Cellular Therapy for Melanoma

Abstract

Melanoma was one of the first tumor types that responded to modern immunotherapy with the cytokines interferon alpha and interleukin 2. Indeed, since T cells can be identified before an invasive melanoma arises, the disease could be considered one of both melanocytes and T cells. We now know that the high mutational frequency, potential neoepitope abundance, remarkable 85% surgical cure rate for primary lesions, and predominant T-cell infiltrate found in cutaneous melanomas drove early immunotherapy (and likely surgical) successes. Demonstrating that the T cells were important for resistance to the tumor is most facilely demonstrated with adoptive transfer of tumor-specific T cells. Adoptive transfer of tumor infiltrating lymphocytes (TIL) is unusually successful in patients with melanoma. Prior to the development of checkpoint inhibitors, TIL transfer could generate objective responses in a majority of patients. The complete responses in TIL-treated patients are remarkably durable with most patients never recurring even when followed out for several years. The current era has allowed another important observation that uveal melanoma, a low mutational load tumor with few neoepitope targets, can respond to adoptive transfer of TIL. Future approaches will enable the use of T cells with new properties that can overcome the highly evolved, immunosuppressive environment of the melanoma. These include the abrogation and manipulation of nominal checkpoints, expression of common T-cell receptors in transfected autologous T cells, the development of allogeneic off-the-shelf reagents, and delivery of immunologic cytokines and signaling molecules that can sustain a durable long-term response.