Skip to main content
SpringerLink
Log in

CTLA-4

  • Reference work entry
  • First Online:
Cancer Therapeutic Targets

  • 1903 Accesses

Abstract

This is a brief summary of the biologic basis for use of CTLA-4 blockade in the treatment of cancer, specifically melanoma and renal cell carcinoma. Included is the biology of CTLA-4, the preclinical and clinical studies to date. Lastly, the future goals and directions of CTLA-4 are discussed including combination with newer immunotherapies.

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 649.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 949.99
Price excludes VAT (USA)
  • Durable hardcover 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

  • 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(25):6043–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Beck KE, Blansfield JA, Tran KQ, et al. Enterocolitis in patients with cancer after antibody blockade of cytotoxic T-lymphocyte-associated antigen 4. J Clin Oncol. 2006;24(15):2283–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Berman DM, Wolchok JD, Weber J, et al. Association of peripheral blood absolute lymphocyte count (ALC) and clinical activity in patients (pts) with advanced melanoma treated with ipilimumab. [Abstract]. J Clin Oncol. 2009;27(15)(Supp). Abstract nr 3020.

    Google Scholar 

  • Bruneis WB, Tarazona-Santos E, Chen R, Kiley M, Rosenberg SA, Chanock SJ. Influence of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) common polymorphisms on outcome in treatment of melanoma patients with CTLA-4 blockade. J Immunother. 2008;31(6):586–90.

    Article  Google Scholar 

  • Chen H, Liakou CI, Kamat A, et al. Anti-CTLA-4 therapy results in higher CD4+ICOShi T cell frequency and IFN-gamma levels in both nonmalignant and malignant prostate tissues. Proc Natl Acad Sci U S A. 2009;106(8):2729–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Comin-Anduix B, Lee Y, Jalil J, 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  PubMed Central  Google Scholar 

  • Corse E, Allison JP. Cutting edge: CTLA-4 on effector T cells inhibits in trans. J Immunol. 2012;189(3):1123–7.

    Article  CAS  PubMed  Google Scholar 

  • 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  PubMed Central  Google Scholar 

  • Curran MA, Kim M, Montalvo W, Al-Shamkhani A, Allison JP. Combination CTLA-4 blockade and 4-1BB activation enhances tumor rejection by increasing T-cell infiltration, proliferation, and cytokine production. PLoS One. 2011;6(4):e19499.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Freeman HJ. Colitis associated with biological agents. World J Gastroenterol. 2012;18(16):1871–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gough SCL, Walker LSK, Sansom DM. CTLA4 gene polymorphism and autoimmunity. Immunol Rev. 2005;204:102–15.

    Article  CAS  PubMed  Google Scholar 

  • Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363(8):711–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kavanagh B, O’Brien S, Lee D, 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  PubMed Central  Google Scholar 

  • Ku GY, Yuan J, Page DB, et al. Single institution experience with ipilimumab in advanced melanoma patients in the compassionate use setting: lymphocyte count after two doses correlates with survival. Cancer. 2010;116(7):1767–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kwon ED, Hurwitz AA, Foster BA, et al. Manipulation of T cell costimulatory and inhibitory signals for immunotherapy of prostate cancer. Proc Natl Acad Sci U S A. 1997;94:8099–103.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Maker AV, Attia P, Rosenberg SA. Analysis of the cellular mechanisms of antitumor responses and autoimmunity in patients treated with CTLA-4 blockade. J Immunol. 2005a;175(11):7746–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Maker AJ, Phan GQ, Attia P, 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. 2005b;12(12):1005–16.

    Article  PubMed  PubMed Central  Google Scholar 

  • Mitsui J, Nishikawa H, Muraoka D, et al. Two distinct mechanisms of augmented antitumor activity by modulation of immunostimulatory/inhibitory signals. Clin Cancer Res. 2010;16(10):2781–91.

    Article  CAS  PubMed  Google Scholar 

  • 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(8):1712–7.

    Article  PubMed  Google Scholar 

  • Ott PA, Kaufman HL, Hodi FS. Management of ipilimumab-related toxicities. Pers Med Oncol. 2012;1(2):43–53.

    Google Scholar 

  • Parry RV, Chemnitz JM, Frauwirth KA, et al. CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol Cell Biol. 2005;25(21):9543–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pedicord VA, Montalvo W, Leiner IM, Allison JP. Single dose anti-CTLA-4 enhances CD8+ T-cell memory formation, function and maintenance. Proc Natl Acad Sci U S A. 2011;108(1):266–71.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Prieto PA, Yang JC, Sherry RM, et al. CTLA-4 blockade with ipilimumab: long-term follow-up of 177 patients with metastatic melanoma. Clin Cancer Res. 2012;18(7):2039–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Quezada SA, Peggs KS, Curran MA, Allison JP. CTLA-4 blockade and GM-CSF combination immunotherapy alters the intratumor balance of effector and regulatory T cells. J Clin Invest. 2006;116(7):1935–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Quezada SA, Simpson TR, Peggs KS, et al. Tumor-reactive CD4(+) T cells develop cytotoxic activity and eradicate large established melanoma after transfer into lymphopenic hosts. J Exp Med. 2010;207(3):637–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Reuben JM, Lee BN, Li C, et al. Biologic and immunomodulatory events after CTLA-4 blockade with ticilimumab in patients with advanced malignant melanoma. Cancer. 2006;106(11):2437–44.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • 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 II and IV melanoma. J Clin Oncol. 2005;23(4):741–50.

    Article  CAS  PubMed  Google Scholar 

  • Sharma P, Wagner K, Wolchok JD, Allison JP. Novel cancer immunotherapy agents with survival benefit: recent successes and next steps. Nat Rev Cancer. 2011;11:805–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tivol EA, Borriello F, Schweitzer AN, Lynch WP, Bluestone JA, Sharpe AH. Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity. 1995;3:541–7.

    Article  CAS  PubMed  Google Scholar 

  • 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  PubMed Central  Google Scholar 

  • Waitz R, Solomon SB, Petre EN, 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 

  • Weber JS, Sarnaik A, Targan S, et al. Phase II trial of extended dose anti-CTLA-4 antibody ipilimumab (formerly MDX-010) with a multipeptide vaccine for resected stages IIIC and IV melanoma. J Clin Oncol. 2009;27(15s):9023 [Abstract].

    Google Scholar 

  • Wilmott JS, Long GV, Howle JR, et al. Selective BRAF inhibitors induce marked T-cell infiltration into human metastatic melanoma. Clin Cancer Res. 2012;18:1386–94.

    Article  CAS  PubMed  Google Scholar 

  • 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(23):7412–20.

    Article  CAS  PubMed  Google Scholar 

  • Wolchok JD, 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 

  • Yang A, Kendle R, Ginsberg B, et al. CTLA-4 blockade with ipilimumab increases peripheral CD8+ T cells: correlation with clinical outcomes. J Clin Oncol. 2010;28(15suppl):2555 [Abstract].

    Article  Google Scholar 

  • Yu P, Steel JC, ZHang M. Simultaneous inhibition of two regulatory T-cell subsets enhanced interleukin-15 efficacy in a prostate tumor model. Proc Natl Acad Sci U S A. 2012;109(16):6187–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Rush University, Chicago, IL, USA

    Tasha Hughes

  2. Division of Surgical Oncology, Rutgers Robert Wood Johnson Medical School, Rutgers Cancer Institute of New Jersey, 195 Little Albany Street Room 2007, New Brunswick, NJ, 08901, USA

    Howard L. Kaufman

Authors
  1. Tasha Hughes
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Howard L. Kaufman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tasha Hughes .

Editor information

Editors and Affiliations

  1. Division of Hematology & Oncology, Georgetown Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia, USA

    John L. Marshall

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer Science+Business Media New York

About this entry

Cite this entry

Hughes, T., Kaufman, H.L. (2017). CTLA-4. In: Marshall, J. (eds) Cancer Therapeutic Targets. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-0717-2_59

Download citation

Publish with us

Policies and ethics

Search

Navigation