Immunotherapy has emerged as the most effective treatment for patients with metastatic melanoma. Much of the information concerning the immune response to melanoma has come from the study of tumor-infiltrating lymphocytes (TIL), immune cells that infiltrate into the stroma of the growing tumor and can be grown in vitro in the cytokine IL-2.¹ TIL have been used to identify dozens of antigens that are presented on melanomas.² Some antigens such as MART-1 and gp100 are shared by both melanomas and normal melanocytes, whereas others, such as NY-ESO-1, can be expressed on melanomas, but on no other adult tissue except the testes.

Most studies of immunotherapy for melanoma patients have been directed at those with metastatic disease. Although multiple trials of cancer vaccines have been performed in patients with resected lymph nodes at high risk of recurrence, none of these clinical trials have convincingly demonstrated prolonged survival.³ Some controversy exists surrounding the use of interferon alpha for the treatment of stage 3 melanoma; prolonged follow-up of patients in prospective randomized trials has yielded ambiguous results, and many oncologists are concluding that the toxicities of highdose interferon are not warranted given the lack of conclusive evidence of effectiveness in this setting.

Substantial progress has been made, however, in the treatment of patients with metastatic melanoma. It is now possible to cause complete regressions of widely metastatic melanoma at multiple sites in the body utilizing immunotherapy approaches. Immunotherapy Approaches To Metastatic Melanoma Approaches to the treatment of patients with metastatic melanoma fall into three major categories, which are summarized in Table 1.

Nonspecific stimulation of immune reactions

Because natural immune responses to melanoma exist, attempts at nonspecific immunomodulation have shown some effectiveness. Administration of a hormone involved in T cell growth, called interleukin-2 (IL-2), can activate naturally occurring antimelanoma immune cells. Of 305 consecutive metastatic melanoma patients treated in the Surgery Branch at NCI, 13 percent achieved objective responses by standard RECIST (Response Evaluation Criteria in Solid Tumors) criteria; four percent had complete regressions.⁴

Patients who experience complete regression rarely recur. It was the durability of the regressions induced by IL-2 that led to its approval by the US Food and Drug Administration in 1998 for the treatment of patients with metastatic melanoma (Figure 1). IL-2 administration is the only FDA-approved treatment capable of curing patients with metastatic melanoma. The capillary leak syndrome associated with the administration of IL-2 has limited its widespread use, but this side effect can be readily managed, and treatment-related mortalities add up to less than one percent of patients seen in experienced centers.

Figure 1 Survival of patients with metastatic melanoma or metastatic renal cell cancer who underwent a complete response to treatment with high-dose IL-2. Complete responses tend to be highly durable.

Another experimental approach to nonspecific immunomodulation, not FDA-approved, is the administration of an antibody that reacts with (inhibits) a cell surface inhibitory molecule, cytotoxic T lymphocyte-associated 4 (CTLA-4). Of 139 patients with metastatic melanoma treated with anti-CTLA-4 in the Surgery Branch at NCI, 17.7 percent have achieved objective clinical responses, including some complete responses ongoing beyond 5 years.⁵ Approximately 15 percent of patients who receive anti-CTLA-4 will develop severe enterocolitis, and 5-10 percent of patients will develop hypophysitis requiring steroid replacement.

Active immunization to enhance antitumor reactions

A second major approach to the immunotherapy of metastatic disease involves active immunization with cancer vaccines. Despite much work in this field, only rare and highly sporadic objective regressions of metastatic melanoma are seen using this approach.³ Though it is possible to generate large numbers of antitumor lymphocytes in patients utilizing active immunization, many of these lymphocytes are of very low avidity for melanoma recognition and have little clinical impact.

Adoptive cell transfer (ACT) immunotherapy

The third and most effective treatment for patients with metastatic melanoma is adoptive cell transfer (ACT).⁶ This approach involves the ex vivo identification of autologous lymphocytes with antitumor activity that can be stimulated in the laboratory, grown to large numbers, and then infused into cancer patients along with appropriate growth factors to keep these transferred cells alive and functional in the patient.

ACT has several advantages compared to other forms of immunotherapy. It is necessary to identify only a small number of highly reactive antitumor lymphocytes, which can then be further stimulated and expanded in vitro to large numbers for patient administration. In vitro tests can be used to identify the cellular characteristics required to mediate tumor regression.

An important factor for the success of ACT is the ability to deplete the host of inhibitory factors that can negatively influence the transferred cells. Utilizing lymphodepletion with cyclophosphamide and fludarabine and adoptive cell transfer of autologous TIL, an objective response rate of 49 percent was seen in 43 consecutive patients with metastatic melanoma (Table 2).^7,8 Increasing the prior lymphodepletion by adding total-body irradiation increased the objective response rate to 72 percent in 25 consecutive patients.⁸ Durable responses have been seen in multiple metastatic sites including lung, liver, brain, lymph nodes and subcutaneous sites (Figure 2 A,B). Following lymphodepletion, the transferred cells expand in vivo and persist in the peripheral blood, sometimes adding up to 75 percent of all circulating CD8+ lymphocytes.

Figure 2A Complete response of multiple liver metastases in a patient with metastatic melanoma treated with cell transfer therapy. This patient remains disease-free over 4 years later.

Figure 2B Regression of metastases in the heart (upper panel), the adrenal gland (middle panel), and intraperitoneum (lower panel) in a patient with melanoma treated with cell transfer therapy.

Prolonged survival of patients is seen using the ACT approach (Figure 3). The Surgery Branch at NCI is now seeing patients with metastatic melanoma from around the world, and other centers are beginning to study the application of cell transfer therapy for the treatment of patients with metastatic disease. (To refer a patient to the Surgery Branch, call 301-451-1929.)

Figure 3 Survival curves of patients treated with cell transfer therapy using autologous TIL, either with no lymphodepleting chemotherapy, with a non-myeloblative chemotherapy, or with the nonmyeloblative chemotherapy plus the addition of total body irradiation (TBI).

ACT Approaches and Gene Therapy

The success of ACT approaches has led to the development of gene therapy for the treatment of patients with metastatic melanoma.⁹ TIL with antitumor activity can be generated from only half of patients with melanoma. We have thus developed techniques to genetically alter the normal circulating lymphocytes of a patient to endow these cells with antitumor activity. TIL express T cell receptors that can recognize melanoma antigens. The genes encoding these T cell receptors have been cloned into retroviruses that can be used to convert normal peripheral lymphocytes into cells capable of recognizing the melanoma.

The first applications of this gene therapy approach were recently published.⁹ Two patients, one with metastatic melanoma to the liver and another to the lung hilum, experienced objective regressions when treated with these genetically modified cells, and both of these patients are diseasefree more than three years later.

Current gene therapy trials are yielding objective response rates of 30 percent. Thus, the ability to modify normal lymphocytes genetically represents an exciting new approach to the treatment of metastatic melanoma patients. It is now being explored for the treatment of other cancer types as well.

Summary

Melanoma is a disease that appears to be susceptible to immunotherapy, and to date, adoptive cell transfer approaches are, by far, the most effective treatment for patients with metastatic melanoma. Some patients with metastatic melanoma treated with immunotherapy appear to be cured, with follow-up more than 20 years after treatment. Further development of immunotherapy holds promise for even more effective treatments in the future.

References

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