Combining targeted therapy and immune checkpoint inhibitors in the treatment of metastatic melanoma

Abstract

Melanoma is the deadliest form of skin cancer and has an incidence that is rising faster than any other solid tumor. Metastatic melanoma treatment has considerably progressed in the past five years with the introduction of targeted therapy (BRAF and MEK inhibitors) and immune checkpoint blockade (anti-CTLA4, anti-PD-1, and anti-PD-L1). However, each treatment modality has limitations. Treatment with targeted therapy has been associated with a high response rate, but with short-term responses. Conversely, treatment with immune checkpoint blockade has a lower response rate, but with long-term responses. Targeted therapy affects antitumor immunity, and synergy may exist when targeted therapy is combined with immunotherapy. This article presents a brief review of the rationale and evidence for the potential synergy between targeted therapy and immune checkpoint blockade. Challenges and directions for future studies are also proposed.

Keywords: BRAF inhibition; Melanoma; checkpoint blockade; immunotherapy.

Figure 1

Putative effects of adding BRAF targeted therapy to immune-based therapies. Without treatment, melanomas demonstrate an immunosuppressive environment with generally low levels of melanoma antigens, low levels of infiltrating cytotoxic T lymphocytes, and high levels of immunosuppressive cytokines and VEGF (A). Treatment with a BRAF inhibitor results in a favorable tumor microenvironment with increased antigens and CD8+ T cells and decreased immunosuppressive cytokines and VEGF, but with concurrent increase in immunomodulatory molecules, such as PD-1 on T cells and PD-L1, in the tumor microenvironment (B). BRAF-targeted therapy may synergize with different treatment modalities, and this phenomenon is being tested in murine models and in clinical trials. Evidence for synergy exists with immune checkpoint blockade (C), considering that the BRAF inhibitor addition has positive effects on the tumor microenvironment (with increased antigens, CD8+ T cells, and decreased immunosuppressive cytokines/VEGF) and that the simultaneous increase in immunomodulatory molecules is tempered by immune checkpoint blockade (D). The potential synergy includes combined treatment with IL2 (E), in which the addition of BRAF-targeted therapy may augment the antitumor immune response by its favorable effects on the tumor microenvironment (F). Nevertheless, regulatory T cells in this setting may be controversial. Adoptive cell therapy works through ex vivo activation of autologous antigen-reactive T cells (G), and this behavior may be enhanced by the favorable effects of BRAF-targeted therapy on the tumor microenvironment (H). Radiation therapy has clear effects on the tumor microenvironment with effects on both tumor cells and antitumor immunity (I), which may be augmented by the addition of BRAF-targeted therapy (J).