Intralesional Cytokine Therapy in Cutaneous Melanoma: A Call for Clinical Trials


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Cutaneous melanomas are mostly an immunogenic group of tumors, but they are also heterogeneous. Therefore, therapeutic specificity and autogenetic approaches are essential to secure beneficial results.

The objective of sentinel lymph node biopsy, at the time of diagnosis, is to identify patients with early regional lymph node metastases to initiate early adjuvant therapy after lymphadenectomy. At the present time, surgical excision of the primary site with or without regional lymph node dissection followed by systemic administration of allogeneic material did not result in major survival benefits. Postoperative systemic adjuvant therapy has resulted in some benefit, but the fact remains that over 60% of patients develop recurrences and metastases and over 50% die of their disease in the first 5 years.

Variety of Approaches

Patients with dermal and subdermal metastases offer an excellent opportunity to evaluate the effects of intralesional therapy in cutaneous melanoma. Historically, several approaches had been utilized in the management of in-transit metastases with limited success. These included repeated local excisions, hyperthermic isolated limb perfusion with melphalan with or without tumor necrosis factor, limb infusion with a variety of agents, laser therapy, intralesional injection of various chemotherapeutic and biologic agents, gene therapy, and as a final resort, radiation therapy and systemic
therapy.

In addition, intralesional therapy with either of two cytokines—namely, granulocyte-macrophage colony-stimulating factor (GM-CSF, Leukine)1 and interleukin-2 (IL-2, Proleukin)2—each gave promising results, but they were never used sequentially or in combination. Intralesional therapy with GM-CSF can increase the number and activation of dendritic cells,3 which are very efficient antigen-presenting cells that are capable of processing tumor antigens and crosstalk to lymphocytes. On the other hand, IL-2 administration can stimulate and activate tumor-infiltrating lymphocytes, which can result in the induction of cytotoxic T cells. Therefore, we felt that sequential intralesional administration of intralesional GM-CSF followed by IL-2 might complement one another, using the patient’s own tumor as a source for tumor antigens.

Exploratory Study

In an exploratory study in patients with dermal and subdermal metastatic melanoma, we explored the use of intra lesional therapy with low-dose GM-CSF (500 µg once weekly). In case of failure to obtain a complete response in 4 to 6 weeks, IL-2 was substituted (18 million IU/wk).4 The results revealed that such intralesional therapy was well tolerated without major side effects.

Complete responses were obtained in patients with small lesions ranging in size from a few mm up to 1 cm regardless of whether these were primary, satellite, or in-transit metastases. However, none of the large sclerotic lesions responded to intralesional therapy with either cytokine. The complete responses were noted clinically and confirmed pathologically by rebiopsy of some of the injected sites at 6 to 8 weeks after cessation of the therapy, and showed absence of tumor cells and no mononuclear cell infiltrates.

Of note, two patients in whom prior treatment failed (relatively high doses of systemic adjuvant therapy with GM-CSF at 125 µg/m2/d for 14 consecutive days followed by IL-2 at 9 million IU/m2/d for 4 days, repeated every 28 days for 2 years) had a complete response to intralesional therapy—one to GM-CSF and the other to IL-2 after failure of GM-CSF therapy. This suggested that intralesional therapy could be more effective than systemic administration of the same cytokines. The overall survival of the responders varied from 31 to 48 months to date.

When both cytokines were administered preoperatively in the primary melanoma, 1 week before surgery, the resected tissues gave us a chance to evaluate the early effects of intralesional therapy. The pathology examination of the resected tissues showed complete tumor necrosis with massive pigmented histiocytes at the primary and the satellite. At the same time, the histiocytes were also noted in the regional lymph nodes.

Immunohistochemical studies showed overexpression of various immune cells at the injection sites and the lymph nodes. This approach is supported by a recent report showing that the number of tumor-infiltrating lymphocytes in the primary melanoma is an independent predictor of sentinel lymph node status and patient survival.5 Whether the activation of these cells at the tumor sites could be established by IL-2 alone remains unclear; in theory, it may require the presence of antigen-presenting cells to process the tumor antigens. Intralesional therapy can induce in vivo tumor-specific autoimmunity, regardless of tumor antigenic and genetic profiles, and can overcome tumor heterogeneity.

Conclusions

Intralesional therapy is less expensive and more effective than other approaches to cutaneous melanoma. These observations open up new possibilities for clinical trials. The strategy could be used to standardize the management of in-transit metastases and to initiate new approaches to adjuvant therapy in high-risk melanoma patients. ■

—E. George Elias, MD, PhD
University of Maryland at
St. Joseph Medical Center
Baltimore, Maryland

Disclosure: Dr. Elias reported no potential conflicts of interest.

References

1. Vaquerano JE, Cadbury P, Treseler P, et al: Regression of in-transit melanoma of the scalp with intralesional recombinant human granulocyte-macrophage colony-stimulating factor. Arch Dermatol 135:1276-1277, 1999.

2. Weide B, Derhovanessian E, Pflugfelder A, et al: High response rate after intratumoral treatment with interleukin-2: Results from a phase 2 study of 51 patients with metastasized melanoma. Cancer 116:4139-4146, 2010.

3. Nasi ML, Lieberman P, Busam KJ, et al: Intradermal injection of granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients with metastatic melanoma recruits dendritic cells. Cytokines Cell Mol Ther 5:139-144, 1999.

4. Elias EG, Sharma BK: Targeting melanoma sites in vivo can induce complete tumor ablation and prolong patient survival: An exploratory study. J Cancer Sci Ther 5:244-248, 2013.

5. Azimi F, Scolyer RA, Rumcheva P, et al: Tumor infiltrating lymphocytes grade is an independent predictor of sentinel lymph node status and survival in patients with cutaneous melanoma. J Clin Oncol 30:2678-2683, 2012.



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