Skip to main content
SpringerLink
Log in

Emerging Biomarkers During Clinical Development of Anti-CTLA4 Antibody Therapy

  • Chapter
  • First Online:
Cancer Immunology

  • 3088 Accesses

Abstract

Ipilimumab, an antibody that blocks cytotoxic T-lymphocyte antigen 4 (CTLA4), was approved by the US Food and Drug Administration for advanced melanoma. However, only a subset of patients benefit, often with delayed radiographic response and at the expense of immune-related toxicity. Biomarker studies provide a platform to analyze pharmacodynamic changes during ipilimumab treatment, elucidating potential mechanisms of action and identifying patients who are more likely to benefit and/or are at greatest risk of developing immune-related toxicities. A variety of immunological assays are currently available to monitor phenotypic changes in different immune cell populations (activated T cells, regulatory T cells, myeloid-derived suppressor cells) and assess antigen-specific responses, as well as to assess the functionality and gene expression profile of antigen-specific T cell populations. New tools and directions include the use of protein arrays, the evaluation of other inhibitory molecules like programmed death 1 (PD-1), lymphocyte-activation gene-3 (LAG-3), T cell immunoglobulin mucin 3 (Tim-3), and the evaluation of immune response at the tumor site. Any promising biomarker will ultimately require validation in prospective clinical trials. In this chapter, we describe the progress of biomarker assay development in anti-CTLA4 trials and review putative biomarkers. We provide a forward-looking perspective on immune monitoring of anti-CTLA4 immunotherapy in the context of increasingly complex and effective combination therapies.

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. Brunner MC, Chambers CA, Chan FK, Hanke J, Winoto A, Allison JP. CTLA-4-Mediated inhibition of early events of T cell proliferation. J Immunol. 1999;162(10):5813–20.

    CAS  PubMed  Google Scholar 

  2. Karandikar NJ, Vanderlugt CL, Walunas TL, Miller SD, Bluestone JA. CTLA-4: a negative regulator of autoimmune disease. J Exp Med. 1996;184(2):783–8.

    Article  CAS  PubMed  Google Scholar 

  3. Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma. New Engl J Med. 2010;363(8):711–23.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  4. Robert C, Thomas L, Bondarenko I, O’Day S, Weber J, Garbe C. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. New Engl J Med. 2011;364(26):2517–26.

    Article  CAS  PubMed  Google Scholar 

  5. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. New Engl J Med. 2012;366(26):2443–54.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. Atkins MB, Lotze MT, Dutcher JP, Fisher RI, Weiss G, Margolin K, et al. High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol. 1999;17(7):2105–16.

    CAS  PubMed  Google Scholar 

  7. Slovin SF, Higano CS, Hamid O, Tejwani S, Harzstark A, Alumkal JJ, 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):18–21.

    Article  Google Scholar 

  8. Sprinzl MF, Galle PR. Facing the dawn of immunotherapy for hepatocellular carcinoma. J Hepatol. 2013;59(1):1–9.

    Article  Google Scholar 

  9. Genova C, Rijavec E, Barletta G, Sini C, Dal Bello MG, Truini M, et al. Ipilimumab (MDX-010) in the treatment of non-small cell lung cancer. Exp Opin Biol Ther. 2012;12(7):939–48.

    Article  CAS  Google Scholar 

  10. Royal RE, Levy C, Turner K, Mathur A, Hughes M, Kammula US, et al. Phase 2 trial of single agent Ipilimumab (anti-CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma. J Immunother. 2010;33(8):828–33.

    Article  CAS  PubMed  Google Scholar 

  11. 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 

  12. O’Mahony D, Morris JC, Quinn C, Gao W, Wilson WH, Gause B, et al. A pilot study of CTLA-4 blockade after cancer vaccine failure in patients with advanced malignancy. Clin Cancer Res. 2007;13(3):958–64.

    Article  PubMed  Google Scholar 

  13. Attia P, Phan GQ, Maker AV, Robinson MR, Quezado MM, Yang JC, 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(25):6043–53.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Hoos A, Ibrahim R, Korman A, Abdallah K, Berman D, Shahabi V, et al. Development of ipilimumab: contribution to a new paradigm for cancer immunotherapy. Semin Oncol. 2010;37(5):533–46.

    Article  CAS  PubMed  Google Scholar 

  15. Wolchok JD, Neyns B, Linette G, Negrier S, Lutzky J, Thomas L, et al. Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. Lancet Oncol. 2010;11(2):155–64.

    Article  CAS  PubMed  Google Scholar 

  16. Berman D, Wolchok JD, Weber J. Association of peripheral blood absolute lymphocyte count (ALC) and clinical activity in patients (pts) with advanced melanoma treated with ipilimumab. J Clin Oncol. 2009;27(15 Suppl):abstr 3020.

    Google Scholar 

  17. Ku GY, Yuan J, Page DB, Schroeder SE, Panageas KS, Carvajal RD, et al. Single-institution experience with ipilimumab in advanced melanoma patients in the compassionate use setting: lymphocyte count after 2 doses correlates with survival. Cancer. 2010;116(7):1767–75.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Postow M, Yuan J, Panageas KS, Chang M, Ku D, Wolchok JD. Evaluation of the absolute lymphocyte count as a biomarker for melanoma patients treated with the commercially available dose of ipilimumab (3 mg/kg). J Clin Oncol. 2012;30(Suppl):abstr 8575.

    Google Scholar 

  19. Wilgenhof S, Four SD, Vandenbroucke F, Everaert H, Salmon I, Lienard D, et al. Single-center experience with ipilimumab in an expanded access program for patients with pretreated advanced melanoma. J Immunother. 2013;36(3):215–22.

    Article  CAS  PubMed  Google Scholar 

  20. Santegoets SJ, Stam AG, Lougheed SM, Gall H, Scholten PE, Reijm M, et al. T cell profiling reveals high CD4+CTLA-4 + T cell frequency as dominant predictor for survival after prostate GVAX/ipilimumab treatment. Cancer Immunol Immunother. 2013;62(2):245–56.

    Article  CAS  PubMed  Google Scholar 

  21. Yang AS, Kendle RF, Ginsberg BA, Roman A, Heine AI, Pogoriler HE, et al. CTLA-4 blockade with Ipilimumab increases peripheral CD8+ T Cells: Correlation with Clinical Outcomes. J Clin Oncol. 2010;28(15 Suppl):abstr 2555.

    Google Scholar 

  22. Phan GQ, Yang JC, Sherry RM, Hwu P, Topalian SL, Schwartzentruber DJ, 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(14):8372–7.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Maker AV, Yang JC, Sherry RM, Topalian SL, Kammula US, Royal RE, et al. Intrapatient dose escalation of anti-CTLA-4 antibody in patients with metastatic melanoma. J Immunother. 2006;29(4):455–63.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Maker AV, Phan GQ, Attia P, Yang JC, Sherry RM, Topalian SL, et al. Tumor regression and autoimmunity in patients treated with cytotoxic T lymphocyte-associated antigen 4 blockade and interleukin 2: a phase I/II study. Ann Surg Oncol. 2005;12(12):1005–16.

    Article  PubMed Central  PubMed  Google Scholar 

  25. Weber JS, Hamid O, Chasalow SD, Wu DY, Parker SM, Galbraith S, et al. Ipilimumab increases activated T cells and enhances humoral immunity in patients with advanced melanoma. J Immunother. 2012;35(1):89–97.

    Article  CAS  PubMed  Google Scholar 

  26. Comin-Anduix B, Lee Y, Jalil J, Algazi A, de la Rocha P, Camacho LH, et al. Detailed analysis of immunologic effects of the cytotoxic T lymphocyte-associated antigen 4-blocking monoclonal antibody tremelimumab in peripheral blood of patients with melanoma. J Transl Med. 2008;6:22.

    Article  PubMed Central  PubMed  Google Scholar 

  27. Carthon BC, Wolchok JD, Yuan J, Kamat A, Ng Tang DS, Sun J, et al. Preoperative CTLA-4 blockade: tolerability and immune monitoring in the setting of a presurgical clinical trial. Clin Cancer Res. 2010;16(10):2861–71.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Wang W, Yu D, Sarnaik AA, Yu B, Hall M, Morelli D, et al. Biomarkers on melanoma patient T cells associated with ipilimumab treatment. J Transl Med. 2012;10:146.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Liakou CI, Kamat A, Tang DN, Chen H, Sun J, Troncoso P, et al. CTLA-4 blockade increases IFNgamma-producing CD4+ICOShi cells to shift the ratio of effector to regulatory T cells in cancer patients. Proc Natl Acad Sci U S A. 2008;105(39):14987–92.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. Vonderheide RH, LoRusso PM, Khalil M, Gartner EM, Khaira D, Soulieres D, 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(13):3485–94.

    Article  CAS  PubMed  Google Scholar 

  31. Sakaguchi S. Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self. Nat Immunol. 2005;6(4):345–52.

    Article  CAS  PubMed  Google Scholar 

  32. Graca L. New tools to identify regulatory T cells. Eur J Immunol. 2005;35(6):1678–80.

    Article  CAS  PubMed  Google Scholar 

  33. Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol. 1995;155(3):1151–64.

    CAS  PubMed  Google Scholar 

  34. Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science. 2003;299(5609):1057–61.

    Article  CAS  PubMed  Google Scholar 

  35. Liyanage UK, Moore TT, Joo HG, Tanaka Y, Herrmann V, Doherty G, et al. Prevalence of regulatory T cells is increased in peripheral blood and tumor microenvironment of patients with pancreas or breast adenocarcinoma. J Immunol. 2002;169(5):2756–61.

    Article  CAS  PubMed  Google Scholar 

  36. Curiel TJ, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P, et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med. 2004;10(9):942–9.

    Article  CAS  PubMed  Google Scholar 

  37. Viguier M, Lemaitre F, Verola O, Cho MS, Gorochov G, Dubertret L, et al. Foxp3 expressing CD4+CD25(high) regulatory T cells are overrepresented in human metastatic melanoma lymph nodes and inhibit the function of infiltrating T cells. J Immunol. 2004;173(2):1444–53.

    Article  CAS  PubMed  Google Scholar 

  38. 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(4):1175–83.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Wang R, Kozhaya L, Mercer F, Khaitan A, Fujii H, Unutmaz D. Expression of GARP selectively identifies activated human FOXP3+ regulatory T cells. Proc Natl Acad Sci U S A. 2009;106(32):13439–44.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  40. Thornton AM, Korty PE, Tran DQ, Wohlfert EA, Murray PE, Belkaid Y, et al. Expression of Helios, an Ikaros transcription factor family member, differentiates thymic-derived from peripherally induced Foxp3+ T regulatory cells. J Immunol. 2010;184(7):3433–41.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  41. Whiteside TL. Disarming suppressor cells to improve immunotherapy. Cancer Immunol Immunother. 2012;61(2):283–8.

    Article  CAS  PubMed  Google Scholar 

  42. Mazzoni A, Bronte V, Visintin A, Spitzer JH, Apolloni E, Serafini P, et al. Myeloid suppressor lines inhibit T cell responses by an NO-dependent mechanism. J Immunol. 2002;168(2):689–95.

    Article  CAS  PubMed  Google Scholar 

  43. Kusmartsev SA, Li Y, Chen SH. Gr-1+ myeloid cells derived from tumor-bearing mice inhibit primary T cell activation induced through CD3/CD28 costimulation. J Immunol. 2000;165(2):779–85.

    Article  CAS  PubMed  Google Scholar 

  44. Talmadge JE. Pathways mediating the expansion and immunosuppressive activity of myeloid-derived suppressor cells and their relevance to cancer therapy. Clin Cancer Res. 2007;13(18):5243–8.

    Article  CAS  PubMed  Google Scholar 

  45. Peranzoni E, Zilio S, Marigo I, Dolcetti L, Zanovello P, Mandruzzato S, et al. Myeloid-derived suppressor cell heterogeneity and subset definition. Curr Opin Immunol. 2010;22(2):238–44.

    Article  CAS  PubMed  Google Scholar 

  46. Poschke I, Mougiakakos D, Hansson J, Masucci GV, Kiessling R. Immature immunosuppressive CD14+HLA-DR-/low cells in melanoma patients are Stat3hi and overexpress CD80, CD83, and DC-sign. Cancer Res. 2010;70(11):4335–45.

    Article  CAS  PubMed  Google Scholar 

  47. Kitano S, Postow M, Rasalan T, Gallardo HF, Panageas K, Yuan J, et al. Myeloid derived suppressor cell quantity prior to treatment with ipilimumab at 10mg/kg predicts for clinical benefit and improved overall survival in patients with metastatic melanoma. J Clin Oncol. 2012;30(Suupl):abstract 2518.

    Google Scholar 

  48. Preuss KD, Zwick C, Bormann C, Neumann F, Pfreundschuh M. Analysis of the B-cell repertoire against antigens expressed by human neoplasms. Immunol Rev. 2002;188:43–50.

    Article  CAS  PubMed  Google Scholar 

  49. Boon T, Coulie PG, Van den Eynde BJ, van der Bruggen P. Human T cell responses against melanoma. Ann Rev Immunol. 2006;24:175–208.

    Article  CAS  Google Scholar 

  50. Gnjatic S, Nishikawa H, Jungbluth AA, Gure AO, Ritter G, Jager E, et al. NY-ESO-1: review of an immunogenic tumor antigen. Adv Cancer Res. 2006;95:1–30.

    Article  CAS  PubMed  Google Scholar 

  51. Jager E, Karbach J, Gnjatic S, Neumann A, Bender A, Valmori D, et al. Recombinant vaccinia/fowlpox NY-ESO-1 vaccines induce both humoral and cellular NY-ESO-1-specific immune responses in cancer patients. Proc Natl Acad Sci U S A. 2006;103(39):14453–8.

    Article  PubMed Central  PubMed  Google Scholar 

  52. Bendandi M, Gocke CD, Kobrin CB, Benko FA, Sternas LA, Pennington R, et al. Complete molecular remissions induced by patient-specific vaccination plus granulocyte-monocyte colony-stimulating factor against lymphoma. Nat Med. 1999;5(10):1171–7.

    Article  CAS  PubMed  Google Scholar 

  53. Jinushi M, Hodi FS, Dranoff G. Therapy-induced antibodies to MHC class I chain-related protein A antagonize immune suppression and stimulate antitumor cytotoxicity. Proc Natl Acad Sci U S A. 2006;103(24):9190–5.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  54. Hodi FS, Butler M, Oble DA, Seiden MV, Haluska FG, Kruse A, et al. Immunologic and clinical effects of antibody blockade of cytotoxic T lymphocyte-associated antigen 4 in previously vaccinated cancer patients. Proc Natl Acad Sci U S A. 2008;105(8):3005–10.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  55. Yuan J, Adamow M, Ginsberg BA, Rasalan TS, Ritter E, Gallardo HF, et al. 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 U S A. 2011;108(40):16723–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  56. Goff SL, Robbins PF, El-Gamil M, Rosenberg SA. No correlation between clinical response to CTLA-4 blockade and presence of NY-ESO-1 antibody in patients with metastatic melanoma. J Immunother. 2009;32(8):884–5.

    Article  PubMed  Google Scholar 

  57. Fong L, Kwek SS, O’Brien S, Kavanagh B, McNeel DG, Weinberg V, et al. Potentiating endogenous antitumor immunity to prostate cancer through combination immunotherapy with CTLA4 blockade and GM-CSF. Cancer Res. 2009;69(2):609–15.

    Article  CAS  PubMed  Google Scholar 

  58. Kwek SS, Dao V, Roy R, Hou Y, Alajajian D, Simko JP, et al. Diversity of antigen-specific responses induced in vivo with CTLA-4 blockade in prostate cancer patients. J Immunol. 2012;189(7):3759–66.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  59. Sewell WA, North ME, Webster AD, Farrant J. Determination of intracellular cytokines by flow-cytometry following whole-blood culture. J Immunol Methods. 1997;209(1):67–74.

    Article  CAS  PubMed  Google Scholar 

  60. Seder RA, Darrah PA, Roederer M. T-cell quality in memory and protection: implications for vaccine design. Nat Rev Immunol. 2008;8(4):247–58.

    Article  CAS  PubMed  Google Scholar 

  61. Newell EW, Klein LO, Yu W, Davis MM. Simultaneous detection of many T-cell specificities using combinatorial tetramer staining. Nat Methods. 2009;6(7):497–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  62. Guillaume P, Dojcinovic D, Luescher IF. Soluble MHC-peptide complexes: tools for the monitoring of T cell responses in clinical trials and basic research. Cancer Immun. 2009;9:7.

    PubMed Central  PubMed  Google Scholar 

  63. Horton H, Thomas EP, Stucky JA, Frank I, Moodie Z, Huang YD, et al. Optimization and validation of an 8-color intracellular cytokine staining (ICS) assay to quantify antigen-specific T cells induced by vaccination. J Immunol Methods. 2007;323(1):39–54.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  64. Yuan J, Gnjatic S, Li H, Powel S, Gallardo HF, Ritter E, et al. CTLA-4 blockade enhances polyfunctional NY-ESO-1 specific T cell responses in metastatic melanoma patients with clinical benefit. Proc Natl Acad Sci U S A. 2008;105(51):20410–5.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  65. Klein O, Ebert LM, Nicholaou T, Browning J, Russell SE, Zuber M, et al. Melan-A-specific cytotoxic T cells are associated with tumor regression and autoimmunity following treatment with anti-CTLA-4. Clin Cancer Res. 2009;15(7):2507–13.

    Article  CAS  PubMed  Google Scholar 

  66. Weide B, Zelba H, Derhovanessian E, Pflugfelder A, Eigentler TK, Di Giacomo AM, et al. Functional T cells targeting NY-ESO-1 or Melan-A are predictive for survival of patients with distant melanoma metastasis. J Clin Oncol. 2012;30(15):1835–41.

    Article  CAS  PubMed  Google Scholar 

  67. Zhang L, Conejo-Garcia JR, Katsaros D, Gimotty PA, Massobrio M, Regnani G, et al. Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. New Engl J Med. 2003;348(3):203–13.

    Article  CAS  PubMed  Google Scholar 

  68. Sato E, Olson SH, Ahn J, Bundy B, Nishikawa H, Qian F, et al. Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proc Natl Acad Sci U S A. 2005;102(51):18538–43.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  69. Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pages C, et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science. 2006;313(5795):1960–4.

    Article  CAS  PubMed  Google Scholar 

  70. Cipponi A, Wieers G, van Baren N, Coulie PG. Tumor-infiltrating lymphocytes: apparently good for melanoma patients. But why? Cancer Immunol Immunother. 2011;60(8):1153–60.

    Article  PubMed  Google Scholar 

  71. Fridman WH, Galon J, Dieu-Nosjean MC, Cremer I, Fisson S, Damotte D, et al. Immune infiltration in human cancer: prognostic significance and disease control. Curr Top Microbiol Immunol. 2011;344:1–24.

    CAS  PubMed  Google Scholar 

  72. Hamid O, Schmidt H, Nissan A, Ridolfi L, Aamdal S, Hansson J, et al. A prospective phase II trial exploring the association between tumor microenvironment biomarkers and clinical activity of ipilimumab in advanced melanoma. J Transl Med. 2011;9:204.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  73. Huang RR, Jalil J, Economou JS, Chmielowski B, Koya RC, Mok S, et al. CTLA4 blockade induces frequent tumor infiltration by activated lymphocytes regardless of clinical responses in humans. Clin Cancer Res. 2011;17(12):4101–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  74. Ji RR, Chasalow SD, Wang L, Hamid O, Schmidt H, Cogswell J, et al. An immune-active tumor microenvironment favors clinical response to ipilimumab. Cancer Immunol Immunother. 2012;61(7):1019–31.

    Article  CAS  PubMed  Google Scholar 

  75. Ascierto PA, Kalos M, Schaer DA, Callahan MK, Wolchok JD. Biomarkers for immunostimulatory monoclonal antibodies in combination strategies for melanoma and other tumor types. Clin Cancer Res. 2013;19(5):1009–20.

    Article  CAS  PubMed  Google Scholar 

  76. Drake CG. Combination immunotherapy approaches. Ann Oncol. 2012;23 Suppl 8:viii 41–6.

    Article  Google Scholar 

  77. Waitz R, Solomon SB, Petre EN, Trumble AE, Fasso M, Norton L, et al. Potent induction of tumor immunity by combining tumor cryoablation with anti-CTLA-4 therapy. Cancer Res. 2012;72(2):430–9.

    Article  CAS  PubMed  Google Scholar 

  78. 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(9):4275–80.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  79. 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(3):355–66.

    Article  PubMed Central  PubMed  Google Scholar 

  80. Gulley JL, Dahut WL. Future directions in tumor immunotherapy: CTLA4 blockade. Nat Clin Pract Oncol. 2007;4(3):136–7.

    Article  CAS  PubMed  Google Scholar 

  81. Monney L, Sabatos CA, Gaglia JL, Ryu A, Waldner H, Chernova T, et al. Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease. Nature. 2002;415(6871):536–41.

    Article  CAS  PubMed  Google Scholar 

  82. Barber DL, Wherry EJ, Masopust D, Zhu B, Allison JP, Sharpe AH, et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature. 2006;439(7077):682–7.

    Article  CAS  PubMed  Google Scholar 

  83. Petrovas C, Price DA, Mattapallil J, Ambrozak DR, Geldmacher C, Cecchinato V, et al. SIV-specific CD8+ T cells express high levels of PD1 and cytokines but have impaired proliferative capacity in acute and chronic SIVmac251 infection. Blood. 2007;110(3):928–36.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  84. Fourcade J, Sun Z, Benallaoua M, Guillaume P, Luescher IF, Sander C, et al. Upregulation of Tim-3 and PD-1 expression is associated with tumor antigen-specific CD8+ T cell dysfunction in melanoma patients. J Exp Med. 2010;207(10):2175–86.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  85. Goldberg MV, Drake CG. LAG-3 in cancer immunotherapy. Curr Top Microbiol Immunol. 2011;344:269–78.

    CAS  PubMed  Google Scholar 

  86. 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(19):12293–7.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  87. Grosso JF, Kelleher CC, Harris TJ, Maris CH, Hipkiss EL, De Marzo A, et al. LAG-3 regulates CD8+ T cell accumulation and effector function in murine self- and tumor-tolerance systems. J Clin Invest. 2007;117(11):3383–92.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  88. Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med. 2002;8(8):793–800.

    CAS  PubMed  Google Scholar 

  89. Matsuzaki J, Gnjatic S, Mhawech-Fauceglia P, Beck A, Miller A, Tsuji T, 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 USA. 2010;107(17):7875–80.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  90. Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. New Engl J Med. 2012;366(26):2455–65.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgements

This chapter is dedicated to the memory of Dr. Lloyd Old, our mentor and friend and one of the true leaders in investigational cancer immunotherapy. His many profound insights inspired much of our group’s immune biomarker studies.

Author information

Authors and Affiliations

  1. Gastrointestinal Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, 10065, USA

    Geoffery Y. Ku MD

  2. Department of Internal Medicine, New York-Presbyterian Hospital, Weill Cornell Medical College of Cornell University, New York, NY, 10065, USA

    Chrisann Kyi MD, BA

  3. Immunology Program, Ludwig Center for Cancer Immunotherapy, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center New York, New York, NY, 10065, USA

    Jianda Yuan MD, PhD

Authors
  1. Geoffery Y. Ku MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chrisann Kyi MD, BA
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jianda Yuan MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jianda Yuan MD, PhD .

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

Ku, G.Y., Kyi, C., Yuan, J. (2015). Emerging Biomarkers During Clinical Development of Anti-CTLA4 Antibody Therapy. In: Rezaei, N. (eds) Cancer Immunology. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-662-44946-2_24

Download citation

  • DOI: https://doi.org/10.1007/978-3-662-44946-2_24

  • 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