Immune Checkpoint Inhibitors in the Treatment of Metastatic Melanoma

The notion that the immune system could be harnessed to treat metastatic cancer goes back at least 100 years to the observations of Coley, who noted that the development of postoperative infections was associated in some cases with “spontaneous” regression of metastatic tumors. Coley went on to show that tumor regression could be induced, at least in some cancer patients, by the administration of sterile bacterial-conditioned medium containing streptococcal exotoxins. 1,2 More than 50 years later, the therapeutic potential of the immune system was again demonstrated with the advent of recombinant cytokines such as interferon and interleukin (IL)-2, the latter of which has been shown to induce complete and durable tumor regression in a small fraction of patients with melanoma or renal cell carcinoma. 3,4 IL-2 is now approved by the US Food and Drug Administration for the treatment of patients with these malignancies. The clinical development of IL-2 was quickly followed by the cloning and complementary DNA sequencing of additional T-cell stimulatory cytokines (IL-4, -6, -12, -15, -18, and -21) and the subsequent production of recombinant proteins, many of which showed promise in murine cancer models. 5–7 With few exceptions, however, these cytokines were either ineffective or prohibitively toxic when tested in humans. Thus, as of 10 years ago, the only immunotherapy of metastatic cancer that had any prospect of success was the treatment of melanoma or renal cell carcinoma patients with high doses of IL-2. The immune system has an elaborate set of signaling pathways that exist solely to limit the intensity and duration of T-cell activation. These pathways are essential for normal homeostasis because their deletion or suppression often leads to the development of inflammation unprovoked by a specific pathogen and/or autoimmunity. This concept of negative immune regulation has been reinforced by the discovery of cytotoxic T-lymphocyte antigen-4 (CTLA-4), the programmed death-1 receptor (PD-1), and other immunoglobulin-like molecules that are expressed on activated T cells and inhibit their function. 8,9 The development of neutralizing antibodies against these proteins has led to a paradigm shift in the immunotherapy of cancer in which the goal of directly stimulating T cells (with IL-2 or a vaccine) has been supplanted by a seemingly more nuanced objective of simply eliminating the inhibitory effects of CTLA-4 and PD-1. The fact that the neutralization of CTLA-4 or PD-1 with antibodies that block their interaction with their respective ligands can lead to tumor regression suggests that the ability of tumors to evade the immune system may not be due to the downmodulation of class I human leukocyte antigen molecules, the lack of tumor antigens, or the inability to process them and display antigenderived peptides in a context capable of eliciting T-cell recognition and activation, as was once widely believed. The efficacy of these agents in fact suggests that immune evasion is often specifically due to the expression by the tumor cells (or certain immune regulatory cells) of 1 or more of the ligands for PD-1 or CTLA-4, which upon engagement of their respective receptors, leads to the downmodulation of T-cell function.