Click to enlarge
The PD-1 receptors and its ligands are among the signals that play a role in the body’s complex immune system.
Adapted from Sharma P. Immune checkpoint strategies (Introduction). Presented at: 2012 ASCO Annual Meeting, Clinical Science Symposium; June 1-5, 2012; Chicago, IL.
Increasing evidence suggests that the ability to outsmart the body’s immune response represents a hallmark of tumor development. As such, researchers have begun to look at ways in which we might be able to reinstate the immune response with targeted agents, essentially indirectly treating cancer by treating the immune system. One particularly promising strategy for doing this is to target so-called immune checkpoints, which act as the off-switch on the T cells of the immune system.
A first-in-class immunotherapy, ipilimumab (Yervoy), a monoclonal antibody that targets cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) on the surface of T cells, was granted approval by the FDA in March 2011 for the treatment of melanoma. Now, a new targeted immunotherapy aimed at the programmed death-1 (PD-1) T-cell receptor is causing great excitement, and may prove to be more effective and even safer than ipilimumab.
The immune system has long been postulated to be important in protecting the body against cancer. The theory of immunosurveillance was proposed back in the 1950s, and it suggested that the immune system is able to detect cancerous cells and mount an immune response against them in order to kill them off.
Until 1995, researchers believed that the simple recognition of an antigen was enough to generate an immune response, noted immunotherapy pioneer James P. Allison, PhD, during a presentation at the 2012 American Society of Clinical Oncology (ASCO) annual meeting in June. “We didn’t realize how complex regulation of T-cell responses was,” he said.
That understanding began to change when scientists demonstrated that antigenpresenting cells provide costimulatory signals, which led to the identification of CTLA-4, said Allison. His theory that an antibody to CTLA-4 would “take the brakes off” the immune system resulted in ipilimumab.
Now, scientists have an increasingly complex view of how the immune system operates. It has become clear that cancer cells have, in turn, evolved mechanisms to evade an immune response. One way in which they do this is to hijack the immune system’s own fail-safe mechanisms, which are designed to suppress the immune response at the appropriate time in order to minimize collateral damage to healthy tissue.
These fail-safe mechanisms include immune checkpoints, which are inhibitory signaling pathways that switch off T cells at the correct time. Cancer cells are thought to co-opt these pathways to dampen down the immune response at inappropriate times and allow cancer cells to thrive.
Researchers are using this knowledge to fight back by developing cancer immunotherapies, which aim to treat cancer indirectly by inducing or enhancing cancer-specific immune responses. Since many of the immune checkpoints are regulated by interactions between specific receptor and ligand pairs, monoclonal antibodies can be used to block this interaction and prevent immunosuppression.
The two checkpoint receptors that have received the most attention in recent years are CTLA-4 and PD-1. Success with antibodies targeting CTLA-4 led to the approval of ipilimumab, the first targeted immunotherapy agent. PD-1-targeted agents are now hot on its heels.
Like CTLA-4, PD-1 and its ligands are members of the CD28-B7 family of co-signaling molecules that play important roles throughout all stages of T-cell function. The PD-1 receptor is expressed on the surface of activated T cells and, under normal circumstances, binds to its ligands (PD-L1 and PD-L2) that are expressed on the surface of antigen-presenting cells, such as dendritic cells or macrophages. This interaction sends a signal into the T cell and essentially switches it off. Cancer cells take advantage of this system by driving high levels of expression of PD-L1 on their surface. This allows them to gain control of the PD-1 pathway and switch off T cells expressing PD-1 that may enter the tumor microenvironment, thus suppressing the anticancer immune response.
PD-L1 expression was linked to poor clinical outcomes in a variety of different tumor types, reinforcing the idea that the PD-1 pathway was a key target for cancer manipulation of the immune response. This, in turn, makes it a key target for the development of immunotherapy to induce targeted antitumor responses.
In preclinical models, blockade of the PD-1 pathway using monoclonal antibodies directed against both PD-1 and the ligand PD-L1 drove cytotoxic activity and inhibited tumor growth. Thus, there has been a frenzy of activity among pharmaceutical companies to begin developing anti-PD-1 and anti-PD-L1 agents.
Currently, at least seven agents are in the clinic. Among them are monoclonal anti-PD-1 antibodies, both fully human and humanized, as well as a fully human anti-PD-L1 antibody and a fusion protein combining the extracellular domain of PD-L2 and IgG1 (See Page 3). Each of these agents is designed to block the interaction between PD-1 and its ligands, and thus keep the T-cell on/off switch in the “on” position, although they each have slightly different mechanisms of action.
The humanized anti-PD-1 antibody CT-011 from CureTech/Teva is in the most advanced stages of development, having completed phase II trials in patients with diffuse large B-cell lymphoma (DLBCL) following autologous stem cell transplantation.
Two agents from Bristol-Myers Squibb (BMS-936558 and BMS-936559), which developed ipilimumab, are producing impressive, durable responses in several phase I trials in patients with a variety of advanced cancers, including melanoma, renal cell carcinoma, and lung cancer, who had been heavily pretreated.
The results of these trials, reported at this year’s ASCO meeting in June and subsequently published in The New England Journal of Medicine, have generated a great deal of excitement for a number of reasons. Until now, the best response rates observed with immunotherapy have been little more than 10%, while response rates with BMS-936558 ranged from 18% to 28%. The responses observed in lung cancer patients were particularly noteworthy, given that this type of cancer was previously thought to be resistant to immunotherapy.
Furthermore, the two agents target two sides of the same interaction: the receptor (PD-1) and its ligand (PD-L1). In an interview with OncologyLive, Suzanne L. Topalian, MD, of John Hopkins University School of Medicine in Baltimore, Maryland, who was lead author on the study of BMS-936558 and a coauthor on the BMS-936559 study, commented on the fact that durable responses were observed with both agents. She said, “This indicates that the PD-1 pathway is an extremely important target for cancer therapy.” Topalian also emphasized that these trials are ongoing and that patients were able to receive up to two years of continuous therapy if they were showing tumor regression or disease stabilization. Therefore, we can expect subsequent follow-up reports as these patients complete their therapy.
A disadvantage of immunotherapy is that it can cause serious toxicities if the enhanced activity of the immune system begins to affect healthy tissue. However, it is hoped that PD-1-targeted therapies will be less toxic since they only target activated T cells where inflammation already exists. Although three patients developed fatal pneumonitis in the phase I trial of BMS-936558, Topalian said, “researchers are now able to better identify patients at higher risk for developing complications such as pneumonitis, to recognize pneumonitis earlier, and to take measures to manage it.”
Furthermore, Topalian stated, “I am optimistic that in the near future we will have established treatment algorithms that will make this toxicity more manageable.” She also highlighted that the deaths represented only 1% of the total study population, which included patients with advanced disease who had received numerous prior therapies. Therefore, it seems that the benefit-to-risk ratio of this agent is likely to be favorable.
Targeting the PD-1 pathway alone does not result in restoration of T-cell function and tumor regression in all patients. As with other targeted cancer agents, combination therapy will likely provide a route to greater success and even higher response rates with PD-1 agents. As such, researchers have already begun to consider logical combinations, and some combination therapies are already being tested in the clinic (See Page 3).
To this end, researchers have been searching for alternative regulators of the PD-1 pathway. In preclinical studies, combined targeting of PD-1 with the T-cell immunoglobulin mucin (Tim-3) protein, which is also expressed on the surface of tumor-infiltrating T cells, has proved highly effective in controlling tumor growth. Although targeting PD-1 will prevent T cells from being switched off, it doesn’t enhance T-cell activity; therefore, combinations with agents that do are also being evaluated. Preclinical testing of PD-1 agents in combination with an anti-CD137 agonist, for example, significantly enhanced tumor regression.
Other combinations that could prove fruitful include cancer vaccines, kinase inhibitors, or epigenetic therapy. Topalian further clarified the reasoning behind some of these potential combinations. “Cancer vaccines that don’t cause tumor regression by themselves could orient the immune system to better recognize the cancer, making the PD-1 agent even more effective and leading to tumor regression,” she said. “Kinase inhibitors, on the other hand, typically have a rapid mechanism for killing tumor cells, releasing tumor-associated proteins, which can then be taken up by antigen-presenting cells and be presented to the immune system. So, kinase inhibitors could create an autologous vaccine scenario.”