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Michigan Oncology Journal Summer 2000

Immunotherapy of Melanoma

Bruce G. Redman, D.O. Bruce G. Redman, D.O.,
Clinical Associate Professor
Department of Internal Medicine

Vernon Sondak, M.D. Vernon Sondak, M.D.,
Associate Professor, Department of Surgery

It is currently estimated that the risk of developing melanoma is one in 75, and if current trends continue this risk will continue to rise (1). While surgery remains the mainstay of curative treatment in early-stage disease, large numbers of patients continue to progress to a more advanced stage of disease. Standard chemotherapy options, whether single agent dacarbazine or combination therapy, have had little impact on the natural history of advanced disease. Dacarbazine, when administered as a single agent, produces response rates of 15 to 20% of short duration (2). Multiple randomized trials have failed to show a benefit of adding additional agents to dacarbazine (3,4). Newer treatment modalities are obviously needed if we are to impact on this potentially lethal disease. Immunotherapeutic approaches are one area of intense research at the University of Michigan Comprehensive Cancer Center.

Immunobiology of Melanoma

Why should immunotherapeutic approaches to the treatment of melanoma be expected to have any impact on this disease? There are several lines of evidence that support such an approach. Patients with melanoma have been found to have circulating T cells that are specific against their own melanoma cells (5). These specific T cells have also been isolated from metastatic melanoma tumor nodules referred to as tumor infiltrating lymphocytes (TIL). The tumor-specific T cells also have been found to recognize specific antigens, including some unique to cells of melanocytic differentiation and some specific to a broad range of tumor cells (tumor specific antigens) (Table 1). This evidence has been used to hypothesize that there is some form of an immune response against melanoma occurring in these patients.

If there is an ongoing immune response in patients with melanoma, why hasn't the disease been eradicated in these individuals? There are several hypotheses that have been generated based on clinical findings. Melanoma cells may be able to avoid immune detection by loss of the major histocompat-ibility complex (MHC) or accessory molecules (e.g. B7, ICAM-1), which are required for an appropriate T cell response. Melanoma cells may express tumor antigens but at low levels insufficient to expand an adequate immune response for tumor eradication. Finally tumor cells have been found to secrete various soluble factors (e.g. TGF-b, interleukin-10, Fas ligand), which are potentially immune suppressive. All these possible mechanisms are operational to some extent, resulting in the inability of an immune response to eradicate melanoma.

Immunotherapeutic Approaches

The immunotherapeutic approaches to melanoma can be categorized into; 1) administration of cytokines to expand or enhance an immune response, 2) adoptive transfer of autologous lymphocytes that have been manipulated in vitro, 3) vaccination of patients against antigens associated with melanoma and finally 4) combinations of the above.

The cytokine interleukin-2 (IL-2) has been evaluated as a single agent in the treatment of metastatic melanoma. When administered in the FDA approved high dose bolus regimen of 600,000-720,000 IU/kg every 8 hours for 14 doses 16% of patients respond (6% complete response) (6). The majority of the CRs to high dose IL-2 have lasted beyond 4.5 years. IL-2 has also been evaluated in combination regimens with interferon-alpha and multi-agent chemotherapy (biochemotherapy). Reports from several single institution trials have reported response rates with biochemotherapy of 55-60% (10-20% CR) (7,8). A small randomized trial from the NCI surgery branch evaluating chemotherapy vs. biochemotherapy failed to show an advantage for biochemotherapy when survival was used as the endpoint (9). Hopefully an ongoing large intergroup trial randomizing patients with metastatic melanoma between a combination chemotherapy regimen of cisplatin, dacarbazine and vinblastine vs. the same chemotherapy with IL-2 and interferon-alpha will clarify the issue of whether adding immunotherapy to chemotherapy is better then chemotherapy alone. Evaluations of other cytokine and cytokine combinations including the combination of flt3-ligand and interferon (Table 2 ) at our institution remains an area of active research.

The adoptive immunotherapy of melanoma is an area of active investigation either alone or with added cytokines. The source of lymphocytes and the in vitro manipulation utilized differ from trial to trial. TIL with systemic IL-2 has been evaluated in the treatment of metastatic melanoma. Though response rates have been encouraging, treatment is complicated by a need for autologous tumor (which sometimes does not provide adequate numbers of TIL) and the time required to grow out adequate TIL (resulting in disease progression in patients). Other investigators are evaluating alternative sources of lymphocytes for in vitro manipulation and adoptive transfer. Potential sources of lymphocytes include tumor draining lymph nodes, in situ manipulated tumor nodules and peripheral blood lymphocytes.

At the University of Michigan we have pursued several approaches to adoptive therapy of melanoma (Table 2 ). One approach has been to "infect" a tumor nodule with the gene for the HLA-B7 MHC protein in patients who are HLA-B7 negative. The rationale behind this approach is that expression of a foreign MHC protein will induce an immune response, which will lead to recognition of melanoma antigens that are expressed at low levels. In prior trials utilizing this approach, several injected tumor nodules have regressed, the regressions being associated with an intense inflammatory response. We have expanded on this initial work by harvesting an injected tumor nodule and expanding the infiltrating lymphocytes in vitro with IL-2. These expanded lymphocytes are then adoptively transferred back to the patient with systemic IL-2. Another adoptive immunotherapy approach we are evaluating involves taking peripheral blood lymphocytes from patients who are HLA-A2 positive and in vitro inserting the gene for a T cell receptor (TCR) specific for the MART-1 melanoma antigen. These lymphocytes, which now express the specific TCR for MART-1, are adoptively transferred back to the patient.

Vaccine-based strategies also are being evaluated in the treatment of melanoma. In the past, vaccines were made of whole cells or crude cell extracts either alone or with an immune adjuvant. With the recognition and purification of melanoma antigens (Table 1) and new knowledge about professional antigen presenting cells (APC), vaccination strategies are once again an area of active clinical research. One type of APC that has generated the most clinical interest is the dendritic cell (DC). The DC is unique in that it has the ability to present antigen and stimulate a naive T cell response from both CD4 (helper cells) and CD8 (cytotoxic) T cells (10). A naive T cell response is a T cell responding to an antigen which it has not been exposed to previously and therefore has no memory for the eliciting antigen. As an APC the DC expresses both MHC Class I and II, as well as multiple accessory molecules required for the appropriate stimulation of an effective T cell response.

We are evaluating two such approaches to the vaccination of patients with melanoma. In the first we are administering DC that have been obtained from a patient by leukapheresis and pulsed with melanoma associated antigens gp100 and tyrosinase in vitro. This trial is evaluating this approach in patients who are HLA-A2 positive and who have Stage IIA and IIB resected melanoma (primary tumor >1.5 mm and negative lymph nodes). We are also evaluating DC based vaccination strategies in patients with metastatic melanoma. In this trial we are utilizing DC pulsed with autologous melanoma. The use of autologous tumor avoids one of the problems of utilizing defined peptide antigens in that all melanoma cells in an individual patient may not express the peptide(s) that are being used as part of the vaccine. These autologous tumor-pulsed DC are then administered back to the patient either alone or with IL-2.

The Cutaneous Oncology Program and the Tumor Immunology Program of the University of Michigan Comprehensive Cancer Center are working together to develop new strategies for the treatment of patients with melanoma. For the future, new immunotherapeutic trials are being developed based on basic and clinical research that is currently ongoing at the University of Michigan.

References

1. Balch CM, Reintgen DS, Kirkwood JM, et al: Cutaneous melanoma, in DeVita VT Jr, Hellman S, Rosenberg SA (Eds): Cancer: Principles and Practice of Oncology. Philadelphia, PA, Lippincott-Raven, 1997, pp 1947-1994.

2. Hill GJ 2d, Krementz ET, Hill HZ: Dimethyl triazeno imidazole carboxamide and combination therapy for melanoma: IV. Late results after complete response to chemotherapy (Central Oncology Group protocols 7130, 7131, and 7131A). Cancer 1984;53:1299-1305.

3. Falkson CI, Ibrahim J, Kirkwood J, et al: Phase III trial of dacarbazine versus dacarbazine with interferon-2b versus dacarbazine with tamoxifen versus dacarbazine with interferon-2b and tamoxifen in patients with metastatic malignant melanoma: An Eastern Cooperative Oncology Group study. J Clin Oncol 1998;16: 1743-1751.

4. Chapman PB, Finhorn LH, Meyers ML, et al. Phase III multicenter randomized trial of Dartmouth regimen versus dacarbazine in patients with metastatic melanoma. J Clin Oncol 1999;17:2745-2751.

5. Schwartzentruber D, Hom SS, Rosenberg SA, Topalian SL. In vitro predictors of therapeutic response in melanoma patients receiving TIL and IL-2. J Clin Oncol 1994;12: 1475-1480.

6. Atkins MB, Lotze MT, Dutcher JP, et al. High dose recombinant interleukin-2 therapy for patients with metastatic melanoma. Analysis of 270 patients treated between 1985 and 1993. J Clin Oncol 1999;17:2105-2116.

7. Richards JM, Mehta N, Ramming K, et al. Sequential chemoimmunotherapy in the treatment of metastatic melanoma. J Clin Oncol 1992;8:1338-1343.

8. Legha SS, Ring S, Eton O, et al. Development of a biochemotherapy regimen with concurrent administration of cisplatin vinblastine, dacarbazine, interferon alfa, and interleukin-2 for patients with metastatic melanoma. J Clin Oncol 1998;16: 1752-1759.

9. Rosenberg SA, Yang JC, Schwartzentruber DJ, et al. Prospective randomized trials of the treatment of patients with metastatic melanoma using chemotherapy with cisplatin, dacarbazine, and tamoxifen alone or in combination with interleukin-2 and interferon alfa-2b. J Clin Oncol 1999;17:968-975.

10. Inoba K, Metlay JP, Crowley MT, et al. Dendritic cells pulsed with protein antigens in vitro can prime antigen specific, MHC restricted T cells in situ. J Exp Med 1990;172:631-640.

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