Melanoma of the skin remains a fatal disease, and its incidence continues to rise, mostly in young adults during their prime. Surgery remains the most effective therapeutic modality, but patients’ survival depends on the stage of the disease at the time of diagnosis. Various therapeutic agents have been administered systemically as adjuvant therapy following complete surgical elimination of the disease to improve survival. However, most of these approaches have either failed or met with very limited success, and new approaches are needed.
Allogeneic vs Autologous Vaccines
Cutaneous melanoma is potentially a chemoresistant disease, but it is an immunogenic tumor, and several melanoma-specific antigens, epitopes, peptides, and gangliosides have been identified. Nevertheless, it is also a heterogeneous tumor, and targeting any of these molecules singly or in combinations for therapeutic use has failed to produce meaningful results. Theoretically, even if there is an initial response, heterogeneity of the tumor can overcome this response. In addition, adjuvant therapy with allogeneic melanoma cell vaccines or their extracts have failed to show any benefit. This clearly indicates that the use of nonautologous melanoma cells or their antigens is not effective.
Theoretically, autologous whole cell tumor vaccine includes all the patient’s own tumor-specific antigens and could be more effective as adjuvant therapy. However, autologous tumor cells are not always available for clinical use. A small amount of tumor cells can be identified postoperatively in the lymph nodes in fixed tissues, but this would be too late to use them for vaccination. If a large metastatic deposit is resected, special laboratory facilities to safely process tumor cells for vaccination are usually lacking. Even if the vaccination process is completed, the results of such an approach have been equivocal, and this could be due to ex vivo processing of the melanoma cells. It has also been shown that systemic administration of biotherapy or vaccines in metastatic disease can induce high levels of immune response in the peripheral blood, but the tumor continues to grow.
Cytokine Administration
The intralesional administration of granulocyte-macrophage colony-stimulating factor (GM-CSF, Leukine) or interleukin-2 (IL-2, Proleukin) in satellitosis and in-transit metastases each gave over 60% complete responses of 
long duration. Biologically, GM‑CSF administration activates dendritic cells, which are very efficient antigen-presenting cells capable of processing tumor antigens and crosstalk to T lymphocytes, creating potentially efficient cytotoxic T cells. Dendritic cells are rich in costimulatory factors such as B7-1, B7-2, and others that are essential to complete the second immunologic signal. Dendritic cells also increase IL-2 receptors on T cells and enhance the efficacy of IL-2–induced cytotoxic T cells. The administration of GM-CSF at the primary site induced dendritic cells in the paracortical zone of sentinel lymph nodes—ie, the agent can travel to the regional lymph nodes and is biologically active. In addition, the administration of IL-2 can stimulate natural killer cells, CD8-positive cells, and tumor-infiltrating lymphocyte proliferation and function. However, while the systemic administration of these two cytokines in patients with metastatic disease was safe, well tolerated, and induced T-cell activation and elevated serum level of IL-2 receptors, they produced no clinical response.
Of interest, the method of administration can play a major role in initiating antitumor immunity. It was recently reported that the administration of naked antigen-encoding RNA vaccine in the skin, subcutaneous tissue, or near a groin lymph node in an animal model did not initiate antigen-specific T cells. Only when the vaccine was injected intranodally did it induce an immune response.
New Approach
A new approach to adjuvant therapy for melanoma utilizes what is available to us clinically. Applying the aforementioned results to early-stage disease, newly diagnosed high-risk patients such as those with deeply invasive primary melanoma measuring over 1.0 mm deep, mitosis, ulceration, and/or regional lymph node metastases, can have their primary sites put to use for immune manipulation, prior to the excision. The preoperative intradermal administration of low doses of GM-CSF (500 µg on day 1) followed by IL-2 (11 million IU/d on days 2 and 3) at the primary site is safe and well tolerated (except for moderate-sized skin reaction at the injection site).
This strategy results in complete tumor necrosis at the primary site with overexpression of CD8-positive, CD25-positive, and CD83-positive cells at the primary site and regional lymph nodes. The administration of GM-CSF/IL-2 can activate and stimulate dendritic cells and T cells in the presence of tumor cells, regardless of the amount of tumor present. This forms a triad of actions that can potentially initiate tumor-specific cytotoxic T cells. The two biologic agents and the induced antitumor immune cells can flow to the regional lymph nodes and systemically induce the same effects.
Such an approach is easily available to all practitioners, less expensive than preparing an autologous vaccine ex vivo, and does not utilize the addition of adjunct agents that cause a massive inflammatory reaction at the vaccination sites. Standard operative procedure is then carried out a week later, as wide excision of the primary with either sentinel lymph node(s) biopsy or regional lymph node dissection, depending on the stage. Postoperatively, patients with no metastases to their regional lymph nodes would have no major side effects from this approach and can be observed with no further therapy. On the other hand, those with metastases to their regional lymph nodes should be considered for additional systemic adjuvant therapy postoperatively in the form of the same low-dose of GM-CSF/IL-2 given subcutaneously to maintain and magnify the immune response.
This approach can initially be evaluated in a phase I clinical trial prior to being assessed for survival benefit in a prospective, controlled randomized study. ■
—E. George Elias, MD, PhD
Molecular Oncology Program
Georgetown Lombardi Comprehensive Cancer Center
Washington, DC
Financial Disclosure: Dr. Elias reported no potential conflicts of interest.
Suggested Readings
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