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Immunotherapy holds a highly promising treatment approach for metastatic melanoma patients. Adoptive cell transfer (ACT) involves the ex vivo expansion of autologous antitumor reactive lymphocytes and their reinfusion into lymphodepleted patients, accompanied by IL-2 administration. ACT with tumor-infiltrating T lymphocytes demonstrates objective clinical responses in 50-72% of the patients, including 10-40% complete responses and was shown to produce durable disease control with long progression-free survival. Tumor-infiltrating T-lymphocyte ACT might even have curative potential as the vast majority of the complete responders are without any evidence of disease many years after treatment. Other adoptive transfer studies employ the genetic modification of T lymphocytes with genes encoding tumor-specific T cell receptors or antibody-based chimeric antigen receptors. These approaches opened numerous possibilities to treat cancers other than melanoma. In this article we will summarize the ACT strategies in melanoma, the new developments in this field and combinations with other therapies.

Cancer therapy was traditionally centered on the neoplastic cells. This included mainly surgery, radiation, and chemotherapy, in some cases hormone therapy and to a lesser extent immunotherapy--all traditionally targeted to the highly proliferating mutated tumor cells. In view of our present understanding of the powerfull influence of the tumor microenvironment (TME) on cancer behavior and response--and lack of response--to treatment, this previously ignored constituent of cancer now has to be considered as an important, even indispensable target for therapy. The TME may be targeted both to its immune and to its nonimmune components. The various immune evasion elements of the TME should be targeted as well.

For years the mutated, highly proliferating neoplastic cells were presented as the only important agent in tumors; however, during the last 3-4 decades it has become clear that the microenvironment of the cancer cells plays a determinative role in the malignant evolution of neoplasia. Cancers are in fact heterogeneous entities containing, in addition to the neoplastic cell component, cells derived of multiple lineages (fibroblasts, endothelial cells lining blood and lymphatic vessels, pericytes, adipocytes and immune system cells belonging to both innate and adaptive responses), as well as the extracellular matrix, with a large variety of soluble molecules of biological importance, constituting a complex organ-like structure. The tumor microenvironment consists in a tissue that may have a predictive significance for tumor behavior and response to therapy.