Phase II trial of the regulatory T cell-depleting agent, denileukin diftitox, in patients with unresectable stage IV melanoma
Sucheta Telang, Mary Ann Rasku, Amy L Clem, Karen Carter, Alden C Klarer, Wesley R Badger, Rebecca A Milam, Shesh N Rai, Jianmin Pan, Hana Gragg, Brian F Clem, Kelly M McMasters, Donald M Miller, Jason Chesney, Sucheta Telang, Mary Ann Rasku, Amy L Clem, Karen Carter, Alden C Klarer, Wesley R Badger, Rebecca A Milam, Shesh N Rai, Jianmin Pan, Hana Gragg, Brian F Clem, Kelly M McMasters, Donald M Miller, Jason Chesney
Abstract
Background: We previously found that administration of an interleukin 2/diphtheria toxin conjugate (DAB/IL2; Denileukin Diftitox; ONTAK) to stage IV melanoma patients depleted CD4(+)CD25(HI)Foxp3(+) regulatory T cells and expanded melanoma-specific CD8(+) T cells. The goal of this study was to assess the clinical efficacy of DAB/IL2 in an expanded cohort of stage IV melanoma patients.
Methods: In a single-center, phase II trial, DAB/IL2 (12 μg/kg; 4 daily doses; 21 day cycles) was administered to 60 unresectable stage IV melanoma patients and response rates were assessed using a combination of 2-[(18)F]-fluoro-2-deoxy-glucose (FDG)-positron emission tomography (PET) and computed tomography (CT) imaging.
Results: After DAB/IL2 administration, 16.7% of the 60 patients had partial responses, 5% stable disease and 15% mixed responses. Importantly, 45.5% of the chemo/immuno-naïve sub-population (11/60 patients) experienced partial responses. One year survival was markedly higher in partial responders (80 ± 11.9%) relative to patients with progressive disease (23.7 ± 6.5%; p value < 0.001) and 40 ± 6.2% of the total DAB/IL2-treated population were alive at 1 year.
Conclusions: These data support the development of multi-center, randomized trials of DAB/IL2 as a monotherapy and in combination with other immunotherapeutic agents for the treatment of stage IV melanoma.
Trial registration: NCT00299689.
Figures
References
- Korn EL, Liu PY, Lee SJ, Chapman JA, Niedzwiecki D, Suman VJ, Moon J, Sondak VK, Atkins MB, Eisenhauer EA. et al.Meta-analysis of phase II cooperative group trials in metastatic stage IV melanoma to determine progression-free and overall survival benchmarks for future phase II trials. J Clin Oncol. 2008;26(4):527–534.
- Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, Thun MJ. Cancer statistics, 2008. CA Cancer J Clin. 2008;58(2):71–96.
- Atkins MB, Lotze MT, Dutcher JP, Fisher RI, Weiss G, Margolin K, Abrams J, Sznol M, Parkinson D, Hawkins M. 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):2105–2116.
- Kirkwood JM, Strawderman MH, Ernstoff MS, Smith TJ, Borden EC, Blum RH. Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol. 1996;14(1):7–17.
- Kirkwood JM, Ibrahim JG, Sondak VK, Richards J, Flaherty LE, Ernstoff MS, Smith TJ, Rao U, Steele M, Blum RH. High- and low-dose interferon alfa-2b in high-risk melanoma: first analysis of intergroup trial E1690/S9111/C9190. J Clin Oncol. 2000;18(12):2444–2458.
- Eggermont AM, Suciu S, Santinami M, Testori A, Kruit WH, Marsden J, Punt CJ, Sales F, Gore M, Mackie R. et al.Adjuvant therapy with pegylated interferon alfa-2b versus observation alone in resected stage III melanoma: final results of EORTC 18991, a randomised phase III trial. Lancet. 2008;372(9633):117–126.
- Wolchok JD, Neyns B, Linette G, Negrier S, Lutzky J, Thomas L, Waterfield W, Schadendorf D, Smylie M, Guthrie T, Jr, Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. Lancet Oncol. pp. 155–164.
- Robert C, Thomas L, Bondarenko I, O'Day S, M DJ, Garbe C, Lebbe C, Baurain JF, Testori A, Grob JJ, Ipilimumab plus Dacarbazine for Previously Untreated Metastatic Melanoma. N Engl J Med.
- Zou W. Regulatory T cells, tumour immunity and immunotherapy. Nat Rev Immunol. 2006;6(4):295–307.
- 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):1151–1164.
- Curiel TJ. Regulatory T cells and treatment of cancer. Curr Opin Immunol. 2008;20(2):241–246.
- Jones E, Dahm-Vicker M, Golgher D, Gallimore A. CD25+ regulatory T cells and tumor immunity. Immunol Lett. 2003;85(2):141–143.
- Jones E, Dahm-Vicker M, Simon AK, Green A, Powrie F, Cerundolo V, Gallimore A. Depletion of CD25+ regulatory cells results in suppression of melanoma growth and induction of autoreactivity in mice. Cancer Immun. 2002;2:1.
- Turk MJ, Guevara-Patino JA, Rizzuto GA, Engelhorn ME, Sakaguchi S, Houghton AN. Concomitant tumor immunity to a poorly immunogenic melanoma is prevented by regulatory T cells. J Exp Med. 2004;200(6):771–782.
- Viguier M, Lemaitre F, Verola O, Cho MS, Gorochov G, Dubertret L, Bachelez H, Kourilsky P, Ferradini L. 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):1444–1453.
- Foss FM. DAB(389)IL-2 (denileukin diftitox, ONTAK): a new fusion protein technology. Clin Lymphoma. 2000;1(Suppl 1):S27–31.
- Barnett B, Kryczek I, Cheng P, Zou W, Curiel TJ. Regulatory T cells in ovarian cancer: biology and therapeutic potential. Am J Reprod Immunol. 2005;54(6):369–377.
- Litzinger MT, Fernando R, Curiel TJ, Grosenbach DW, Schlom J, Palena C. IL-2 immunotoxin denileukin diftitox reduces regulatory T cells and enhances vaccine-mediated T-cell immunity. Blood. 2007;110(9):3192–3201.
- Rasku MA, Clem AL, Telang S, Taft B, Gettings K, Gragg H, Cramer D, Lear SC, McMasters KM, Miller DM. et al.Transient T cell depletion causes regression of melanoma metastases. J Transl Med. 2008;6(1):1–18.
- Gottlieb RH, Litwin A, Gupta B, Taylor J, Raczyk C, Mashtare T, Wilding G, Fakih M. Qualitative radiology assessment of tumor response: does it measure up? Clin Imaging. 2008;32(2):136–140.
- Attia P, Maker AV, Haworth LR, Rogers-Freezer L, Rosenberg SA. Inability of a fusion protein of IL-2 and diphtheria toxin (Denileukin Diftitox, DAB389IL-2, ONTAK) to eliminate regulatory T lymphocytes in patients with melanoma. J Immunother. 2005;28(6):582–592.
- Curiel TJ. Tregs and rethinking cancer immunotherapy. J Clin Invest. 2007;117(5):1167–1174.
Source: PubMed