1932

Abstract

Ipilimumab is the prototypical immunomodulatory antibody, approved by the FDA in 2011 for advanced melanoma on the basis of survival benefit. Since that time, we have made significant strides in optimizing this therapy: we have characterized the spectrum of immune-related adverse events and learned how to mitigate them with treatment algorithms, discovered potential biomarkers of activity, and identified the potential synergy between checkpoint modulation and other therapeutic modalities. Recent phase I trials have established the efficacy and safety of next-generation checkpoint agents, including PD-1 and PD-L1 inhibitors, across multiple tumor types. Much work lies ahead in developing these next-generation checkpoint agents, testing them in combination, and determining how to integrate them into the treatment paradigms of various tumor types.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-med-092012-112807
2014-01-14
2024-05-22
Loading full text...

Full text loading...

/deliver/fulltext/med/65/1/annurev-med-092012-112807.html?itemId=/content/journals/10.1146/annurev-med-092012-112807&mimeType=html&fmt=ahah

Literature Cited

  1. Hodi FS, O'Day SJ, McDermott DF. 1.  et al. 2010. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363:711–23First phase III study to demonstrate an overall survival benefit with therapy in metastatic melanoma. [Google Scholar]
  2. Robert C, Thomas L, Bondarenko I. 2.  et al. 2011. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N. Engl. J. Med. 364:2517–26Phase III study showing improved overall survival with ipilimumab + dacarbazine compared to a previous standard of care, dacarbazine. [Google Scholar]
  3. Andre F, Dieci MV, Dubsky P. 3.  et al. 2013. Molecular pathways: involvement of immune pathways in the therapeutic response and outcome in breast cancer. Clin. Cancer Res. 19:28–33 [Google Scholar]
  4. May KF Jr, Gulley JL, Drake CG. 4.  et al. 2011. Prostate cancer immunotherapy. Clin. Cancer Res. 17:5233–38 [Google Scholar]
  5. Topalian SL, Hodi FS, Brahmer JR. 5.  et al. 2012. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N. Engl. J. Med. 366:2443–54Sentinel phase I trial demonstrating safety and clinical activity for PD-1 blockade. [Google Scholar]
  6. Brahmer JR, Tykodi SS, Chow LQ. 6.  et al. 2012. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N. Engl. J. Med. 366:2455–65Sentinel phase I trial demonstrating safety and clinical activity for PD-L1 blockade. [Google Scholar]
  7. Hamid O, Robert C, Daud A. 7.  et al. 2013. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N. Engl. J. Med. 369:134–44Phase I trial demonstrating safety and clinical activity for MK-3475, a second PD-1 antibody. [Google Scholar]
  8. Krummel MF, Allison JP. 8.  1995. CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation. J. Exp. Med. 182:459–65 [Google Scholar]
  9. Peggs KS, Quezada SA, Chambers CA. 9.  et al. 2009. 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. 206:1717–25 [Google Scholar]
  10. Wolchok JD, Neyns B, Linette G. 10.  et al. 2010. Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. Lancet Oncol. 11:155–64 [Google Scholar]
  11. Robert C, Schadendorf D, Messina M. 11.  et al. 2013. Efficacy and safety of retreatment with ipilimumab in patients with pretreated advanced melanoma who progressed after initially achieving disease control. Clin. Cancer Res. 19:2232–39 [Google Scholar]
  12. Margolin KA, Hamid O, Weber JS. 12.  et al. 2013. Ipilimumab retreatment following induction therapy: the expanded access program (EAP) experience Presented at Annu. Meet. Am. Soc. Clin. Oncol., Chicago, May 31–June 4 [Google Scholar]
  13. Kirkwood JM, Lorigan P, Hersey P. 13.  et al. 2010. Phase II trial of tremelimumab (CP-675,206) in patients with advanced refractory or relapsed melanoma. Clin. Cancer Res. 16:1042–48 [Google Scholar]
  14. Ribas A, Kefford R, Marshall MA. 14.  et al. 2013. Phase III randomized clinical trial comparing tremelimumab with standard-of-care chemotherapy in patients with advanced melanoma. J. Clin. Oncol. 31:616–22 [Google Scholar]
  15. Dong H, Strome SE, Salomao DR. 15.  et al. 2002. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat. Med. 8:793–800 [Google Scholar]
  16. Freeman GJ, Long AJ, Iwai Y. 16.  et al. 2000. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J. Exp. Med. 192:1027–34 [Google Scholar]
  17. Topalian SL, Sznol M, Brahmer JR. 17.  et al. 2013. Nivolumab (anti-PD-1; BMS-936558; ONO-4538) in patients with advanced solid tumors: survival and long-term safety in a phase I trial Presented at Annu. Meet. Am. Soc. Clin. Oncol., Chicago, May 31–June 4
  18. Lipson EJ, Sharfman WH, Drake CG. 18.  et al. 2013. Durable cancer regression off-treatment and effective reinduction therapy with an anti-PD-1 antibody. Clin. Cancer Res. 19:462–68 [Google Scholar]
  19. Infante JR, Powderly JD, Burris HA 3rd. 19.  et al. 2013. Clinical and pharmacodynamic (PD) results of a phase I trial with AMP-224 (B7-DC Fc) that binds to the PD-1 receptor Presented at Annu. Meet. Am. Soc. Clin. Oncol., Chicago, May 31–June 4 [Google Scholar]
  20. Berger R, Rotem-Yehudar R, Slama G. 20.  et al. 2008. Phase I safety and pharmacokinetic study of CT-011, a humanized antibody interacting with PD-1, in patients with advanced hematologic malignancies. Clin. Cancer Res. 14:3044–51 [Google Scholar]
  21. Park JJ, Omiya R, Matsumura Y. 21.  et al. 2010. B7-H1/CD80 interaction is required for the induction and maintenance of peripheral T-cell tolerance. Blood 116:1291–98 [Google Scholar]
  22. Herbst RS, Gordon MS, Fine GD. 22.  et al. 2013. A study of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic tumors Presented at Annu. Meet. Am. Soc. Clin. Oncol., Chicago, May 31–June 4
  23. Hamid O, Sosman JA, Lawrence DP. 23.  et al. 2013. Clinical activity, safety, and biomarkers of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced metastatic melanoma (mM) Presented at Annu. Meet. Am. Soc. Clin. Oncol., Chicago, May 31–June 4 [Google Scholar]
  24. Tabernero J, Powderly JD, Hamid O. 24.  et al. 2013. Clinical activity, safety, and biomarkers of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic CRC, gastric cancer (GC), SCCHN, or other tumors Annu. Meet. Am. Soc. Clin. Oncol., Chicago, May 31–June 4 [Google Scholar]
  25. Parham P. 25.  2005. MHC class I molecules and KIRs in human history, health and survival. Nat. Rev. Immunol. 5:201–14 [Google Scholar]
  26. Wolchok JD, Hoos A, O'Day S. 26.  et al. 2009. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin. Cancer Res. 15:7412–20 [Google Scholar]
  27. Prieto PA, Yang JC, Sherry RM. 27.  et al. 2012. CTLA-4 blockade with ipilimumab: long-term follow-up of 177 patients with metastatic melanoma. Clin. Cancer Res. 18:2039–47 [Google Scholar]
  28. Wolchok JD, Weber JS, Maio M. 28.  et al. 2013. Four-year survival rates for patients with metastatic melanoma who received ipilimumab in phase II clinical trials. Ann. Oncol. 24:2174–80 [Google Scholar]
  29. Weber JS, Kahler KC, Hauschild A. 29.  2012. Management of immune-related adverse events and kinetics of response with ipilimumab. J. Clin. Oncol. 30:2691–97 [Google Scholar]
  30. Hodi FS, Mihm MC, Soiffer RJ. 30.  et al. 2003. Biologic activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade in previously vaccinated metastatic melanoma and ovarian carcinoma patients. Proc. Natl. Acad. Sci. USA 100:4712–17 [Google Scholar]
  31. Johnston RL, Lutzky J, Chodhry A. 31.  et al. 2009. Cytotoxic T-lymphocyte-associated antigen 4 antibody-induced colitis and its management with infliximab. Dig. Dis. Sci. 54:2538–40 [Google Scholar]
  32. Weber JS, Dummer R, de Pril V. 32.  et al. 2013. Patterns of onset and resolution of immune-related adverse events of special interest with ipilimumab: detailed safety analysis from a phase 3 trial in patients with advanced melanoma. Cancer 119:1675–82 [Google Scholar]
  33. O'Day S, Weber JS, Wolchok JD. 33.  et al. 2011. Effectiveness of treatment guidance on diarrhea and colitis across ipilimumab studies Presented at Annu. Meet. Am. Soc. Clin. Oncol., Chicago, June 3–7
  34. Pages C, Gornet JM, Monsel G. 34.  et al. 2013. Ipilimumab-induced acute severe colitis treated by infliximab. Melanoma Res 23:227–30 [Google Scholar]
  35. Downey SG, Klapper JA, Smith FO. 35.  et al. 2007. Prognostic factors related to clinical response in patients with metastatic melanoma treated by CTL-associated antigen-4 blockade. Clin. Cancer Res. 13:6681–88 [Google Scholar]
  36. Revicki DA, van den Eertwegh AJ, Lorigan P. 36.  et al. 2012. Health related quality of life outcomes for unresectable stage III or IV melanoma patients receiving ipilimumab treatment. Health Qual. Life Outcomes 10:66 [Google Scholar]
  37. Ascierto P, Simeone E, V C-S. 37.  et al. 2013. Sequential treatment with ipilimumab and BRAF inhibitors in patients wiht metastatic melanoma: data from the Italian cohort of ipilimumab expanded access programme (EAP) Presented at Annu. Meet. Am. Soc. Clin. Oncol., Chicago, May 31–June 4 [Google Scholar]
  38. Ackerman A, McDermott D, Lawrence D. 38.  et al. 2012. Outcomes of patients with malignant melanoma treated with immunotherapy prior to or after vemurafenib Presented at Annu. Meet. Am. Soc. Clin. Oncol., Chicago, June 1–5
  39. Wolchok J. 39.  2012. How recent advances in immunotherapy are changing the standard of care for patients with metastatic melanoma. Ann. Oncol. 23:Suppl. 8viii15–21 [Google Scholar]
  40. Mangana J, Goldinger SM, Schindler K. 40.  et al. 2013. Analysis of BRAF and NRAS mutation status in advanced melanoma patients treated with anti-CTLA-4 antibodies: association with overall survival Annu. Meet. Am. Soc. Clin. Oncol., Chicago, May 31–June 4
  41. Johnson D, Lovly CM, Flavin M. 41.  et al. 2013. NRAS mutation: a potential biomarker of clinical response to immune-based therapies in metastatic melanoma (MM) Annu. Meet. Am. Soc. Clin. Oncol., Chicago, May 31–June 4 [Google Scholar]
  42. Shahabi V, Whitney G, Hamid O. 42.  et al. 2012. Assessment of association between BRAF-V600E mutation status in melanomas and clinical response to ipilimumab. Cancer Immunol. Immunother. 61:733–37 [Google Scholar]
  43. Luke JJ, Callahan MK, Postow MA. 43.  et al. 2013. Clinical activity of ipilimumab for metastatic uveal melanoma: a retrospective review of the Dana-Farber Cancer Institute, Massachusetts General Hospital, Memorial Sloan-Kettering Cancer Center, and University Hospital of Lausanne experience. Cancer. In press
  44. Del Vecchio M, Simeone E, Chiarion Sileni V. 44.  et al. 2012. Efficacy and safety of ipilimumab in patients with pretreated, mucosal melanoma: experience from Italian clinics participating in the European expanded access programme (EAP) Presented at Congr. Eur. Soc. Med. Oncol., Vienna, Austria, Sep. 28–Oct. 2 [Google Scholar]
  45. Postow MA, Luke JJ, Bluth MJ. 45.  et al. 2013. Ipilimumab for patients with advanced mucosal melanoma. Oncologist 18:726–32 [Google Scholar]
  46. Carvajal RD, Sosman JA, Quevedo F. 46.  et al. 2013. Phase II study of selumetinib (sel) versus temozolomide (TMZ) in gnaq/Gna11 (Gq/11) mutant (mut) uveal melanoma (UM) Annu. Meet. Am. Soc. Clin. Oncol., Chicago, May 31–June 4 [Google Scholar]
  47. Bafaloukos D, Gogas H. 47.  2004. The treatment of brain metastases in melanoma patients. Cancer Treat. Rev. 30:515–20 [Google Scholar]
  48. Wilson EH, Weninger W, Hunter CA. 48.  2010. Trafficking of immune cells in the central nervous system. J. Clin. Invest. 120:1368–79 [Google Scholar]
  49. Margolin K, Ernstoff MS, Hamid O. 49.  et al. 2012. Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. Lancet Oncol. 13:459–65 [Google Scholar]
  50. Di Giacomo AM, Ascierto PA, Pilla L. 50.  et al. 2012. Ipilimumab and fotemustine in patients with advanced melanoma (NIBIT-M1): an open-label, single-arm phase 2 trial. Lancet Oncol. 13:879–86 [Google Scholar]
  51. Wang J, Patel SG, Hwu WJ. 51.  et al. 2012. Development of brain metastases in patients with metastatic melanoma treated with ipilimumab plus temozolomide Presented at Annu. Meet. Am. Soc. Clin. Oncol., Chicago, June 1–5
  52. Patel SP, Hwu WJ, Kim KB. 52.  et al. 2012. Phase II study of the frontline combination of ipilimumab and temozolomide in patients with metastatic melanoma Presented at Annu. Meet. Am. Soc. Clin. Oncol., Chicago, June 1–5
  53. Ku GY, Yuan J, Page DB. 53.  et al. 2010. Single-institution experience with ipilimumab in advanced melanoma patients in the compassionate use setting: lymphocyte count after 2 doses correlates with survival. Cancer 116:1767–75 [Google Scholar]
  54. Postow MA, Yuan J, Panageas KS. 54.  et al. 2012. Evaluation of the absolute lymphocyte count as a biomarker for melanoma patients treated with the commercially available dose of ipilimumab (3 mg/kg) Presented at Annu. Meet. Am. Soc. Clin. Oncol., Chicago, June 1–5
  55. Postow MA, Chasalow SD, Yuan J. 55.  et al. 2013. Pharmacodynamic effect of ipilimumab on absolute lymphocyte count (ALC)and association with overall survival in patients with advanced melanoma Presented at Annu. Meet. Am. Soc. Clin. Oncol., Chicago, May 31–June 4 [Google Scholar]
  56. Delyon J, Mateus C, Lefeuvre D. 56.  et al. 2013. Experience in daily practice with ipilimumab for the treatment of patients with metastatic melanoma: an early increase in lymphocyte and eosinophil counts is associated with improved survival. Ann. Oncol. 24:1697–703 [Google Scholar]
  57. Schindler K, Harmankaya K, Postow MA. 57.  et al. 2013. Pretreatment levels of absolute and relative eosinophil count to improve oversall survival (OS) in patients with metastatic melanoma under treatment with ipilimumab, an anti-CTLA-4 antibody Presented at Annu. Meet. Am. Soc. Clin. Oncol., Chicago, May 31–June 4 [Google Scholar]
  58. Callahan MK, Horak CE, Curran MA. 58.  et al. 2013. Peripheral and tumor immune correlates in patients with advanced melanoma treated with combination nivolumab (anti-PD-1, BMS-936558, ONO-4358) and ipilimumab Presented at Annu. Meet. Am. Soc. Clin. Oncol., Chicago, May 31–June 4 [Google Scholar]
  59. Wolchok JD, Kluger H, Callahan MK. 59.  et al. 2013. Nivolumab plus Ipilimumab in Advanced Melanoma. N. Engl. J. Med. 369:122–33Phase I trial demonstrating dramatic overall response and tolerable safety profile with combination ipilimumab + nivolumab. [Google Scholar]
  60. Grosso JF, Horak CE, Inzunza D. 60.  et al. 2013. Association of tumor PD-L1 expression and immune biomarkers with clinical activity in patients (pts) with advanced solid tumors treated with nivolumab (anti-PD-1; BMS-936558; ONO-4538) Presented at Annu. Meet. Am. Soc. Clin. Oncol., Chicago, May 31–June 4 [Google Scholar]
  61. Carthon BC, Wolchok JD, Yuan J. 61.  et al. 2010. Preoperative CTLA-4 blockade: tolerability and immune monitoring in the setting of a presurgical clinical trial. Clin. Cancer Res. 16:2861–71 [Google Scholar]
  62. Yuan J, Adamow M, Ginsberg BA. 62.  et al. 2011. Integrated NY-ESO-1 antibody and CD8+ T-cell responses correlate with clinical benefit in advanced melanoma patients treated with ipilimumab. Proc. Natl. Acad. Sci. USA 108:16723–28 [Google Scholar]
  63. Hamid O, Schmidt H, Nissan A. 63.  et al. 2011. A prospective phase II trial exploring the association between tumor microenvironment biomarkers and clinical activity of ipilimumab in advanced melanoma. J. Transl. Med. 9:204 [Google Scholar]
  64. Ji RR, Chasalow SD, Wang L. 64.  et al. 2012. An immune-active tumor microenvironment favors clinical response to ipilimumab. Cancer Immunol. Immunother. 61:1019–31 [Google Scholar]
  65. Kitano S, Postow MA, Cortez C. 65.  et al. 2012. Myeloid-derived suppressor cell quantity prior to treatment with ipilimumab at 10 mg/kg to predict for overall survival in patients with metastatic melanoma Presented at Annu. Meet. Am. Soc. Clin. Oncol., Chicago, June 1–5
  66. Ellis SG, Wheater M, Tier K. 66.  et al. 2012. Biomarker for benefit from ipilimumab: correlation of breadth of humor tumor-antigen-specific immunity with outcome Presented at Annu. Meet. Am. Soc. Clin. Oncol., Chicago, June 1–5
  67. Saenger YM, Magidson J, Liaw BC. 67.  et al. 2013. Blood mRNA signature to predict survival in patients with metastatic melanoma treated with tremelimumab Presented at Annu. Meet. Am. Soc. Clin. Oncol., Chicago, May 31–June 4
  68. Shahabi V, Berman D, Chasalow SD. 68.  et al. 2012. Gene expression profiling of whole blood in ipilimumab-treated patients for identification of potential biomarkers of immune-mediated gastrointestinal adverse events Presented at Annu. Meet. Am. Soc. Clin. Oncol., Chicago, June 1–5
  69. Melero I, Grimaldi AM, Perez-Gracia JL. 69.  et al. 2013. Clinical development of immunostimulatory monoclonal antibodies and opportunities for combination. Clin. Cancer Res. 19:997–1008 [Google Scholar]
  70. Atkins MB, Hsu J, Lee S. 70.  et al. 2008. Phase III trial comparing concurrent biochemotherapy with cisplatin, vinblastine, dacarbazine, interleukin-2, and interferon alfa-2b with cisplatin, vinblastine, and dacarbazine alone in patients with metastatic malignant melanoma (E3695): a trial coordinated by the Eastern Cooperative Oncology Group. J. Clin. Oncol. 26:5748–54 [Google Scholar]
  71. Chi M, Dudek AZ. 71.  2011. Vaccine therapy for metastatic melanoma: systematic review and meta-analysis of clinical trials. Melanoma Res. 21:165–74 [Google Scholar]
  72. Bernatchez C, Radvanyi LG, Hwu P. 72.  2012. Advances in the treatment of metastatic melanoma: adoptive T-cell therapy. Semin. Oncol. 39:215–26 [Google Scholar]
  73. Boni A, Cogdill AP, Dang P. 73.  et al. 2010. Selective BRAFV600E inhibition enhances T-cell recognition of melanoma without affecting lymphocyte function. Cancer Res. 70:5213–19 [Google Scholar]
  74. Wilmott JS, Long GV, Howle JR. 74.  et al. 2012. Selective BRAF inhibitors induce marked T-cell infiltration into human metastatic melanoma. Clin. Cancer Res. 18:1386–94 [Google Scholar]
  75. Vanneman M, Dranoff G. 75.  2012. Combining immunotherapy and targeted therapies in cancer treatment. Nat. Rev. Cancer 12:237–51 [Google Scholar]
  76. Ribas A, Hodi FS, Callahan M. 76.  et al. 2013. Hepatotoxicity with combination of vemurafenib and ipilimumab. N. Engl. J. Med. 368:1365–66 [Google Scholar]
  77. Hodi FS, Friedlander PA, Atkins MB. 77.  et al. 2011. A phase I trial of ipilimumab plus bevacizumab in patients with unresectable stage III or stage IV melanoma Presented at Annu. Meet. Am. Soc. Clin. Oncol., Chicago, June 3–7
  78. Hodi FS, Lee SJ, McDermott DF. 78.  et al. 2013. Multicenter, randomized phase II trial of GM-CSF (GM) plus ipilimumab (Ipi) versus Ipi alone in metastatic melanoma: E1608 Presented at Annu. Meet. Am. Soc. Clin. Oncol., Chicago, May 31–June 4 [Google Scholar]
  79. Postow MA, Callahan MK, Barker CA. 79.  et al. 2012. Immunologic correlates of the abscopal effect in a patient with melanoma. N. Engl. J. Med. 366:925–31Case report demonstrating immune correlates of the abscopal effect in a patient treated with ipilimumab and external beam radiation. [Google Scholar]
  80. Dewan MZ, Galloway AE, Kawashima N. 80.  et al. 2009. Fractionated but not single-dose radiotherapy induces an immune-mediated abscopal effect when combined with anti-CTLA-4 antibody. Clin. Cancer Res. 15:5379–88 [Google Scholar]
  81. Shoukat S, Marcus DM, Rizzo M. 81.  et al. 2013. Outcome with stereotactic radiosurgery (SRS) and ipilimumab (Ipi) for malignant melanoma brain metastases Presented at Annu. Meet. Am. Soc. Clin. Oncol., Chicago, May 31–June 4 [Google Scholar]
  82. Simeone E, Benedetto L, Gentilcore G. 82.  et al. 2013. Combination therapy with ipilimumab and electrochemotherapy: preliminary efficacy results and correlation with immunologic parameters Presented at Annu. Meet. Am. Soc. Clin. Oncol., Chicago, May 31–June 4
  83. Slovin SF, Higano CS, Hamid O. 83.  et al. 2013. 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. 24:1813–21 [Google Scholar]
  84. Gertner-Dardenne J, Fauriat C, Orlanducci F. 84.  et al. 2013. The co-receptor BTLA negatively regulates human Vγ9Vδ2 T-cell proliferation: a potential way of immune escape for lymphoma cells. Blood 122:922–31 [Google Scholar]
  85. Berrien-Elliott MM, Jackson SR, Meyer JM. 85.  et al. 2013. Durable adoptive immunotherapy for leukemia produced by manipulation of multiple regulatory pathways of CD8+ T-cell tolerance. Cancer Res. 73:605–16 [Google Scholar]
  86. Fu T, He Q, Sharma P. 86.  2011. The ICOS/ICOSL pathway is required for optimal antitumor responses mediated by anti-CTLA-4 therapy. Cancer Res. 71:5445–54 [Google Scholar]
  87. Vonderheide RH, Flaherty KT, Khalil M. 87.  et al. 2007. Clinical activity and immune modulation in cancer patients treated with CP-870,893, a novel CD40 agonist monoclonal antibody. J. Clin. Oncol. 25:876–83 [Google Scholar]
  88. Vonderheide RH, Glennie MJ. 88.  2013. Agonistic CD40 antibodies and cancer therapy. Clin. Cancer Res. 19:1035–43 [Google Scholar]
  89. Melero I, Hirschhorn-Cymerman D, Morales-Kastresana A. 89.  et al. 2013. Agonist antibodies to TNFR molecules that costimulate T and NK cells. Clin. Cancer Res. 19:1044–53 [Google Scholar]
  90. Vinay DS, Kwon BS. 90.  2012. Immunotherapy of cancer with 4-1BB. Mol. Cancer Ther. 11:1062–70 [Google Scholar]
  91. Schaer DA, Murphy JT, Wolchok JD. 91.  2012. Modulation of GITR for cancer immunotherapy. Curr. Opin. Immunol. 24:217–24 [Google Scholar]
  92. Small EJ, Tchekmedyian NS, Rini BI. 92.  et al. 2007. A pilot trial of CTLA-4 blockade with human anti-CTLA-4 in patients with hormone-refractory prostate cancer. Clin. Cancer Res. 13:1810–15 [Google Scholar]
  93. Yang JC, Hughes M, Kammula U. 93.  et al. 2007. Ipilimumab (anti-CTLA4 antibody) causes regression of metastatic renal cell cancer associated with enteritis and hypophysitis. J. Immunother. 30:825–30 [Google Scholar]
  94. Spigel DR, Gettinger SN, Horn L. 94.  et al. 2013. Clinical activity, safety, and biomarkers of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) Presented at Annu. Meet. Am. Soc. Clin. Oncol., Chicago, May 31–June 4 [Google Scholar]
  95. Cho DH, Sosman JA, Sznol M. 95.  et al. 2013. Clinical activity, safety, and biomarkers of MPDL3280A, an engineered PD-L1 antibody in patients with metastatic renal cell carcinoma (mRCC) Presented at Annu. Meet. Am. Soc. Clin. Oncol., Chicago, May 31–June 4 [Google Scholar]
  96. Sznol M, Kluger HM, Hodi FS. 96.  et al. 2013. Survival and long-term follow-up of safety and response in patients (pts) with advanced melanoma (MEL) in a phase I trial of nivolumab (anti-PD-1; BMS-936558; ONO-4538) Presented at Annu. Meet. Am. Soc. Clin. Oncol., Chicago, May 31–June 4 [Google Scholar]
  97. Brahmer JR, Horn L, Antonia SJ. 97.  et al. 2013. Survival and long-term follow-up of the phase I trial of nivolumab (anti-PD-1; BMS-936558; ONO-4358) in patients (pts) with previously treated advanced non-small cell lung cancer (NSCLC) Presented at Annu. Meet. Am. Soc. Clin. Oncol., Chicago, May 31–June 4 [Google Scholar]
  98. Drake CG, McDermott DF, Sznol M. 98.  et al. 2013. Survival, safety, and response duration results of nivolumab (anti-PD-1; BMS-936558; ONO-4538) in a phase I trial in patients with previously treated metastatic renal cell carcinoma (mRCC): long-term patient follow-up Presented at Annu. Meet. Am. Soc. Clin. Oncol., Chicago, May 31–June 4 [Google Scholar]
  99. Chung KY, Gore I, Fong L. 99.  et al. 2010. 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. 28:3485–90 [Google Scholar]
  100. Ralph C, Elkord E, Burt DJ. 100.  et al. 2010. Modulation of lymphocyte regulation for cancer therapy: a phase II trial of tremelimumab in advanced gastric and esophageal adenocarcinoma. Clin. Cancer Res. 16:1662–72 [Google Scholar]
  101. Zatloukal P, Heo DS, Park K. 101.  et al. 2009. Randomized phase II clinical trial comparing tremelimumab (CP-675,206) with best supportive care (BSC) following first-line platinum-based therapy in patients with advanced non-small cell lung cancer (NSCLC) Presented at Annu. Meet. Am. Soc. Clin. Oncol., Orlando, Florida [Google Scholar]
  102. Vonderheide RH, LoRusso PM, Khalil M. 102.  et al. 2010. 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. 16:3485–94 [Google Scholar]
  103. Reck M, Bondarenko I, Luft A. 103.  et al. 2013. Ipilimumab in combination with paclitaxel and carboplatin as first-line therapy in extensive-disease-small-cell lung cancer: results from a randomized, double-blind, multicenter phase 2 trial. Ann. Oncol. 24:75–83 [Google Scholar]
  104. Gibney GT, Weber JS, Kudchadkar RR. 104.  et al. 2013. Safety and efficacy of adjuvant anti-PD1 therapy (nivolumab) in combination with vaccine in resected high-risk metastatic melanoma Presented at Annu. Meet. Am. Soc. Clin. Oncol., Chicago, May 31–June 4 [Google Scholar]
  105. Kudchadkar RR, Gibney GT, Weber JS. 105.  et al. 2013. A phase IB study of ipilimumab with peginterferon alfa-2b in patients with unresectable melanoma Presented at Annu. Meet. Am. Soc. Clin. Oncol., Chicago, May 31–June 4
  106. Tarhini AA, Cherian J, Moschos SJ. 106.  et al. 2012. Safety and efficacy of combination immunotherapy with interferon alfa-2b and tremelimumab in patients with stage IV melanoma. J. Clin. Oncol. 30:322–28 [Google Scholar]
  107. Millward M, Underhill C, Lobb S. 107.  et al. 2013. Phase I study of tremelimumab (CP-675 206) plus PF-3512676 (CPG 7909) in patients with melanoma or advanced solid tumours. Br. J. Cancer 108:1998–2004 [Google Scholar]
  108. Lynch TJ, Bondarenko I, Luft A. 108.  et al. 2012. 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. 30:2046–54 [Google Scholar]
  109. Rizvi NA, Antonia SJ, Quan Man Chow L. 109.  et al. 2013. A phase I study of nivolumab (anti-PD-1; BMS-936558, ONO-4358) plus platinum-based doublet chemotherapy (PT-doublet) in chemotherapy-naive non-small cell lung cancer (NSCLC) patients (pts) Presented at Annu. Meet. Am. Soc. Clin. Oncol., Chicago, May 31–June 4 [Google Scholar]
  110. Madan RA, Mohebtash M, Arlen PM. 110.  et al. 2012. Ipilimumab and a poxviral vaccine targeting prostate-specific antigen in metastatic castration-resistant prostate cancer: a phase 1 dose-escalation trial. Lancet Oncol. 13:501–8 [Google Scholar]
  111. Tollefson MK, Karnes RJ, Thompson RH. 111.  et al. 2010. A randomized phase II study of ipilimumab with androgen ablation compared with androgen ablation alone in patients with advanced prostate cancer Presented at Genitourinary Cancers Symp., San Francisco,
  112. Small EJ, Higano CS, Tchekmedyian NS. 112.  et al. 2006. Randomized phase II study comparing 4 monthly doses of ipilimumab (MDX-010) as a single agent or in combination with a single dose of docetaxel in patients with hormone-refractory prostate cancer Presented at Annu. Meet. Am. Soc. Clin. Oncol., Atlanta [Google Scholar]
  113. McNeel DG, Smith HA, Eickhoff JC. 113.  et al. 2012. Phase I trial of tremelimumab in combination with short-term androgen deprivation in patients with PSA-recurrent prostate cancer. Cancer Immunol. Immunother. 61:1137–47 [Google Scholar]
  114. Rini BI, Stein M, Shannon P. 114.  et al. 2011. Phase 1 dose-escalation trial of tremelimumab plus sunitinib in patients with metastatic renal cell carcinoma. Cancer 117:758–67 [Google Scholar]
/content/journals/10.1146/annurev-med-092012-112807
Loading
/content/journals/10.1146/annurev-med-092012-112807
Loading

Data & Media loading...

Supplementary Data

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error