antitumor activity of anti-CTLA-4 antibodies. J Exp Med. 2009;206:1717–25.

    CAS  PubMed Central  PubMed  Google Scholar 

  220. Curran MA, Montalvo W, Yagita H, Allison JP. PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proc Natl Acad Sci U S A. 2010;107:4275–80.

    CAS  PubMed Central  PubMed  Google Scholar 

  221. Wada S, Jackson CM, Yoshimura K, et al. Sequencing CTLA-4 blockade with cell-based immunotherapy for prostate cancer. J Transl Med. 2013;11:89.

    CAS  PubMed Central  PubMed  Google Scholar 

  222. de Vries TJ, Fourkour A, Wobbes T, Verkroost G, Ruiter DJ, van Muijen GN. Heterogeneous expression of immunotherapy candidate proteins gp100, MART-1, and tyrosinase in human melanoma cell lines and in human melanocytic lesions. Cancer Res. 1997;57:3223–9.

    PubMed  Google Scholar 

  223. Schwartzentruber DJ, Lawson DH, Richards JM, et al. gp100 peptide vaccine and interleukin-2 in patients with advanced melanoma. N Engl J Med. 2011;364:2119–27.

    CAS  PubMed Central  PubMed  Google Scholar 

  224. Madan RA, Mohebtash M, Arlen PM, et al. Ipilimumab and a poxviral vaccine targeting prostate-specific antigen in metastatic castration-resistant prostate cancer: a phase 1 dose-escalation trial. Lancet Oncol. 2012;13:501–8.

    CAS  PubMed  Google Scholar 

  225. Rosenberg SA, Yang JC, White DE, Steinberg SM. Durability of complete responses in patients with metastatic cancer treated with high-dose interleukin-2: identification of the antigens mediating response. Ann Surg. 1998;228:307–19.

    CAS  PubMed Central  PubMed  Google Scholar 

  226. Fong L, Kwek SS, O’Brien S, et al. Potentiating endogenous antitumor immunity to prostate cancer through combination immunotherapy with CTLA4 blockade and GM-CSF. Cancer Res. 2009;69:609–15.

    CAS  PubMed  Google Scholar 

  227. Woo S-R, Turnis ME, Goldberg MV, et al. Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T-cell function to promote tumoral immune escape. Cancer Res. 2012;72:917–27.

    CAS  PubMed Central  PubMed  Google Scholar 

  228. Duraiswamy J, Kaluza KM, Freeman GJ, Coukos G. Dual blockade of PD-1 and CTLA-4 combined with tumor vaccine effectively restores T cell rejection function in tumors. Cancer Res. 2014;74(2):632–4.

    Google Scholar 

  229. Okazaki T, Okazaki I-M, Wang J, et al. PD-1 and LAG-3 inhibitory co-receptors act synergistically to prevent autoimmunity in mice. J Exp Med. 2011;208:395–407.

    CAS  PubMed Central  PubMed  Google Scholar 

  230. Kocak E, Lute K, Chang X, et al. Combination therapy with anti-CTL antigen-4 and anti-4-1BB antibodies enhances cancer immunity and reduces autoimmunity. Cancer Res. 2006;66:7276–84.

    CAS  PubMed  Google Scholar 

  231. Triebel F, Jitsukawa S, Baixeras E, Roman-Roman S, Genevee C, Viegas-Pequignot E, Hercend T. LAG-3, a novel lymphocyte activation gene closely related to CD4. J Exp Med. 1990;171:1393–405.

    CAS  PubMed  Google Scholar 

  232. Huard B, Prigent P, Tournier M, Bruniquel D, Triebel F. CD4/major histocompatibility complex class II interaction analyzed with CD4- and lymphocyte activation gene-3 (LAG-3)-Ig fusion proteins. Eur J Immunol. 1995;25:2718–21.

    CAS  PubMed  Google Scholar 

  233. Avice MN, Sarfati M, Triebel F, Delespesse G, Demeure CE. Lymphocyte activation gene-3, a MHC class II ligand expressed on activated T cells, stimulates TNF-alpha and IL-12 production by monocytes and dendritic cells. J Immunol. 1999;162:2748–53.

    CAS  PubMed  Google Scholar 

  234. Huard B, Tournier M, Hercend T, Triebel F, Faure F. Lymphocyte-activation gene 3/major histocompatibility complex class II interaction modulates the antigenic response of CD4+ T lymphocytes. Eur J Immunol. 1994;24:3216–21.

    CAS  PubMed  Google Scholar 

  235. Hannier S, Tournier M, Bismuth G, Triebel F. CD3/TCR complex-associated lymphocyte activation gene-3 molecules inhibit CD3/TCR signaling. J Immunol. 1998;161:4058–65.

    CAS  PubMed  Google Scholar 

  236. Triebel F. LAG-3: a regulator of T-cell and DC responses and its use in therapeutic vaccination. Trends Immunol. 2003;24:619–22.

    CAS  PubMed  Google Scholar 

  237. Camisaschi C, Casati C, Rini F, Perego M, De Filippo A, Triebel F, Parmiani G, Belli F, Rivoltini L, Castelli C. LAG-3 expression defines a subset of CD4(+)CD25(high)Foxp3(+) regulatory T cells that are expanded at tumor sites. J Immunol. 2010;184:6545–51.

    CAS  PubMed  Google Scholar 

  238. Blackburn SD, Shin H, Haining WN, Zou T, Workman CJ, Polley A, Betts MR, Freeman GJ, Vignali DAA, Wherry EJ. Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat Immunol. 2009;10:29–37.

    CAS  PubMed Central  PubMed  Google Scholar 

  239. Grosso JF, Goldberg MV, Getnet D, Bruno TC, Yen H-R, Pyle KJ, Hipkiss E, Vignali DAA, Pardoll DM, Drake CG. Functionally distinct LAG-3 and PD-1 subsets on activated and chronically stimulated CD8 T cells. J Immunol. 2009;182:6659–69.

    CAS  PubMed Central  PubMed  Google Scholar 

  240. Deffrennes V, Vedrenne J, Stolzenberg MC, Piskurich J, Barbieri G, Ting JP, Charron D, Alcaïde-Loridan C. Constitutive expression of MHC class II genes in melanoma cell lines results from the transcription of class II transactivator abnormally initiated from its B cell-specific promoter. J Immunol. 2001;167:98–106.

    CAS  PubMed  Google Scholar 

  241. Martins I, Sylla K, Deshayes F, et al. Coexpression of major histocompatibility complex class II with chemokines and nuclear NFkappaB p50 in melanoma: a rational for their association with poor prognosis. Melanoma Res. 2009;19:226–37.

    CAS  PubMed  Google Scholar 

  242. Matsuzaki J, Gnjatic S, Mhawech-Fauceglia P, et al. Tumor-infiltrating NY-ESO-1-specific CD8+ T cells are negatively regulated by LAG-3 and PD-1 in human ovarian cancer. Proc Natl Acad Sci U S A. 2010;107:7875–80.

    CAS  PubMed Central  PubMed  Google Scholar 

  243. Gandhi MK, Lambley E, Duraiswamy J, Dua U, Smith C, Elliott S, Gill D, Marlton P, Seymour J, Khanna R. Expression of LAG-3 by tumor-infiltrating lymphocytes is coincident with the suppression of latent membrane antigen-specific CD8+ T-cell function in Hodgkin lymphoma patients. Blood. 2006;108:2280–9.

    CAS  PubMed  Google Scholar 

  244. Hemon P, Jean-Louis F, Ramgolam K, et al. MHC class II engagement by its ligand LAG-3 (CD223) contributes to melanoma resistance to apoptosis. J Immunol. 2011;186:5173–83.

    CAS  PubMed  Google Scholar 

  245. Maçon-Lemaître L, Triebel F. The negative regulatory function of the lymphocyte-activation gene-3 co-receptor (CD223) on human T cells. Immunology. 2005;115:170–8.

    PubMed Central  PubMed  Google Scholar 

  246. Grosso JF, Kelleher CC, Harris TJ, et al. LAG-3 regulates CD8+ T cell accumulation and effector function in murine self- and tumor-tolerance systems. J Clin Invest. 2007;117:3383–92.

    CAS  PubMed Central  PubMed  Google Scholar 

  247. Miyazaki T, Dierich A, Benoist C, Mathis D. Independent modes of natural killing distinguished in mice lacking Lag3. Science. 1996;272:|405–8.

    CAS  PubMed  Google Scholar 

  248. Triebel F, Hacene K, Pichon M-F. A soluble lymphocyte activation gene-3 (sLAG-3) protein as a prognostic factor in human breast cancer expressing estrogen or progesterone receptors. Cancer Lett. 2006;235:147–53.

    CAS  PubMed  Google Scholar 

  249. Fougeray S, Brignone C, Triebel F. A soluble LAG-3 protein as an immunopotentiator for therapeutic vaccines: preclinical evaluation of IMP321. Vaccine. 2006;24:5426–33.

    CAS  PubMed  Google Scholar 

  250. Brignone C, Grygar C, Marcu M, Perrin G, Triebel F. IMP321 (sLAG-3), an immunopotentiator for T cell responses against a HBsAg antigen in healthy adults: a single blind randomised controlled phase I study. J Immune Based Ther Vaccines. 2007;5:5.

    PubMed Central  PubMed  Google Scholar 

  251. Brignone C, Escudier B, Grygar C, Marcu M, Triebel F. A phase I pharmacokinetic and biological correlative study of IMP321, a novel MHC class II agonist, in patients with advanced renal cell carcinoma. Clin Cancer Res. 2009;15:6225–31.

    CAS  PubMed  Google Scholar 

  252. Wang-Gillam A, Plambeck-Suess S, Goedegebuure P, et al. A phase I study of IMP321 and gemcitabine as the front-line therapy in patients with advanced pancreatic adenocarcinoma. Invest New Drugs. 2013;31:707–13.

    CAS  PubMed Central  PubMed  Google Scholar 

  253. Ascierto PA, Simeone E, Sznol M, Fu YX, Melero I. Clinical experiences with anti-CD137 and anti-PD1 therapeutic antibodies. Semin Oncol. 2010;37:508–16. YSONC.

    CAS  PubMed  Google Scholar 

  254. Vinay DS, Kwon BS. 4-1BB signaling beyond T cells. Cell Mol Immunol. 2011;8:281–4.

    CAS  PubMed Central  PubMed  Google Scholar 

  255. Watts TH. TNF/TNFR family members in costimulation of T cell responses. Annu Rev Immunol. 2005;23:23–68.

    CAS  PubMed  Google Scholar 

  256. Melero I, Shuford WW, Newby SA, Aruffo A, Ledbetter JA, Hellström KE, Mittler RS, Chen L. Monoclonal antibodies against the 4-1BB T-cell activation molecule eradicate established tumors. Nat Med. 1997;3:682–5.

    CAS  PubMed  Google Scholar 

  257. Palazón A, Teijeira A, Martinez-Forero I, et al. Agonist anti-CD137 mAb act on tumor endothelial cells to enhance recruitment of activated T lymphocytes. Cancer Res. 2011;71:801–11.

    PubMed  Google Scholar 

  258. Miller RE, Jones J, Le T, Whitmore J, Boiani N, Gliniak B, Lynch DH. 4-1BB-specific monoclonal antibody promotes the generation of tumor-specific immune responses by direct activation of CD8 T cells in a CD40-dependent manner. J Immunol. 2000;169:1792–800.

    Google Scholar 

  259. Takahashi C, Mittler RS, Vella AT. Cutting edge: 4-1BB is a bona fide CD8 T cell survival signal. J Immunol. 1999;162:5037–40.

    CAS  PubMed  Google Scholar 

  260. Bukczynski J, Wen T, Watts TH. Costimulation of human CD28- T cells by 4-1BB ligand. Eur J Immunol. 2003;33:446–54.

    CAS  PubMed  Google Scholar 

  261. Wilcox RA, Tamada K, Flies DB, Zhu G, Chapoval AI, Blazar BR, Kast WM, Chen L. Ligation of CD137 receptor prevents and reverses established anergy of CD8+ cytolytic T lymphocytes in vivo. Blood. 2004;103:177–84.

    CAS  PubMed  Google Scholar 

  262. Melero I, Johnston JV, Shufford WW, Mittler RS, Chen L. NK1.1 cells express 4-1BB (CDw137) costimulatory molecule and are required for tumor immunity elicited by anti-4-1BB monoclonal antibodies. Cell Immunol. 1998;190:167–72.

    CAS  PubMed  Google Scholar 

  263. Mittler RS, Bailey TS, Klussman K, Trailsmith MD, Hoffmann MK. Anti-4-1BB monoclonal antibodies abrogate T cell-dependent humoral immune responses in vivo through the induction of helper T cell anergy. J Exp Med. 1999;190:1535–40.

    CAS  PubMed Central  PubMed  Google Scholar 

  264. Hong HJ, Lee JW, Park SS, et al. A humanized anti–4–1BB monoclonal antibody suppresses antigen-induced humoral immune response in nonhuman primates. J Immunother. 2000;23:613–21.

    CAS  PubMed  Google Scholar 

  265. Mittler RS, Foell J, McCausland M, Strahotin S, Niu L, Bapat A, Hewes LB. Anti-CD137 antibodies in the treatment of autoimmune disease and cancer. Immunol Res. 2004;29:197–208.

    CAS  PubMed  Google Scholar 

  266. Fisher TS, Kamperschroer C, Oliphant T, et al. Targeting of 4-1BB by monoclonal antibody PF-05082566 enhances T-cell function and promotes anti-tumor activity. Cancer Immunol Immunother. 2012;61:1721–33.

    CAS  PubMed  Google Scholar 

  267. Murillo O, Arina A, Hervas-Stubbs S, et al. Therapeutic antitumor efficacy of anti-CD137 agonistic monoclonal antibody in mouse models of myeloma. Clin Cancer Res. 2008;14:6895–906.

    CAS  PubMed Central  PubMed  Google Scholar 

  268. Ye Z, Hellström I, Hayden-Ledbetter M, Dahlin A, Ledbetter JA, Hellström KE. Gene therapy for cancer using single-chain Fv fragments specific for 4-1BB. Nat Med. 2002;8:343–8.

    CAS  PubMed  Google Scholar 

  269. Dubrot J, Milheiro F, Alfaro C, et al. Treatment with anti-CD137 mAbs causes intense accumulations of liver T cells without selective antitumor immunotherapeutic effects in this organ. Cancer Immunol Immunother. 2010;59:1223–33.

    CAS  PubMed  Google Scholar 

  270. Ito F, Li Q, Shreiner AB, Okuyama R, Jure-Kunkel MN, Teitz-Tennenbaum S, Chang AE. Anti-CD137 monoclonal antibody administration augments the antitumor efficacy of dendritic cell-based vaccines. Cancer Res. 2004;64:8411–9.

    CAS  PubMed  Google Scholar 

  271. Uno T, Takeda K, Kojima Y, Yoshizawa H, Akiba H, Mittler RS, Gejyo F, Okumura K, Yagita H, Smyth MJ. Eradication of established tumors in mice by a combination antibody-based therapy. Nat Med. 2006;12:693–8.

    CAS  PubMed  Google Scholar 

  272. May KF, Chen L, Zheng P, Liu Y. Anti-4-1BB monoclonal antibody enhances rejection of large tumor burden by promoting survival but not clonal expansion of tumor-specific CD8+ T cells. Cancer Res. 2002;62:3459–65.

    CAS  PubMed  Google Scholar 

  273. Kim YH, Choi BK, Kim KH, Kang SW, Kwon BS. Combination therapy with cisplatin and anti-4-1BB: synergistic anticancer effects and amelioration of cisplatin-induced nephrotoxicity. Cancer Res. 2008;68:7264–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  274. Sznol M, Hodi FS, Margolin K, McDermott DF, Ernstoff MS, Kirkwood JM, et al. Phase I study of BMS-663513, a fully human anti-CD137 agonist monoclonal antibody, in patients (pts) with advanced cancer (CA). J Clin Oncol. 2008;26:15_suppl 3007.

    Google Scholar 

  275. Weinberg AD, Morris NP, Kovacsovics-Bankowski M, Urba WJ, Curti BD. Science gone translational: the OX40 agonist story. Immunol Rev. 2011;244:218–31.

    CAS  PubMed Central  PubMed  Google Scholar 

  276. Mallett S, Fossum S, Barclay AN. Characterization of the MRC OX40 antigen of activated CD4 positive T lymphocytes–a molecule related to nerve growth factor receptor. EMBO J. 1990;9:1063–8.

    CAS  PubMed Central  PubMed  Google Scholar 

  277. Jensen SM, Maston LD, Gough MJ, et al. Signaling through OX40 enhances antitumor immunity. Semin Oncol. 2010;37:524–32. YSONC.

    CAS  PubMed Central  PubMed  Google Scholar 

  278. Gramaglia I, Weinberg AD, Lemon M, Croft M. Ox-40 ligand: a potent costimulatory molecule for sustaining primary CD4 T cell responses. J Immunol. 1998;161:6510–7.

    CAS  PubMed  Google Scholar 

  279. Ishii N, Ndhlovu LC, Murata K, Sato T, Kamanaka M, Sugamura K. OX40 (CD134) and OX40 ligand interaction plays an adjuvant role during in vivo Th2 responses. Eur J Immunol. 2003;33:2372–81.

    CAS  PubMed  Google Scholar 

  280. Murata K, Ishii N, Takano H, Miura S, Ndhlovu LC, Nose M, Noda T, Sugamura K. Impairment of antigen-presenting cell function in mice lacking expression of OX40 ligand. J Exp Med. 2000;191:365–74.

    CAS  PubMed Central  PubMed  Google Scholar 

  281. Gramaglia I, Jember A, Pippig SD, Weinberg AD, Killeen N, Croft M. The OX40 costimulatory receptor determines the development of CD4 memory by regulating primary clonal expansion. J Immunol. 2000;165:3043–50.

    CAS  PubMed  Google Scholar 

  282. Xiao X, Gong W, Demirci G, Liu W, Spoerl S, Chu X, Bishop DK, Turka LA, Li XC. New insights on OX40 in the control of T cell immunity and immune tolerance in vivo. J Immunol. 2012;188:892–901.

    CAS  PubMed Central  PubMed  Google Scholar 

  283. Valzasina B, Guiducci C, Dislich H, Killeen N, Weinberg AD, Colombo MP. Triggering of OX40 (CD134) on CD4(+)CD25+ T cells blocks their inhibitory activity: a novel regulatory role for OX40 and its comparison with GITR. Blood. 2005;105:2845–51.

    CAS  PubMed  Google Scholar 

  284. Murata K, Nose M, Ndhlovu LC, Sato T, Sugamura K, Ishii N. Constitutive OX40/OX40 ligand interaction induces autoimmune-like diseases. J Immunol. 2002;169:4628–36.

    CAS  PubMed  Google Scholar 

  285. Chen AI, McAdam AJ, Buhlmann JE, et al. Ox40-ligand has a critical costimulatory role in dendritic cell:T cell interactions. Immunity. 1999;11:689–98.

    CAS  PubMed  Google Scholar 

  286. Bekiaris V, Gaspal F, Kim M-Y, Withers DR, Sweet C, Anderson G, Lane PJL. Synergistic OX40 and CD30 signals sustain CD8+ T cells during antigenic challenge. Eur J Immunol. 2009;39:2120–5.

    CAS  PubMed  Google Scholar 

  287. Salek-Ardakani S, Moutaftsi M, Crotty S, Sette A, Croft M. OX40 drives protective vaccinia virus-specific CD8 T cells. J Immunol. 2008;181:7969–76.

    CAS  PubMed Central  PubMed  Google Scholar 

  288. Mousavi SF, Soroosh P, Takahashi T, Yoshikai Y, Shen H, Lefrançois L, Borst J, Sugamura K, Ishii N. OX40 costimulatory signals potentiate the memory commitment of effector CD8+ T cells. J Immunol. 2008;181:5990–6001.

    CAS  PubMed Central  PubMed  Google Scholar 

  289. Gough MJ, Ruby CE, Redmond WL, Dhungel B, Brown A, Weinberg AD. OX40 agonist therapy enhances CD8 infiltration and decreases immune suppression in the tumor. Cancer Res. 2008;68:5206–15.

    CAS  PubMed  Google Scholar 

  290. Ruby CE, Redmond WL, Haley D, Weinberg AD. Anti-OX40 stimulation in vivo enhances CD8+ memory T cell survival and significantly increases recall responses. Eur J Immunol. 2007;37:157–66.

    CAS  PubMed  Google Scholar 

  291. Weinberg AD, Rivera MM, Prell R, Morris A, Ramstad T, Vetto JT, Urba WJ, Alvord G, Bunce C, Shields J. Engagement of the OX-40 receptor in vivo enhances antitumor immunity. J Immunol. 2000;164:2160–9.

    CAS  PubMed  Google Scholar 

  292. Morris A, Vetto JT, Ramstad T, Funatake CJ, Choolun E, Entwisle C, Weinberg AD. Induction of anti-mammary cancer immunity by engaging the OX-40 receptor in vivo. Breast Cancer Res Treat. 2001;67:71–80.

    CAS  PubMed  Google Scholar 

  293. Weinberg AD, Vella AT, Croft M. OX-40: life beyond the effector T cell stage. Semin Immunol. 1998;10:471–80.

    CAS  PubMed  Google Scholar 

  294. Evans DE, Prell RA, Thalhofer CJ, Hurwitz AA, Weinberg AD. Engagement of OX40 enhances antigen-specific CD4(+) T cell mobilization/memory development and humoral immunity: comparison of alphaOX-40 with alphaCTLA-4. J Immunol. 2001;167:6804–11.

    CAS  PubMed  Google Scholar 

  295. Houot R, Levy R. T-cell modulation combined with intratumoral CpG cures lymphoma in a mouse model without the need for chemotherapy. Blood. 2009;113:3546–52.

    CAS  PubMed Central  PubMed  Google Scholar 

  296. Gough MJ, Crittenden MR, Sarff M, Pang P, Seung SK, Vetto JT, Hu H-M, Redmond WL, Holland J, Weinberg AD. Adjuvant therapy with agonistic antibodies to CD134 (OX40) increases local control after surgical or radiation therapy of cancer in mice. J Immunother. 2010;33:798–809.

    CAS  PubMed Central  PubMed  Google Scholar 

  297. Vetto JT, Lum S, Morris A, Sicotte M, Davis J, Lemon M, Weinberg A. Presence of the T-cell activation marker OX-40 on tumor infiltrating lymphocytes and draining lymph node cells from patients with melanoma and head and neck cancers. Am J Surg. 1997;174:258–65.

    CAS  PubMed  Google Scholar 

  298. Ramstad T, Lawnicki L, Vetto J, Weinberg A. Immunohistochemical analysis of primary breast tumors and tumor-draining lymph nodes by means of the T-cell costimulatory molecule OX-40. Am J Surg. 2000;179:400–6.

    CAS  PubMed  Google Scholar 

  299. Schaer DA, Murphy JT, Wolchok JD. Modulation of GITR for cancer immunotherapy. Curr Opin Immunol. 2012;24:217–24.

    CAS  PubMed Central  PubMed  Google Scholar 

  300. Tone M, Tone Y, Adams E, Yates SF, Frewin MR, Cobbold SP, Waldmann H. Mouse glucocorticoid-induced tumor necrosis factor receptor ligand is costimulatory for T cells. Proc Natl Acad Sci U S A. 2003;100:15059–64.

    CAS  PubMed Central  PubMed  Google Scholar 

  301. Snell LM, Lin GHY, McPherson AJ, Moraes TJ, Watts TH. T-cell intrinsic effects of GITR and 4-1BB during viral infection and cancer immunotherapy. Immunol Rev. 2011;244:197–17.

    CAS  PubMed  Google Scholar 

  302. Shevach EM, Stephens GL. The GITR-GITRL interaction: co-stimulation or contrasuppression of regulatory activity? Nat Rev Immunol. 2006;6:613–8.

    CAS  PubMed  Google Scholar 

  303. Kim JD, Choi BK, Bae JS, Lee UH, Han IS, Lee HW, Youn BS, Vinay DS, Kwon BS. Cloning and characterization of GITR ligand. Genes Immun. 2003;4:564–9.

    CAS  PubMed  Google Scholar 

  304. Ronchetti S, Zollo O, Bruscoli S, Agostini M, Bianchini R, Nocentini G, Ayroldi E, Riccardi C. GITR, a member of the TNF receptor superfamily, is costimulatory to mouse T lymphocyte subpopulations. Eur J Immunol. 2004;34:613–22.

    CAS  PubMed  Google Scholar 

  305. Stephens GL, McHugh RS, Whitters MJ, Young DA, Luxenberg D, Carreno BM, Collins M, Shevach EM. Engagement of glucocorticoid-induced TNFR family-related receptor on effector T cells by its ligand mediates resistance to suppression by CD4+CD25+ T cells. J Immunol. 2004;173:5008–20.

    CAS  PubMed  Google Scholar 

  306. Kanamaru F, Youngnak P, Hashiguchi M, Nishioka T, Takahashi T, Sakaguchi S, Ishikawa I, Azuma M. Costimulation via glucocorticoid-induced TNF receptor in both conventional and CD25+ regulatory CD4+ T cells. J Immunol. 2004;172:7306–14.

    CAS  PubMed  Google Scholar 

  307. Kohm AP, Williams JS, Miller SD. Cutting edge: ligation of the glucocorticoid-induced TNF receptor enhances autoreactive CD4+ T cell activation and experimental autoimmune encephalomyelitis. J Immunol. 2004;172:4686–90.

    CAS  PubMed  Google Scholar 

  308. Snell LM, McPherson AJ, Lin GHY, Sakaguchi S, Pandolfi PP, Riccardi C, et al. CD8 T cell-intrinsic GITR is required for T cell clonal expansion and mouse survival following severe influenza infection. J Immunol. 2010;185:7223–34.

    CAS  PubMed  Google Scholar 

  309. Cuzzocrea S, Nocentini G, Di Paola R, Agostini M, Mazzon E, Ronchetti S, Crisafulli C, Esposito E, Caputi AP, Riccardi C. Proinflammatory role of glucocorticoid-induced TNF receptor-related gene in acute lung inflammation. J Immunol. 2006;177:631–41.

    CAS  PubMed  Google Scholar 

  310. Cuzzocrea S, Nocentini G, Di Paola R, Mazzon E, Ronchetti S, Genovese T, Muià C, Caputi AP, Riccardi C. Glucocorticoid-induced TNF receptor family gene (GITR) knockout mice exhibit a resistance to splanchnic artery occlusion (SAO) shock. J Leukoc Biol. 2004;76:933–40.

    CAS  PubMed  Google Scholar 

  311. Galuppo M, Nocentini G, Mazzon E, Ronchetti S, Esposito E, Riccardi L, Di Paola R, Bruscoli S, Riccardi C, Cuzzocrea S. GITR gene deletion and GITR-FC soluble protein administration inhibit multiple organ failure induced by zymosan. Shock. 2011;36:263–71.

    CAS  PubMed  Google Scholar 

  312. Cohen AD, Schaer DA, Liu C, et al. Agonist anti-GITR monoclonal antibody induces melanoma tumor immunity in mice by altering regulatory T cell stability and intra-tumor accumulation. PLoS One. 2010;5:e10436.

    PubMed Central  PubMed  Google Scholar 

  313. Ko K, Yamazaki S, Nakamura K, Nishioka T, Hirota K, Yamaguchi T, Shimizu J, Nomura T, Chiba T, Sakaguchi S. Treatment of advanced tumors with agonistic anti-GITR mAb and its effects on tumor-infiltrating Foxp3+CD25+CD4+ regulatory T cells. J Exp Med. 2005;202:885–91.

    CAS  PubMed Central  PubMed  Google Scholar 

  314. Zhou P, L’italien L, Hodges D, Schebye XM. Pivotal roles of CD4+ effector T cells in mediating agonistic anti-GITR mAb-induced-immune activation and tumor immunity in CT26 tumors. J Immunol. 2007;179:7365–75.

    CAS  PubMed  Google Scholar 

  315. Boczkowski D, Lee J, Pruitt S, Nair S. Dendritic cells engineered to secrete anti-GITR antibodies are effective adjuvants to dendritic cell-based immunotherapy. Cancer Gene Ther. 2009;16:900–11.

    CAS  PubMed  Google Scholar 

  316. Nishikawa H, Kato T, Hirayama M, Orito Y, Sato E, Harada N, Gnjatic S, Old LJ, Shiku H. Regulatory T cell-resistant CD8+ T cells induced by glucocorticoid-induced tumor necrosis factor receptor signaling. Cancer Res. 2008;68:5948–54.

    CAS  PubMed  Google Scholar 

  317. Cohen AD, Diab A, Perales M-A, et al. Agonist anti-GITR antibody enhances vaccine-induced CD8(+) T-cell responses and tumor immunity. Cancer Res. 2006;66:4904–12.

    CAS  PubMed Central  PubMed  Google Scholar 

  318. Eliopoulos AG, Young LS. The role of the CD40 pathway in the pathogenesis and treatment of cancer. Curr Opin Pharmacol. 2004;4:360–7.

    CAS  PubMed  Google Scholar 

  319. van Kooten C, Banchereau J. CD40-CD40 ligand. J Leukoc Biol. 2000;67:2–17.

    PubMed  Google Scholar 

  320. Wang Y, Kelly CG, Karttunen JT, et al. CD40 is a cellular receptor mediating mycobacterial heat shock protein 70 stimulation of CC-chemokines. Immunity. 2001;15:971–83.

    CAS  PubMed  Google Scholar 

  321. Brodeur SR, Angelini F, Bacharier LB, et al. C4b-binding protein (C4BP) activates B cells through the CD40 receptor. Immunity. 2003;18:837–48.

    CAS  PubMed  Google Scholar 

  322. Mach F, Schönbeck U, Sukhova GK, Bourcier T, Bonnefoy JY, Pober JS, Libby P. Functional CD40 ligand is expressed on human vascular endothelial cells, smooth muscle cells, and macrophages: implications for CD40-CD40 ligand signaling in atherosclerosis. Proc Natl Acad Sci U S A. 1997;94:1931–6.

    CAS  PubMed Central  PubMed  Google Scholar 

  323. Stout RD, Suttles J, Xu J, Grewal IS, Flavell RA. Impaired T cell-mediated macrophage activation in CD40 ligand-deficient mice. J Immunol. 1996;156:8–11.

    CAS  PubMed  Google Scholar 

  324. Mackey MF, Barth RJ, Noelle RJ. The role of CD40/CD154 interactions in the priming, differentiation, and effector function of helper and cytotoxic T cells. J Leukoc Biol. 1998;63:418–28.

    CAS  PubMed  Google Scholar 

  325. Bennett SR, Carbone FR, Karamalis F, Flavell RA, Miller JF, Heath WR. Help for cytotoxic-T-cell responses is mediated by CD40 signalling. Nature. 1998;393:478–80.

    CAS  PubMed  Google Scholar 

  326. Ridge JP, Di Rosa F, Matzinger P. A conditioned dendritic cell can be a temporal bridge between a CD4+ T-helper and a T-killer cell. Nature. 1998;393:474–8.

    CAS  PubMed  Google Scholar 

  327. Schoenberger SP, Toes RE, van der Voort EI, Offringa R, Melief CJ. T-cell help for cytotoxic T lymphocytes is mediated by CD40-CD40L interactions. Nature. 1998;393:480–3.

    CAS  PubMed  Google Scholar 

  328. Callard RE, Armitage RJ, Fanslow WC, Spriggs MK. CD40 ligand and its role in X-linked hyper-IgM syndrome. Immunol Today. 1993;14:559–64.

    CAS  PubMed  Google Scholar 

  329. Hill SC, Youde SJ, Man S, et al. Activation of CD40 in cervical carcinoma cells facilitates CTL responses and augments chemotherapy-induced apoptosis. J Immunol. 2005;174:41–50.

    CAS  PubMed  Google Scholar 

  330. Mackey MF, Gunn JR, Maliszewsky C, Kikutani H, Noelle RJ, Barth RJ. Dendritic cells require maturation via CD40 to generate protective antitumor immunity. J Immunol. 1998;161:2094–8.

    CAS  PubMed  Google Scholar 

  331. Mackey MF, Gunn JR, Ting PP, Kikutani H, Dranoff G, Noelle RJ, Barth RJ. Protective immunity induced by tumor vaccines requires interaction between CD40 and its ligand, CD154. Cancer Res. 1997;57:2569–74.

    CAS  PubMed  Google Scholar 

  332. Sotomayor EM, Borrello I, Tubb E, Rattis FM, Bien H, Lu Z, Fein S, Schoenberger S, Levitsky HI. Conversion of tumor-specific CD4+ T-cell tolerance to T-cell priming through in vivo ligation of CD40. Nat Med. 1999;5:780–7.

    CAS  PubMed  Google Scholar 

  333. Diehl L, den Boer AT, Schoenberger SP, van der Voort EI, Schumacher TN, Melief CJ, Offringa R, Toes RE. CD40 activation in vivo overcomes peptide-induced peripheral cytotoxic T-lymphocyte tolerance and augments anti-tumor vaccine efficacy. Nat Med. 1999;5:774–9.

    CAS  PubMed  Google Scholar 

  334. French RR, Chan HT, Tutt AL, Glennie MJ. CD40 antibody evokes a cytotoxic T-cell response that eradicates lymphoma and bypasses T-cell help. Nat Med. 1999;5:548–53.

    CAS  PubMed  Google Scholar 

  335. Tutt AL, O’Brien L, Hussain A, Crowther GR, French RR, Glennie MJ. T cell immunity to lymphoma following treatment with anti-CD40 monoclonal antibody. J Immunol. 2002;168:2720–8.

    CAS  PubMed  Google Scholar 

  336. Todryk SM, Tutt AL, Green MH, Smallwood JA, Halanek N, Dalgleish AG, Glennie MJ. CD40 ligation for immunotherapy of solid tumours. J Immunol Methods. 2001;248:139–47.

    CAS  PubMed  Google Scholar 

  337. Vonderheide RH, Glennie MJ. Agonistic CD40 antibodies and cancer therapy. Clin Cancer Res. 2013;19:1035–43.

    CAS  PubMed Central  PubMed  Google Scholar 

  338. Pellat-Deceunynck C, Amiot M, Robillard N, Wijdenes J, Bataille R. CD11a-CD18 and CD102 interactions mediate human myeloma cell growth arrest induced by CD40 stimulation. Cancer Res. 1996;56:1909–16.

    CAS  PubMed  Google Scholar 

  339. Funakoshi S, Longo DL, Beckwith M, Conley DK, Tsarfaty G, Tsarfaty I, Armitage RJ, Fanslow WC, Spriggs MK, Murphy WJ. Inhibition of human B-cell lymphoma growth by CD40 stimulation. Blood. 1994;83:2787–94.

    CAS  PubMed  Google Scholar 

  340. Vonderheide RH, Dutcher JP, Anderson JE, et al. Phase I study of recombinant human CD40 ligand in cancer patients. J Clin Oncol. 2001;19:3280–7.

    CAS  PubMed  Google Scholar 

  341. Vonderheide RH, Flaherty KT, Khalil M, et al. Clinical activity and immune modulation in cancer patients treated with CP-870,893, a novel CD40 agonist monoclonal antibody. J Clin Oncol. 2007;25:876–83.

    CAS  PubMed  Google Scholar 

  342. Rüter J, Antonia SJ, Burris HA, Huhn RD, Vonderheide RH. Immune modulation with weekly dosing of an agonist CD40 antibody in a phase I study of patients with advanced solid tumors. Cancer Biol Ther. 2010;10:983–93.

    PubMed Central  PubMed  Google Scholar 

  343. Beatty GL, Chiorean EG, Fishman MP, et al. CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans. Science. 2011;331:1612–6.

    CAS  PubMed Central  PubMed  Google Scholar 

  344. Vonderheide RH, Burg JM, Mick R, Trosko JA, Li D, Shaik MN, Tolcher AW, Hamid O. Phase I study of the CD40 agonist antibody CP-870,893 combined with carboplatin and paclitaxel in patients with advanced solid tumors. Oncoimmunol. 2013;2:e23033.

    Google Scholar 

  345. Hussein M, Berenson JR, Niesvizky R, Munshi N, Matous J, Sobecks R, Harrop K, Drachman JG, Whiting N. A phase I multidose study of dacetuzumab (SGN-40; humanized anti-CD40 monoclonal antibody) in patients with multiple myeloma. Haematologica. 2010;95:845–8.

    CAS  PubMed Central  PubMed  Google Scholar 

  346. Furman RR, Forero-Torres A, Shustov A, Drachman JG. A phase I study of dacetuzumab (SGN-40, a humanized anti-CD40 monoclonal antibody) in patients with chronic lymphocytic leukemia. Leuk Lymphoma. 2010;51:228–35.

    CAS  PubMed  Google Scholar 

  347. Lewis TS, McCormick RS, Emmerton K, Lau JT, Yu S-F, McEarchern JA, Grewal IS, Law C-L. Distinct apoptotic signaling characteristics of the anti-CD40 monoclonal antibody dacetuzumab and rituximab produce enhanced antitumor activity in non-Hodgkin lymphoma. Clin Cancer Res. 2011;17:4672–81.

    CAS  PubMed  Google Scholar 

  348. Forero-Torres A, Bartlett N, Beaven A, Myint H, Nasta S, Northfelt DW, Whiting NC, Drachman JG, Lobuglio AF, Moskowitz CH. Pilot study of dacetuzumab in combination with rituximab and gemcitabine for relapsed or refractory diffuse large B-cell lymphoma. Leuk Lymphoma. 2013;54:277–83.

    CAS  PubMed  Google Scholar 

  349. Johnson PW, Steven NM, Chowdhury FJD, Hall E, Ashton-Key M, et al. A cancer research UK phase I study evaluating safety, tolerability, and biological effects of chimeric anti-CD40 monoclonal antibody (MAb), Chi Lob 7/4. 28:2507 abs. J Clin Oncol. 2010;28(15 Suppl):2507.

    Google Scholar 

  350. Planken EV, Dijkstra NH, Willemze R, Kluin-Nelemans JC. Proliferation of B cell malignancies in all stages of differentiation upon stimulation in the ‘CD40 system’. Leukemia. 1996;10:488–93.

    CAS  PubMed  Google Scholar 

  351. Byrd JC, Kipps TJ, Flinn IW, et al. Phase I study of the anti-CD40 humanized monoclonal antibody lucatumumab (HCD122) in relapsed chronic lymphocytic leukemia. Leuk Lymphoma. 2012;53:2136–42.

    CAS  PubMed  Google Scholar 

  352. Bensinger W, Maziarz RT, Jagannath S, et al. A phase 1 study of lucatumumab, a fully human anti-CD40 antagonist monoclonal antibody administered intravenously to patients with relapsed or refractory multiple myeloma. Br J Haematol. 2012;159:58–66.

    CAS  PubMed  Google Scholar 

  353. Suntharalingam G, Perry MR, Ward S, Brett SJ, Castello-Cortes A, Brunner MD, Panoskaltsis N. Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N Engl J Med. 2006;355:1018–28.

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. General Surgery Department, Blanchfield Army Community Hospital, 650 Joel Drive, Fort Campbell, KY, 42223, USA

    Guy T. Clifton MD

  2. Fort Campbell, Army Community Hospital, Fort Campbell, KY, USA

    Guy T. Clifton MD

  3. Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA

    Elizabeth A. Mittendorf MD, PhD

  4. Department of Surgery, Cancer Vaccine Development Program, Brooke Army Medical Center, 3851 Roger Brooke Dr, Fort Sam Houston, TX, 78234, USA

    George E. Peoples MD

Authors
  1. Guy T. Clifton MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Elizabeth A. Mittendorf MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. George E. Peoples MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Guy T. Clifton MD .

Editor information

Editors and Affiliations

  1. Research Center for Immunodeficiencies, Children’s Medical Center, Pediatrics Center of Excellence, Tehran University of Medical Sciences, Tehran, Iran

    Nima Rezaei

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Clifton, G.T., Mittendorf, E.A., Peoples, G.E. (2015). Overcoming Cancer Tolerance with Immune Checkpoint Blockade. In: Rezaei, N. (eds) Cancer Immunology. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-662-44946-2_6

Download citation

  • DOI: https://doi.org/10.1007/978-3-662-44946-2_6

  • Published:

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-662-44945-5

  • Online ISBN: 978-3-662-44946-2

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation