How effective is immunotherapy in malignant melanoma?

The lack of effective treatment for advanced-stage melanoma by conventional therapies, such as radiation and chemotherapy, has highlighted the need to develop alternative therapeutic strategies. Among them, immunotherapy has attracted much attention because immunologic events appear to play a role in the clinical course of the disease and may occasionally cause clinical regressions.

Monoclonal antibody (mAb) therapy has been investigated using a variety of nonconjugated and conjugated (linked to toxins or radioisotopes) mAb directed against glycolipids, glycoproteins, and proteoglycans expressed by melanoma cells. Occasional dramatic responses have been reported, but the overall efficacy is quite limited, and responses have been noted only in about 10% to 12% of treated patients. More recent studies have investigated the use of mAb that targets immunomodulatory pathways that regulate immune effector cells. In this regard, considerable attention has been given toward targeting either CD28 or CTLA-4 on immune effector cells. It should be stressed that targeting the CD28/CTLA-4 pathway is fraught with hazard, because affinity and concentration of the administrated mAb must be balanced to prevent superinflammatory responses. The CTLA-4–specific ipilimumab (MDX-010) and tremelimumab (CP-675,206), which are fully human IgG1 and IgG2 mAbs, respectively, are being tested in patients with metastatic melanoma. The use of tremelimumab is also currently being investigated in a phase I trial in stage IV melanoma patients in combination with the Toll-like receptor (TLR)9 agonist PF-3512676.

A number of new mAbs are directed against various targets, including vascular endothelial growth factor (VEGF), tumor necrosis family costimulatory receptors (e.g., DR4, DR5, glucocorticoid-induced tumor necrosis factor receptor [GITR], CD134 [OX40], CD137 [4-1BB], and CD40), and integrins also are currently being investigated in clinical trials. Recently, T-cell–based immunotherapy has been emphasized, because there have been disappointing results in the clinical trials implemented with mAbs, and because T cells are believed to play the major role in the control of tumor growth. In general, these vaccines have been relatively successful in animals; however, these results have not translated into human trials. These studies have demonstrated that cell-based, heat shock protein–based, T-cell–defined peptide epitopes and dendritic cell–based vaccinations can effectively induce tumor-specific immune responses. Nonetheless, a lack of clinical response and/or recurrence of disease occurs frequently, in spite of induction and/or persistence of TA-specific immune responses. This lack of correlation is caused, at least in part, by the multiple immune escape mechanisms utilized by melanoma cells.


An additional means of cellular immunotherapy is the adoptive transfer of immune effector cells into patients. The ex vivo expansion of lymphokine-activated killer (LAK) cells or tumor-infiltrating lymphocytes (TIL), with or without interleukin-2 (IL-2), has achieved some remarkable response rates in cancer patients.

The use of biologic response modifiers, such as interferon (IFN) and other cytokines, has had modest success. The use of IFN-α as a single-agent treatment has yielded response rates of 15% to 20% and complete response rates in up to 5% of patients. However, it should be stressed that the use of IFN-a remains controversial because its use has only been associated with an increase in disease-free interval but not an increase in overall survival in treated patients.

Combination therapy with the chemotherapeutic drugs dacarbazine and cisplatin, along with immunotherapeutic agents such as IFN-α and IL-2, has yielded significantly higher response rates, variously reported in the 40% to 50% range. Most of these cases, however, were limited to metastases involving soft tissues, including lymph nodes and subcutaneous tissue or the lung. Very few responses have been recorded in patients with liver or other visceral metastases. Furthermore, there has been little prolongation of survival with the use of combination therapy.

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