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Despite Past Disappointments the Future of Melanoma Therapy Appears Bright

Despite Past Disappointments the Future of Melanoma Therapy Appears Bright

Annually, about 8,000 patients are found to have metastatic melanoma presenting as recurrence of an earlier primary melanoma, and this number closely approximates the annual number of deaths from the disease. This statistic illustrates the lack of progress that has been made in the treatment of stage IV melanoma over the past several decades. As very nicely reviewed in this issue of ONCOLOGY by Bhatia et al, no therapeutic agent has been shown in randomized clinical trials to prolong survival in patients with metastatic melanoma. Chemotherapy with single-agent dacarbazine is the only US Food and Drug Administration (FDA)-approved chemotherapy agent for metastatic melanoma.

Role of Immunity

Immunity to melanoma appears to be important for disease control in the adjuvant and advanced-disease settings. Spontaneous regression has been reported in melanoma, suggesting a role for host immunity. This possibility is indirectly supported by the regular presence of lymphoid infiltrates at the site of primary melanoma, a phenomenon that is frequently associated with histopathologic evidence of tumor regression.

Host cellular immune response within melanoma has potential prognostic and predictive significance. T-cell infiltrates in primary melanoma are prognostic of disease outcome,[1] and T-cell infiltrates within regional nodal metastasis predict benefit from interferon alfa-2b (IFNα2b, Intron A) therapy.[2-4] Immunologic approaches have yielded the only newly FDA-approved agent for metastatic disease in 30 years—high-dose bolus interleukin-2 (IL-2, Proleukin). This therapy is based on durable responses seen in some patients with metastatic melanoma, but with an associated high toxicity rate and cost.

Novel Agents

Currently the optimal approach to the management of patients with metastatic melanoma is treatment on clinical trials in an effort to maximize treatment options and provide access to promising therapeutic approaches for this disease. The future of melanoma therapy appears promising, with many novel experimental agents being tested in clinic, building upon the continuously deepening knowledge of host immunity and molecular circuitry of the tumor. Cancer vaccines continue to be actively tested in melanoma (peptide vaccines, genetic heat shock proteins, and dendritic cell–based vaccines). Molecular approaches to deranged signaling pathways and proapoptotic strategies are also being widely investigated. A phase III intergroup trial coordinated by the Eastern Cooperative Oncology Group (E2603) was recently completed, in which 800 patients with chemotherapy-naive metastatic melanoma were randomized to carboplatin and paclitaxel with either sorafenib (Nexavar) or placebo. The results of this trial are awaited. The roles of several critical regulatory elements of the immune system have recently been elucidated, providing insight into the disease process and new targets for overcoming tolerance. Enhanced expression of costimulatory molecules on the surface of dendritic cells is one approach to enhancing the presentation of tumor-associated antigens. This can be achieved through stimulation of dendritic cell receptors such as CD40 and Toll-like receptor 9 (TLR9).[57] Another approach is to enhance or prolong T-cell activation by blocking negative-signaling receptors such as CTLA4.[8] New strategies, such as the administration of oligodeoxynucleotides that activate TLR9, monoclonal antibodies (mAbs) that activate CD40 or block CTLA4, and costimulatory antibodies to CD137, or targeting regulators of apoptosis such as PD1 (programmed death-1)[9] may provide more effective immunotherapies that might overcome tumor-induced tolerance.

The closure of the tremelimumab phase III melanoma study for “futility” came as a surprise to many investigators, given clinical observations of durable benefits in some patients. The 1-year survival rate of > 50% for tremelimumab and the median survival of 11.7 months (compared with 10.7 months for chemotherapy) were also surprising, although this may have been the result of the selection criteria for this study. The exclusion of patients with 2× upper limit of normal lactate dehydrogenase (LDH) blood values and crossover of patients in the control arm to another anti-CTLA4 mAb may also have played a role in the results, but this remains to be clarified, and more mature survival and response data are anticipated. Results of the phase III studies testing CTLA4 blockade with ipilimumab (as a single agent or in combination with dacarbazine in one study, and administered in conjunction with the gp100 peptide vaccine in another study) are eagerly anticipated.

The further development of novel agents in melanoma will likely include combinations based on strategies for overcoming tumor-induced immune suppression. Preliminary data from combination biotherapy involving CTLA4-blockade with high-dose IFN-α2b[10] and dendritic cell–based vaccination are promising in melanoma.[9,11,12]

Biomarkers

Future research should incorporate the study of biomarkers to predict therapeutic benefit into randomized trials. This may lead to the identification of biomarkers enabling personalized therapy, which has become a Holy Grail of sorts, particularly in melanoma, for which standard options are so limited. Although subsets of melanoma patients clearly benefit from different approaches, these positive results have not been reproduced in classic randomized trials. Some clues could be found in the now repeatedly reported association between the induction of autoimmunity and therapeutic benefit with IFN-α2b, IL-2, and CTLA4-blocking mAbs.[13] Revealing investigations might involve the induction of autoimmunity to a broad array of endocrine and tumor markers as biomarkers of therapeutic benefit.

In addition, researchers may identify immunogenetic factors that predispose patients to induction of autoimmunity by these agents (eg, human leukocyte antigen genotype, polymorphisms of the CTLA4 gene and the FOXP3 transcription factor loci, as well as other immunogenetic markers). Multiplex analysis—encompassing cytokines, chemokines, angiogenic and growth factors, soluble receptors, signal transduction molecules, and other immune and endocrine markers—in relation to patient outcome could also be studied, building upon promising early results.[13,14] Important data along these lines could be provided from melanoma patients treated with adjuvant high-dose IFN-α2b (E1697), and planned adjuvant trials with CTLA4 blockade (ipilimumab, E1609).

Financial Disclosure: Dr. Tarhini has received research support from Pfizer Oncology and Schering-Plough.

References

1. Clemente CG, Mihm MC Jr, Bufalino R, et al: Prognostic value of tumor infiltrating lymphocytes in the vertical growth phase of primary cutaneous melanoma. Cancer 77:1303- 1310, 1996.
2. Hakansson A, Gustafsson B, Krysander L, et al: Tumour-infiltrating lymphocytes in metastatic malignant melanoma and response to interferon alpha treatment. Br J Cancer 74:670-676, 1996.
3. Mihm MC Jr, Clemente CG, Cascinelli N: Tumor infiltrating lymphocytes in lymph node melanoma metastases: A histopathologic prognostic indicator and an expression of local immune response. Lab Invest 74:43-47, 1996.
4. Moschos SJ, Edington HD, Land SR, et al: Neoadjuvant treatment of regional stage IIIB melanoma with high-dose interferon alfa-2b induces objective tumor regression in association with modulation of tumor infiltrating host cellular immune responses. J Clin Oncol 24:3164-3171, 2006.
5. Kadowaki N, Ho S, Antonenko S, et al: Subsets of human dendritic cell precursors express different toll-like receptors and respond to different microbial antigens. J Exp Med 194:863-869, 2001.
6. Krieg AM: CpG motifs in bacterial DNA and their immune effects. Annu Rev Immunol 20:709-760, 2002.
7. Krieg AM: Therapeutic potential of Tolllike receptor 9 activation. Nat Rev Drug Discov 5:471-484, 2006.
8. 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 23:8968-8977, 2005.
9. Tarhini AA, Moschos SS, Schlesselman JJ, et al: Phase II trial of combination biotherapy of high-dose interferon alfa-2b and tremelimumab for recurrent inoperable stage III or stage IV melanoma (abstract 9009). J Clin Oncol 26 (15S):485s, 2008.
10. Ribas A, Comin-Anduix B, Jalil J, et al: Combination of dendritic cell (DC) vaccination with CTLA4 blockade in patients (pts) with metastatic melanoma: A phase 1 clinical trial (abstract 2537). Presented at the American Association for Cancer Research (AACR) Annual Meeting; San Diego, Calif; Apr 12-16, 2008.
11. Gogas H, Ioannovich J, Dafni U, et al: Prognostic significance of autoimmunity during treatment of melanoma with interferon. N Engl J Med 354:709-718, 2006.
12. 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 19:3477-3482, 2001.
13. Yurkovetsky ZR, Kirkwood JM, Edington HD, et al: Multiplex analysis of serum cytokines in melanoma patients treated with interferon-alpha2b. Clin Cancer Res 13:2422- 2428, 2007.
14. Sabatino M, Kim-Schulze S, Panelli MC, et al: Serum vascular endothelial growth factor and fibronectin predict clinical response to high-dose interleukin-2 therapy. J Clin Oncol Apr 13, 2009 (epub ahead of print).
 
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