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Therapeutic efficacy of ipilimumab, an anti-CTLA-4 monoclonal antibody, in patients with metastatic melanoma unresponsive to prior systemic treatments: clinical and immunological evidence from three patient cases

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Abstract

The management of unresectable metastatic melanoma is a major clinical challenge because of the lack of reliably effective systemic therapies. Blocking cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) has recently been proposed as a strategy to enhance cell-mediated immune responses to cancer, and clinical trials have demonstrated that anti-CTLA-4 therapy can produce durable outcomes with different response patterns than cytotoxic chemotherapy. We enrolled eight out of 155 patients with advanced melanoma in a multicentre phase II trial that evaluated the activity and tolerability of ipilimumab, a fully human, anti-CTLA-4 monoclonal antibody (www.clinicaltrials.gov; NCT00289627; CA184-008). Here we report our experience with three of these patients, who experienced progressive disease after a variety of previous therapies, including prior immunotherapies, and who achieved good outcomes with ipilimumab. One patient had a partial response ongoing at 17+ months on ipilimumab despite failure with four prior therapies, and the other two patients showed durable stable disease, both still ongoing at 17+ and 20+ months, respectively. The patient achieving a partial response experienced no side effects while receiving ipilimumab. The other two patients developed immune-related adverse events (irAEs) including rash (one case; grade 2) and diarrhoea (both cases; grades 1 and 2, respectively); the histopathology of colon biopsy samples from both was suggestive of colitis, with an abundant CD8+ T-cell infiltrate. Nausea, vomiting and acute pancreatitis were also observed in one patient. In addition, immunohistochemical findings of a dense CD8+, TIA1+ and granzyme B+ lymphoid infiltrate within a biopsied lesion provide indirect evidence of functional T-cell activation induced by treatment. These case reports highlight the potential for anti-CTLA-4-based therapy in previously treated patients with advanced melanoma. Moreover, because the patterns of response to ipilimumab differ from chemotherapy, we need to understand how and when patients may respond to treatment so that appropriate clinical decisions can be made.

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References

  1. Agarwala SS (2004) Relevance and necessity of studies on second-line chemotherapy in melanoma. Onkologie 27:527–528

    Article  PubMed  Google Scholar 

  2. Atkins MB, Lotze MT, Dutcher JP, Fisher RI, Weiss G, Margolin K, Abrams J, Sznol M, Parkinson D, Hawkins M, Paradise C, Kunkel L, Rosenberg SA (1999) High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol 17:2105–2116

    PubMed  CAS  Google Scholar 

  3. Attia P, Phan GQ, Maker AV, Robinson MR, Quezado MM, Yang JC, Sherry RM, Topalian SL, Kammula US, Royal RE, Restifo NP, Haworth LR, Levy C, Mauroukakis SA, Nichol G, Yellin MJ, Rosenberg SA (2005) Autoimmunity correlates with tumor regression in patients with metastatic melanoma treated with anti-cytotoxic T-lymphocyte antigen-4. J Clin Oncol 23:6043–6053

    Article  PubMed  CAS  Google Scholar 

  4. Beck KE, Blansfield JA, Tran KQ, Feldan AL, Hughes MS, Royal RE, Kammula US, Topalian SL, Sherry RM, Kleiner D, Quezado M, Lowy I, Yellin M, Rosenberg SA, Yang JC (2006) Enterocolitis in patients with cancer after antibody blockade of cytotoxic T-lymphocyte-associated antigen 4. J Clin Oncol 24:2283–2289

    Article  PubMed  CAS  Google Scholar 

  5. Chen B, Phillips J, Greenbaum M, Klitzing D, Cardarelli PM, Korman A (2007) Efficacy of anti-CTLA-4 antibody in the Sa1 N tumor model when combined with dexamethasone (abstract 2202). In: Presented at the AACR Annual Meeting, 14–28 April 2007, Los Angeles, CA, USA

  6. ClinicalTrials.gov. A single arm study of ipilimumab monotherapy in patients with previously treated unresectable stage III or IV melanoma. http://clinicaltrials.gov/ct/show/NCT00289627

  7. ClinicalTrials.gov. A companion study for patients enrolled in prior/parent ipilimumab studies. http://clinicaltrials.gov/show/NCT00162123

  8. Fischkoff SA, Hersh E, Weber J, Powderly J, Khan K, Pavlick A, Samlowski W, O’Day S, Nichol G, Yellin M (2005) 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 (abstract 7525). J Clin Oncol 23(suppl)

  9. Hamid O, Urba WJ, Yellin M, Nichol GM, Weber J, Hersh EM, Tchekmedyian S, Hodi FS, Weber R, O’Day S (2007) Ipilimumab (MDX-010) in patients with stage III/IV melanoma: kinetics and duration of response. Eur J Cancer Suppl 5:396

    Article  Google Scholar 

  10. Hersh EM, O’Day SJ, Powderly J, Khan KD, Pavlick AC, Cranmer L, Samlowski WE, Nichol GM, Yellin MJ, Fischkoff SA, Weber JS (2008) Disease control and long-term survival in chemotherapy-naive patients with advanced melanoma treated with ipilimumab with or without dacarbazine. J Clin Oncol (submitted)

  11. Hodi FS, The Global Ipilimumab Melanoma Study Group (2008) Novel efficacy criteria for antitumor activity to immunotherapy using the example of ipilimumab, an anti-CTLA-4 monoclonal antibody (abstract 3008). J Clin Oncol 26(suppl)

  12. Lin R, Yellin MJ, Lowy I, Safferman A, Chin K, Ibrahim R (2008) An analysis of the effectiveness of specific guidelines for the management of ipilimumab-mediated diarrhea/colitis: prevention of gastrointestinal perforation and/or colectomy (abstract 9063). J Clin Oncol 26(suppl)

  13. Maker AV, Yang JC, Sherry RM, Topalian SL, Kammula US, Royal RE, Hughes M, Yellin MJ, Haworth LR, Levy C, Allen T, Mavroukakis SA, Attia P, Rosenberg SA (2006) Intrapatient dose escalation of anti-CTLA-4 antibody in patients with metastatic melanoma. J Immunother 29:455–463

    Article  PubMed  CAS  Google Scholar 

  14. O’Day S, Boasberg P (2006) Management of metastatic melanoma 2005. Surg Oncol Clin N Am 15:419–437

    Article  PubMed  Google Scholar 

  15. O’Day SJ, Hamid O, Urba WJ (2007) Targeting cytotoxic T-lymphocyte antigen-4 (CTLA-4): a novel strategy for the treatment of melanoma and other malignancies. Cancer 110:2614–2627

    Article  PubMed  Google Scholar 

  16. Saenger Y, Wolchok J (2008) The heterogeneity of the kinetics of response to ipilimumab in metastatic melanoma: patient cases. Cancer Immun 8:1

    PubMed  Google Scholar 

  17. Sasse AD, Sasse EC, Clark LGO, Ulloa L, Clark OAC (2007) Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma. Cochrane Database of Systematic Reviews 2007, Iss 1. Art No: CD005413. doi:10.1002/14651858.CD005413.pub2

  18. Tarhini AA, Kirkwood JM, Gooding WE, Cai C, Agarwala SS (2007) Durable complete responses with high-dose bolus interleukin-2 in patients with metastatic melanoma who have experienced progression after biochemotherapy. J Clin Oncol 25:3802–3807

    Article  PubMed  CAS  Google Scholar 

  19. Weber J (2007) Anti-CTLA-4 antibody ipilimumab: case studies of clinical response and immune-related adverse effects. Oncologist 12:864–872

    Article  PubMed  CAS  Google Scholar 

  20. Weber JS, Hersh EM, Yellin M, Nichol GM, Urba W, Powderly JD, O’Day SJ (2007) The efficacy and safety of ipilimumab (MDX-010) in patients with unresectable stage III or stage IV malignant melanoma [abstract 8523]. J Clin Oncol 25(suppl)

  21. Weber JS, Targan S, Scotland R, Snively J, Garcia M, Yellin M, Fischkoff S, Nichol G (2006) 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 (abstract 2510). J Clin Oncol 18(suppl)

  22. Wolchok JD, The Global Ipilimumab Melanoma Study Group (2008) Antitumor response and new lesions in advanced melanoma patients on ipilimumab treatment (abstract 3020). J Clin Oncol 26(suppl)

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Acknowledgments

Medical writing and editorial assistance provided by Gardiner-Caldwell US, with financial support from Bristol-Myers Squibb. This work was supported in part by grants awarded to MM from the Associazione Italiana per la Ricerca sul Cancro, and Istituto Superiore di Sanità—Alleanza Contro il Cancro for the project “Rete nazionale per studi clinici e di strutture GMP per le bioterapie dei tumori”. The authors wish to acknowledge the excellent nursing support of Angela Iacovelli, Marilena Piccinelli, Massimo Resti, and Sergio Speranza.

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Correspondence to Michele Maio.

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Di Giacomo, A.M., Danielli, R., Guidoboni, M. et al. Therapeutic efficacy of ipilimumab, an anti-CTLA-4 monoclonal antibody, in patients with metastatic melanoma unresponsive to prior systemic treatments: clinical and immunological evidence from three patient cases. Cancer Immunol Immunother 58, 1297–1306 (2009). https://doi.org/10.1007/s00262-008-0642-y

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