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Immunotherapy for the management of advanced melanoma: the next steps.

Zikich D, Schachter J, Besser MJ.

Am J Clin Dermatol. 2013 Aug;14(4):261-72.

Ella Institute for Melanoma, Sheba Medical Center, 52621 Ramat-Gan, Israel.




Melanoma is an immunogenic tumor that can induce a natural immune response. A number of immunotherapy-based approaches have been developed over the past decades, and certain degrees of effectiveness were achieved by the use of cytokines, adoptive cell transfer and T-cell immune modulators. Currently, interleukin-2 and the immune stimulatory antibody, ipilimumab, are the only two approved immunotherapies for metastaticmelanoma, but various new therapies are in promising developmental stages. This comprehensive review will discuss the latest achievements ofimmunotherapy and emerging directions for the management of advanced melanoma.



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 Additional Information:

Standard therapies for metastatic cancer in general and melanoma in particular, have been mainly based on chemotherapy, radiation and surgery. These modalities produce mostly unsatisfactory results and emphasize the need for new therapeutic strategies. This need gave rise to the rapidly developing field of “immuno-oncology”, which focuses on the enhancement of antitumor responses of the body’s own immune system against cancer cells. Strategies that mobilize and strengthen the immune system to attack cancer are now

widely recognized to have the utmost potential to achieve complete and durable remissions. As a result, two major immunotherapy approaches have emerged; the antibody-based interference of key T cell checkpoints and Adoptive T Cell Therapy (ACT). The essence of both modalities is to enhance T lymphocytes responses.

Numerous immune modulating agents have been developed and tested in recent years, among them, antibodies blocking co-inhibitory T-cell molecules, namely, CTLA-4 (cytotoxic T-lymphocyte-associated antigen 4), PD-1 (programmed death 1), and PD-L1 (programmed death ligand 1). Very recent studies have demonstrated that the combined blockage of CTLA-4 and PD-1 produce rapid and deep tumor regression in a significant portion of patients with advanced melanoma, and show superior antitumor activity than the monotherapy with either agent. Data from a phase II trial testing the concurrent administration of nivolumab (anti PD-1 antibody) and ipilimumab (anti CTLA-4 antibody) showed objective responses in 21 of 52 (40%) patients, according to modified WHO criteria, whereas the overall evidence of clinical activity (conventional, unconfirmed, or immune-related response or stable disease for ≥24 weeks) was observed in 65% of the patients.

Likewise adoptive T cell therapy is being consistently improved over the past two decades. Administration of autologous Tumor-Infiltrating Lymphocytes (TILs) can mediate tumor regression in patients with refractory melanoma and produce durable complete responses. TIL ACT is considered as one the most potential treatments for melanoma, and is currently being explored also in other cancer types. Further improvement of adoptive T cell therapy may derive from the genetic modification of T lymphocytes to express tumor antigen-specific T-cell receptors (TCR) or chimeric antigen receptors (CAR). TIL-based ACT has a substantial clinical potential, both as a standalone therapeutic intervention and in combination with other treatment modalities, such as key checkpoint inhibitors. This approach holds the potential to evolve into a personalized immunotherapy modality, with the ability to adjust the antigen-targeting profile to the individual cancer patient.

Immunotherapy for the Management of Advanced Melanoma