Epigenetic variation and genetic instability in tumor cells yield a variety of tumor antigens that the immune system can recognize to distinguish tumor cells from normal cells. These antigens are shed by tumors and are collected by antigen presenting cells (APC). An immune response is initiated when APCs present tumor antigens to T-cells; a second ligand localized on APCs serves as a co-regulatory signal that can either activate or suppress T-cell responses. This combination of signals modulates the amplitude of ensuing immune responses. With an activating signal, T-cells proliferate, migrate throughout the body to find their target, and lyse tumor cells. While it is evident that lymphocytes infiltrate growing tumors, tumor-infiltrating lymphocytes typically fail to generate a robust anticancer response.
Furthermore, immune checkpoints are inhibitory pathways of the immune system that modulate magnitude and duration of T-cell responses. Immune checkpoints are critical for physiological homeostasis, including maintenance of self-tolerance and protection of tissues from damage as the immune system responds to pathogenic infection. However, these checkpoints may also serve as crucial regulators of immune escape in cancer. Checkpoint pathways are regulated by ligand/receptor interactions, and thus, may be targeted by blocking monoclonal antibodies. Theoretically, utilization of an antibody to prevent interactions of ligands with checkpoint receptors should release the “brake” on the immune system to enhance a response against cancer.
The clinical and commercial feasibility of an immune checkpoint blocking agent has been demonstrated recently with the launch of ipilimumab [Yervoy: Bristol-Myers Squibb], a human cytotoxic T-lymphocyte antigen 4 (CTLA-4)-blocking antibody. It is the first cancer immunotherapeutic agent of this class to gain regulatory approval. CTLA4 is a negative regulator of T-cell activation.
Ipilimumab binds to CTLA-4 and blocks the interaction of CTLA-4 with its ligands, CD80/CD86. It has been demonstrated that CTLA-4 blockade augments T-cell activation and proliferation. The mechanism of action of ipilimumab’s effect in patients with melanoma is indirect, possibly through T-cell mediated antitumor immune responses. Phase 3 clinical trials clearly demonstrated that ipilimumab improved overall survival in previously treated patients with unresectable or metastatic melanoma. In fact, the data were so strong that in March 2011 the U.S. Food and Drug Administration (FDA) granted a broad label to ipilimumab for first-line use or as a therapy for relapsed melanoma.
In July 2011, the European Medicines Agency (EMA) granted BMS approval to market ipilimumab in Europe for treatment of melanoma patients in the relapsed setting. The launch of ipilimumab represents a significant breakthrough in treatment of late-stage melanoma where durable responses lasting years are achieved in as many as 20%-25% of patients. Although around 20% of melanoma patients achieve durable responses, there are no biomarker assays to predict which patients will respond. Ipilimumab’s efficacy comes with a price of toxicity in the form of immune-related adverse events that include skin and gastrointestinal toxicities. Common adverse reactions (any grade) observed in clinical trials included diarrhea (32%), pruritus (31%), rash (29%), fatigue (41%), and severe-to-fatal immune-mediated adverse reactions occurred in 15% of patients.1 While commercialization of ipilimumab is a breakthrough in the treatment of metastatic melanoma and provides proof-of-concept for targeting immune checkpoints to activate the immune system to provide therapeutic benefit for cancer patients, ipilimumab’s toxicity profile and the lack of a predictive biomarker to select patients mostly like to benefit from therapy leave room for improvement.
As discussed, a variety of signals regulate T-cell responses, and it is well established that some tumors are able to suppress immune response by co-opting distinct immune checkpoints. Upon activation, T-cells express the PD-1 (programmed death-1) immune checkpoint receptor on their surface. Binding of PD-1 to its ligand, either PD-ligand 1 (PD-L1) or PD-L2, inhibits immune response and leads to T-cell anergy and death. Typical function of the PD-1 inhibitory pathway is to down-regulate immune response when appropriate and thus prevent destruction of normal tissues. However, PD-L1 is frequently expressed on the surface of tumor cells, and suppression of the antitumor immune response occurs when PD-1 on activated T-cells encounters PD-L1 expressed on the tumor cell surface. Several reports suggest that up-regulation of PD-L1 in tumors correlates with suppressed T-cell activation and poor prognosis.2 This suggests that PD-1 may be a viable target for anticancer treatment; in fact, a number of antibodies directed against PD-1 or its ligands, designed to block the interaction of PD-1 with PD-L1, are now in early stages of development (Table 1).