Skip to main content
SpringerLink
Log in

Immunological Insights from Patients Undergoing Surgery on Ipilimumab for Metastatic Melanoma

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

Abstract

Background

The tumor microenvironment after treatment with ipilimumab is not well described. Furthermore, the safety of surgery for patients being treated with ipilimumab for metastatic melanoma has not been well reported. This study analyzed the safety of surgery and the immune phenotype of tumors resected while on ipilimumab.

Methods

From our prospective melanoma database, we identified patients undergoing surgery for any indication within 30 days of receiving a dose of induction ipilimumab or while on maintenance ipilimumab therapy. Surgical toxicity was graded 1–5 by the Clavien classification. Tumor-infiltrating lymphocytes were classified by flow cytometry and compared with peripheral blood.

Results

23 patients were identified who underwent 34 operations a median of 27 weeks after initiation of ipilimumab (1–123 weeks). Subcutaneous resections were the most frequent, followed by intra-abdominal and nodal procedures. Grade 1 or 2 wound complications were seen in 22 % of patients. No Grade 3–5 complications were seen. Analysis of the T cell infiltrate and matched peripheral blood from ten patients showed an elevated % of CD4+FOXP3+ T-regulatory cells and a 2.8-fold lower ratio of CD8+/CD4+FOXP3+ in the tumor compared with blood (p = 0.02). In addition, all CD8+ T cells had a higher expression of PD-1 in the tumor, compared with peripheral blood.

Conclusions

Surgery for patients on ipilimumab is safe. This study highlights the immunosuppressive phenotype in tumors not responding to immunotherapy. The high percentage of T-regulatory cells and low T-effector cells in progressive tumors suggests a possible mechanism of immune escape.

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

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. 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  PubMed  CAS  Google Scholar 

  2. 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  PubMed  CAS  Google Scholar 

  3. 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  PubMed  CAS  Google Scholar 

  4. 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(26):2443–54.

    Article  PubMed  CAS  Google Scholar 

  5. 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 USA. 107(9):4275–80.

  6. Hodi FS, Butler M, Oble DA, 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 USA. 2008;105(8):3005–10.

    Article  PubMed  CAS  Google Scholar 

  7. 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(7):1935–45.

    Article  PubMed  CAS  Google Scholar 

  8. Jacobs JF, Nierkens S, Figdor CG, de Vries IJ, Adema GJ. Regulatory T cells in melanoma: the final hurdle towards effective immunotherapy? Lancet Oncol. 2012;13(1):e32–42.

    Article  PubMed  CAS  Google Scholar 

  9. Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg. 2004;240(2):205–13.

    Article  PubMed  Google Scholar 

  10. Yuan J, Page DB, Ku GY, et al. Correlation of clinical and immunological data in a metastatic melanoma patient with heterogeneous tumor responses to ipilimumab therapy. Cancer Immun. 2010;10:1.

    PubMed  Google Scholar 

  11. 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(10):2861–71.

    Article  PubMed  CAS  Google Scholar 

  12. 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(8):793–800.

    PubMed  CAS  Google Scholar 

  13. Morton DLM, N; Kashani-Sabet M, Thompson JF, Kelley MC, et al. Long-term cure after complete resection and adjuvant immunotherapy for distant melanoma metastases (Suppl abstr 8534). vol 30. Chicago: American Society of Clinical Oncology (ASCO); 2012.

  14. Howard JH, Thompson JF, Mozzillo N, et al. Metastasectomy for distant metastatic melanoma: analysis of data from the first Multicenter Selective Lymphadenectomy Trial (MSLT-I). Ann Surg Oncol. 2012;19(8):2547–55.

    Article  PubMed  Google Scholar 

  15. Neuman HB, Patel A, Hanlon C, Wolchok JD, Houghton AN, Coit DG. Stage IV melanoma and pulmonary metastases: factors predictive of survival. Ann Surg Oncol. 2007;14(10):2847–53.

    Article  PubMed  Google Scholar 

  16. Tafra L, Dale PS, Wanek LA, Ramming KP, Morton DL. Resection and adjuvant immunotherapy for melanoma metastatic to the lung and thorax. J Thorac Cardiovasc Surg. 1995;110(1):119–28, discussion 129.

    Google Scholar 

  17. Leung AM, Hari DM, Morton DL. Surgery for distant melanoma metastasis. Cancer J. 2012;18(2):176–84.

    Article  PubMed  CAS  Google Scholar 

  18. Wong JH, Skinner KA, Kim KA, Foshag LJ, Morton DL. The role of surgery in the treatment of nonregionally recurrent melanoma. Surgery. 1993;113(4):389–94.

    PubMed  CAS  Google Scholar 

  19. 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  PubMed  CAS  Google Scholar 

  20. Thompson RH, Dong H, Lohse CM, et al. PD-1 is expressed by tumor-infiltrating immune cells and is associated with poor outcome for patients with renal cell carcinoma. Clin Cancer Res. 2007;13(6):1757–61.

    Article  PubMed  CAS  Google Scholar 

  21. Fourcade J, Kudela P, Sun Z, et al. PD-1 is a regulator of NY-ESO-1-specific CD8 + T cell expansion in melanoma patients. J Immunol. 2009;182(9):5240–9.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

Download references

Disclosures

CA and JW serve on advisory board for BMS; JPA is inventor of intellectual property licensed to BMS.

Author information

Authors and Affiliations

  1. Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    David E. Gyorki MBBS MD, Melissa Pulitzer MD, Klaus Busam MD, Mary S. Brady MD FACS, Daniel G. Coit MD FACS, Jedd D. Wolchok MD PhD & Charlotte E. Ariyan MD PhD FACS

  2. Ludwig Center at Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    Jianda Yuan MD PhD, Zhenyu Mu PhD, Bushra Zaidi PhD & Jedd D. Wolchok MD PhD

  3. Weill Cornell Medical College, New York, NY, USA

    Jedd D. Wolchok MD PhD

  4. Ludwig Institute for Cancer Research, New York, NY, USA

    Jedd D. Wolchok MD PhD

  5. MD Anderson Cancer Center, Houston, TX, USA

    James P. Allison PhD

Authors
  1. David E. Gyorki MBBS MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jianda Yuan MD PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zhenyu Mu PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Bushra Zaidi PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Melissa Pulitzer MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Klaus Busam MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Mary S. Brady MD FACS
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Daniel G. Coit MD FACS
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. James P. Allison PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jedd D. Wolchok MD PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Charlotte E. Ariyan MD PhD FACS
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Charlotte E. Ariyan MD PhD FACS.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gyorki, D.E., Yuan, J., Mu, Z. et al. Immunological Insights from Patients Undergoing Surgery on Ipilimumab for Metastatic Melanoma. Ann Surg Oncol 20, 3106–3111 (2013). https://doi.org/10.1245/s10434-013-2999-1

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1245/s10434-013-2999-1

Keywords

Search

Navigation