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Journal of Clinical Oncology, Vol 25, No 25 (September 1), 2007: pp. 3791-3793 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.11.9552
More Support for the Judicious Use of High-Dose Interleukin-2 in Patients With Advanced MelanomaDivision of Hematology/Oncology, Beth Israel Deaconess Medical Center, Boston, MA The incidence of malignant melanoma is increasing faster than any other malignancy.1 Although patients with early-stage disease can be cured with surgical resection, with or without adjuvant therapy, a significant number of patients go on to develop disseminated disease. For patients with metastatic melanoma, common treatment approaches have included chemotherapy and immunotherapy, used alone or in combination. The inability of these agents to improve survival, coupled with their significant toxicity, has justified the enrollment of untreated patients in clinical trials.2 Dacarbazine (DTIC) and its analog temozolomide are generally considered the most active cytotoxic agents, with response rates of 8% to 20%. Despite a lack of evidence that they improve overall survival when compared with a no-treatment control, these agents have achieved widespread application as standard therapy. Randomized trials have failed to provide any evidence for the superiority of other single agents, combination chemotherapy, or the addition of tamoxifen or interferon to DTIC compared with DTIC therapy alone.3 High-dose bolus interleukin-2 (IL-2) was granted US Food and Drug Administration approval based on its ability to produce durable complete responses in a small number of patients with metastatic melanoma. However, the substantial toxicity and limited efficacy of IL-2 has narrowed its application to highly selected patients treated at specialized centers.4 Many investigators have studied combinations of chemotherapy and IL-2–based immunotherapy, or biochemotherapy (BCT), in an effort to improve response rates and survival. The most encouraging results were seen in trials that combined cisplatin-based chemotherapy and IL-2. These phase II trials and a single-institution randomized trial suggested an advantage for BCT compared with chemotherapy or IL-2; therefore, confirmatory multicenter phase III trials were deemed appropriate and necessary.3,5 Unfortunately, in every multicenter phase III trial, BCT failed to produce significantly better response rates, overall survival, or durable complete responses compared with chemotherapy alone. Response durations were no better with BCT than chemotherapy alone (with immunotherapy effects not apparent), and toxicity, particularly grade 4, was greater for BCT.6-11 In this issue, Tarhini et al12 provide further evidence that BCT is not immunotherapy. In this well-conducted study, the investigators described durable responses produced with high-dose IL-2 therapy in patients who had exhibited disease progression after IL-2–based BCT. These results support those of O'Day et al,13 which suggested a role for maintenance IL-2–based immunotherapy in enhancing and prolonging response to BCT. The fact that the durable responses in the study by Tarhini et al12 occurred with a frequency similar to that observed with high-dose IL-2 in untreated patients and that patients exhibiting disease progression after IL-2 therapy do not respond to re-treatment with IL-2 suggest14 that the immune effect of IL-2 is masked within the concurrent BCT regimen. Whether the same can be said for sequential BCT regimens is less certain.5 Nonetheless, because BCT in any form is unlikely to become the standard of care for patients with metastatic melanoma, the impact of this trial on clinical practice will likely be small. As long as high-dose IL-2 remains a necessary component to a curative treatment strategy in patients with metastatic melanoma, it will be essential to improve its therapeutic index. Two active areas of investigation in the field of immunotherapy focus on the elimination of immune suppression/regulation and the improvement of patient selection. Mechanisms of immune suppression likely include suppressor T cells (eg, CD4/C25+ regulatory T cells),15-17 immune inhibitory molecules (eg, B7H1, B7H4),18 cytokines (eg, IL-10, IL-6),19 and amino acid depletion (eg, arginase-diminished arginine and indolamine dioxygenase–diminished tryptophan).18,20 Several groups have reported that IL-2 seems to enhance tumor-induced immune suppression in many melanoma patients. Opportunities to inhibit these tumor escape mechanisms might include lymphodepletion, blockade of B7H1 with monoclonal antibodies, and the initiation of therapy in the adjuvant setting. Lymphodepletion with high-dose chemotherapy followed by transfer of tumor-reactive T cells and IL-2 has been shown by investigators at the National Cancer Institute, Surgery Branch to produce durable responses in patients with IL-2–refractory metastatic melanoma.21 This work suggests that immune suppression can be overcome in a subset of patients, but it requires validation in a multicenter trial. Recent studies suggest that selection of patients for IL-2 is feasible and may enable the restriction of this treatment to those most likely to benefit. In patients with renal cancer, tumor histology and the expression of carbonic anhydrase IX predict responsiveness to immunotherapy with IL-2, and the expression of B7H1 (PD1 ligand), a molecule associated with immune suppression, by the tumor can predict poor survival after nephrectomy.22,23 Results of several recent studies suggest that melanomas can be divided into distinct subgroups on the basis of the genes they express.24 Although the extent to which these subgroups might vary in sensitivity to immunotherapy remains to be established, their existence underscores the potential for information useful to treatment selection to be gleaned from further investigation of the tumor itself. An association between autoimmunity and a favorable antitumor effect has been reported for several forms of immunotherapy, particularly in patients with melanoma. The association between the development of autoimmune thyroid disease and tumor regression in patients treated with IL-2 was first reported in 1988.25 The blockade of cytotoxic T-lymphocyte–associated antigen 4 (CTLA4), a negative regulator of T-cell function, by an anti-CTLA4 antibody has also been reported to cause autoimmune disorders in patients with cancer that seem to be strongly associated with tumor regression.26 Gogas et al27 reported that the development of autoimmunity after adjuvant interferon therapy was associated with an approximate reduction by a factor of 50 in the risk of recurrence of melanoma. These observations suggest that a population of melanoma patients exists with diminished immune regulation and in whom autoimmunity develops during effective immunotherapy. A clearer understanding of the host genetic factors (eg, CTLA4 gene polymorphisms, HLA genotype, and FOXP3 transcription factor mutations) that may contribute to the autoimmunity induced by immunotherapy could help identify biomarkers that predict clinical benefit.28-31 It remains to be determined whether relative deficiencies in these regulatory pathways play a role in either the autoimmunity or the antitumor effects found with IL-2. These studies call for closer collaborations between investigators in the fields of immunotherapy for cancer and autoimmunity to better address some of these critical issues. Although currently of limited benefit, IL-2–based immunotherapy will likely be a necessary component of a potentially curative treatment strategy for patients with metastatic melanoma. Although clinical trials have failed to show any benefit for adding any agent to IL-2, laboratory investigations associated with this research suggest that the potential exists for identifying predictors of response and limiting IL-2 therapy to those patients most likely to benefit. Effective strategies for combating immune suppression may enhance the efficacy of IL-2 but will require thorough evaluation. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: David F. McDermott, Onyx (C); Michael B. Atkins, Novartis (C), Bristol-Myers Squibb Co (C), Bayer (C), Zymogenetics (C), Genentech (C) Stock Ownership: None Honoraria: David F. McDermott, Novartis, Onyx Research Funding: David F. McDermott, Bayer, Genzyme, Novartis; Michael B. Atkins, Novartis, Bayer Expert Testimony: None Other Remuneration: None AUTHOR CONTRIBUTIONS Manuscript writing: David F. McDermott, Michael B. Atkins Final approval of manuscript: David F. McDermott, Michael B. Atkins REFERENCES
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Blood 107:2409-2414, 2006 17. van DerVliet HJ, Koon HB, Yue SC, et al: Effects of the administration of high-dose interleukin-2 on immunoregulatory cell subsets in patients with advanced melanoma and renal cell cancer. Clin Cancer Res 13:2100-2108, 2007 18. Gajewski TF: Identifying and overcoming immune resistance mechanisms in the melanoma tumor microenvironment. Clin Cancer Res 12:2326S-2330S, 2006[CrossRef][Medline] 19. Seo N, Hayakawa S, Takigawa M, et al: Interleukin-10 CD4(+) T-regulatory cells and systemic collapse of antitumour immunity. Immunology 103:449-457, 2001[CrossRef][Medline] 20. Zea AH, Rodriguez PC, Atkins MB, et al: Arginase-producing myeloid suppressor cells in renal cell carcinoma patients: A mechanism of tumor evasion. Cancer Res 65:3044-3048, 2005 21. Dudley ME, Wunderlich JR, Yang JC, et al: Adoptive cell transfer therapy following non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanoma. 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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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