Skip to main content

Advertisement

SpringerLink
Log in

CTLA-4 Blockade with Monoclonal Antibodies in Patients with Metastatic Cancer: Surgical Issues

  • Melanomas
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

CTLA-4 (cytotoxic T lymphocyte–associated antigen 4) is a modulatory receptor on T cells involved in downregulating T cell activation. In animal models, CTLA-4 blockade abrogates tolerance to “self” antigens, resulting in the augmentation of antitumor immunity and induction of autoimmunity. CTLA-4 blockade by means of monoclonal antibodies (ipilimumab and tremelimumab) has been evaluated in multiple clinical trials in patients with metastatic cancer, mainly those with melanoma and renal cell cancer.

Methods

We examine available literature and ongoing clinical trials with ipilimumab and tremelimumab and review our own experience with patients treated with CTLA-4 blockade, with an emphasis on issues of direct relevance to surgical oncologists.

Results

CTLA-4 blockade can cause durable tumor regression in patients with metastatic melanoma and other solid tumors. Grade III/IV autoimmune toxicity has been frequently encountered in clinical trials and includes enterocolitis, dermatitis, hypophysitis, uveitis, and hepatitis. Enterocolitis is the most common immune-related adverse event and may cause severe diarrhea requiring intravenous hydration, high-dose corticosteroids, and blockade of tumor necrosis factor alpha with infliximab. Most patients respond to medical treatment, but up to 12% with grade III/IV enterocolitis develop perforation or bleeding that requires colectomy.

Conclusions

As more patients are enrolled onto clinical trials involving ipilimumab and tremelimumab, an increasing number of surgeons may be involved in the care of these patients who develop treatment-related complications. In this report, we review the rationale for CTLA-4 blockade and review selected clinical studies published so far with ipilimumab and tremelimumab. We offer guidelines on the management of patients who develop enterocolitis.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

References

  1. Bretscher P, Cohn M. A theory of self-nonself discrimination. Science 1970;169:1042–9

    Article  PubMed  CAS  Google Scholar 

  2. Schwartz RH. A cell culture model for T lymphocyte clonal anergy. Science 1990;248:1349–56

    Article  PubMed  CAS  Google Scholar 

  3. Linsley PS, Brady W, Grosmaire L, et al. Binding of the B cell activation antigen B7 to CD28 costimulates T cell proliferation and interleukin 2 mRNA accumulation. J Exp Med 1991;173:721–30

    Article  PubMed  CAS  Google Scholar 

  4. Gross JA, Callas E, Allison JP. Identification and distribution of the costimulatory receptor CD28 in the mouse. J Immunol 1992;149:380–8

    PubMed  CAS  Google Scholar 

  5. Walunas TL, Bakker CY, Bluestone JA. CTLA-4 ligation blocks CD28-dependent T cell activation. J Exp Med 1996;183:2541–50

    Article  PubMed  CAS  Google Scholar 

  6. Krummel MF, Allison JP. CTLA-4 engagement inhibits IL-2 accumulation and cell cycle progression upon activation of resting T cells. J Exp Med 1996;183:2533–40

    Article  PubMed  CAS  Google Scholar 

  7. Brunner MC, Chambers CA, Chan FK, et al. CTLA-4-mediated inhibition of early events of T cell proliferation. J Immunol 1999;162:5813–20

    PubMed  CAS  Google Scholar 

  8. Greenwald RJ, Oosterwegel MA, van der Woude D, et al. CTLA-4 regulates cell cycle progression during a primary immune response. Eur J Immunol 2002;32:366–73

    Article  PubMed  CAS  Google Scholar 

  9. Waterhouse P, Penninger JM, Timms E, et al. Lymphoproliferative disorders with early lethality in mice deficient in CTLA-4. Science 1995;270:985–8

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  11. 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

    Article  PubMed  Google Scholar 

  12. 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

    Article  PubMed  Google Scholar 

  13. Hurtwitz AA, Foster BA, Kwon ED, et al. Combination immunotherapy of primary prostate cancer in a transgenic mouse model using CTLA-4 blockade. Cancer Res 2000;60:2444–8

    Google Scholar 

  14. Phan GQ, Attia P, Steinberg SM, et al. Factors associated with response to high-dose interleukin-2 in patients with metastatic melanoma. J Clin Oncol 2001;19:3477–82

    PubMed  CAS  Google Scholar 

  15. Gogas H, Ioannovich J, Dafni U, et al. Prognostic significance of autoimmunity during treatment of melanoma with interferon. N Engl J Med 2006;354:709–18

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  17. 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 USA 2003;100:8372–7

    Article  PubMed  CAS  Google Scholar 

  18. Papa MZ, Vetto JT, Ettinghausen SE, et al. Effect of corticosteroid on the antitumor activity of lymphokine-activated killer cells and interleukin-2 in mice. Cancer Res 1986;46:5618–23

    PubMed  CAS  Google Scholar 

  19. 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

    Article  PubMed  CAS  Google Scholar 

  20. Maker AV, 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 2005;12:1005–16

    Article  PubMed  Google Scholar 

  21. Fischkoff SA, Hersh E, Weber J, et al. Durable responses and long-term progression-free survival observed in a phase II study of MDX-010 alone or in combination with dacarbazine (DTIC) in metastatic melanoma. J Clin Oncol 2005; 23:Abstract 7525

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

    Article  PubMed  CAS  Google Scholar 

  23. Weber JS, Targan S, Scotland R, et al. Phase II trial of extended dose anti-CTLA-4 antibody ipilimumab (formerly MDX-010) with a multi-peptide vaccine for resected stages IIIC and IV melanoma. J Clin Oncol 2006; 24:Abstract 2510

  24. 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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  26. Ribas A, Antonia S, Sosman J, et al. Results of a phase II clinical trial of 2 doses and schedules of CP-675,206, an anti-CTLA4 monoclonal antibody, in patients (pts) with advanced melanoma. J Clin Oncol 2007; 25:Abstract 3000

  27. Yang JC, Beck KE, Blansfield JA, et al. Tumor regression in patients with metastatic renal cancer treated with monoclonal antibody to CTLA4 (MDX-010). J Clin Oncol 2005; 23:Abstract 2501

  28. 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

    Article  PubMed  CAS  Google Scholar 

  29. Small EJ, Tchekmedyian S, Rini BI, et al. 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

    Article  PubMed  CAS  Google Scholar 

  30. Fong L, Kavanagh B, Hou Y, et al. Combination immunotherapy with GM-CSF and CTLA-4 blockade for hormone refractory prostate cancer: balancing the expansion of activated effector and regulatory T cells. J Clin Oncol 2007;25(18S):3001

    Google Scholar 

  31. Gerritsen WR, van den Eertwegh AJ, de Gruijl TD, et al. Biochemical and immunologic correlates of clinical response in a combination trial of the GM-CSF-gene transduced allogeneic prostate cancer immunotherapy and ipilimumab in patients with metastatic hormone-refractory prostate cancer (mHRPC). J Clin Oncol 2007;25:5120

    Google Scholar 

  32. Blansfield JA, Beck KE, Tran K, et al. Cytotoxic T-lymphocyte–associated antigen-4 blockage can induce autoimmune hypophysitis in patients with metastatic melanoma and renal cancer. J Immunother 2005;28:593–8

    Article  PubMed  CAS  Google Scholar 

  33. Robinson MR, Chan CC, Yang JC, et al. Cytotoxic T lymphocyte–associated antigen 4 blockade in patients with metastatic melanoma: a new cause of uveitis. J Immunother 2004;27:478–9

    Article  PubMed  Google Scholar 

  34. 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;24:2283–9

    Article  PubMed  CAS  Google Scholar 

  35. Weber J. Anti-CTLA-4 antibody ipilimumab: Case studies of clinical response and immune-related adverse events. Oncologist 2007;12:864–72

    Article  PubMed  CAS  Google Scholar 

  36. O’Day SJ, Hamid O, Urba WJ. Targeting cytotoxic T-lymphocyte antigen-4 (CTLA-4): a novel strategy for the treatment of melanoma and other malignancies. Cancer 2007;110:2614–27

    Article  PubMed  CAS  Google Scholar 

  37. 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

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

V.K.S. has served as a paid consultant to Bristol-Myers Squibb and Pfizer. J.S.W. has served as a paid consultant to and received research funding from Bristol-Myers Squibb, Medarex, and Pfizer.

Author information

Authors and Affiliations

  1. Division of Cutaneous Oncology, H. Lee Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL, 33612, USA

    Giao Q. Phan MD, Jeffrey S. Weber MD, PhD & Vernon K. Sondak MD

  2. The Donald A. Adam Comprehensive Melanoma Research Center, H. Lee Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL, 33612, USA

    Jeffrey S. Weber MD, PhD & Vernon K. Sondak MD

  3. Department of Oncologic Sciences, University of South Florida College of Medicine, Tampa, FL, USA

    Jeffrey S. Weber MD, PhD & Vernon K. Sondak MD

  4. Department of Surgery, University of South Florida College of Medicine, Tampa, FL, USA

    Vernon K. Sondak MD

Authors
  1. Giao Q. Phan MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jeffrey S. Weber MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Vernon K. Sondak MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Vernon K. Sondak MD.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Phan, G.Q., Weber, J.S. & Sondak, V.K. CTLA-4 Blockade with Monoclonal Antibodies in Patients with Metastatic Cancer: Surgical Issues. Ann Surg Oncol 15, 3014–3021 (2008). https://doi.org/10.1245/s10434-008-0104-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1245/s10434-008-0104-y

Keywords

Search

Navigation