Learning how to activate and harness the immune system—the body’s built-in defense against disease—has brought the field of oncology to the cusp of a cure for at least some, if not many, types of cancer, according to an international authority in immuno-oncology.
Perhaps no better example of immunotherapy’s potential exists than one of the first patients who received the investigational drug that became ipilimumab (Yervoy). After a diagnosis of metastatic melanoma in 2000, the patient did not respond to any available therapies and then received ipilimumab in 2001.
Four months after a single injection of ipilimumab, all visible tumor had disappeared. The patient remains alive and well today, 18 years after diagnosis. That compares with a median survival of 11 months for all patients who had newly diagnosed metastatic melanoma in 2000.
“A lot of challenges are left, but I sincerely believe that if we pay attention to elucidating the mechanisms and understanding how these things work, we can do this in many types of cancer, and that should be our goal: to do this in as many types of cancer and to benefit as many patients as we can,” said James P. Allison, PhD, Vivian L. Smith Distinguished Chair in Immunology, Department of Immunology, M.D. Anderson Cancer Center, Houston, TX, at a recent international conference of the American Association for Cancer Research.
Unlocking the Potential of Immunotherapy
The key that unlocked the potential of immunotherapy came in the form of discoveries about the activation and regulation of T-cells, which are at the very core of the human immune system’s disease-fighting capability. For years, medical researchers knew that T-cell activation—the “on” switch—fueled the immune system’s disease-fighting activity. T-cells were “turned on” by interaction between the 2 molecules known as B7 and CD28.
In many cases, however, T-cell activation was insufficient to overcome disease, which is a limitation of early efforts to develop immunotherapy for cancer. Finally, in the mid-1990s, scientists discovered a long-hypothesized “off switch” for T-cells, a molecule known as CTLA-4.
Turning Off CTLA-4
“We learned that if we turned off CTLA-4, mice died because of an uncontrolled immune response. The process really has nothing to do with cancer,” said Dr Allison. “We had the idea that you could deal with this problem by just disabling the brakes temporarily and letting T-cells keep dividing as long as they need to, to take the tumor out.”
He noted that this strategy is compelling: because the process has nothing to do with tumor cells, the tactic conceivably could work against any kind of cancer, and could be added to virtually any treatment that kills tumor cells, including chemotherapy, radiation, and targeted therapies.
In a series of laboratory studies, researchers confirmed that injecting a molecule that blocks CTLA-4 leads to tumor death in a wide variety of cancers. Even tumors with limited susceptibility to an immune response (ie, nonimmunogenic) succumb to the strategy when a vaccine or radiation therapy is added to the process. The research led directly to the development of ipilimumab, which blocks CTLA-4.
Studies of ipilimumab in patients with cancer led to a mix of excitement and questions. In a large randomized trial in melanoma that led to ipilimumab’s FDA approval, more than 20% of patients who received ipilimumab remained alive at 3 years. Recently, in an analysis of almost 2000 patients who received ipilimumab and were followed for at least 10 years, approximately 20% of patients were still alive, suggesting that responses to the drug are durable.
Adverse effects were common, but were mostly manageable, said Dr Allison. However, a few patients had severe, life-threatening effects related to the treatment. The patients and their conditions are being studied intensely to learn why the effects occurred, and how they may be prevented.
Arguably, the major question remains why more patients did not obtain long-term benefit from the treatment. The simple explanation involves mechanisms and timing: all the molecules had to be present and interact in a precise manner within a specific time frame. A more intriguing answer is that other checkpoints were involved, noted Dr Allison.
Multiple research groups began looking for other checkpoints that could be inhibited or otherwise manipulated to enhance the immune system’s anticancer activity. One of the first to show therapeutic potential was the receptor called PD-1, along with the binding protein PD-L1.
For several years, the function of PD-1 and PD-L1 remained unclear. Then several research groups found that tumor cells, after exposure to the immune-system protein gamma-interferon, produced PD-L1, which prevented T-cells from dividing and proliferating and possibly interfered with T-cell function.
In 2012, a report from an early-stage study of an anti–PD-1 drug showed good activity across a broad range of tumor types. The study provided early confirmation of researchers’ belief that immunotherapy’s anticancer activity is generalized, and is not limited to specific types of tumors. The study involved the first approved PD-1 inhibitor, nivolumab (Opdivo).
Subsequently, the FDA has approved 4 other drugs in the anti–PD-1 class, including pembrolizumab (Keytruda), atezolizumab (Tecentriq, the first agent that targets PD-L1 rather than the PD-1 receptor), avelumab (Bavencio), and durvalumab (Imfinzi).
Although multiple immunotherapies are available to treat cancer, research continues that focuses on issues related to the optimal use of the drugs, said Dr Allison.
Researchers are learning more about how the drugs work, their effects on the human immune system, the best conventional treatment to combine with anti–PD-1 agents, identifying and targeting new molecules to improve treatment effectiveness, and about the identification of biologic markers to determine which patients may benefit most from treatment and to monitor the progress of treatment.
Interest in combination immunotherapy continues to increase. One of the first clinical trials of combination immunotherapy involved patients with melanoma. In a landmark study, the combination of nivolumab and ipilimumab led to responses in 60% of patients with advanced melanoma, and the responses remained durable for 3 years.
“This is pretty remarkable,” said Dr Allison. “It would be predicted, from the experience with ipilimumab, that if patients make it to 3 years, they are likely to make it to 10 years. Obviously, we don’t know that yet, but I think the chances are pretty good.”
Clues have begun to emerge to some of the questions about immunotherapy, in particular, regarding why some patients and some types of tumors respond better than others. A key finding is that tumors with a high mutation burden (ie, many genetic abnormalities) respond very well to immunotherapy, such as melanoma, lung cancer, stomach cancer, esophageal cancer, and bladder cancer. However, some tumors respond well to immunotherapy despite having a low mutation burden, notably kidney cancer. Prostate, pancreatic, and brain cancers respond poorly to immunotherapy.
Another possible explanation for poor response is a lack of infiltration: T-cells do not penetrate the tumors, and they interfere with the checkpoints. This observation has led to the terms “hot” and “cold” to describe tumors that do and do not have good T-cell penetration. Reflecting the complexity of the processes, studies have shown that some cold tumors have effective immune-cell penetration after treatment, but the treatment appears to activate negative checkpoints.
Combination therapy with an anti–PD-1 or PD-L1 drug plus ipilimumab offers one possible solution to obstacles posed by cold tumors. However, research continues to identify new checkpoints, and drugs that target those checkpoints might also help optimize the use of immunotherapy.
Dr Allison and his colleagues have developed a process for evaluating multiple immunotherapy combinations. Not all of them will prove to be as important as CTLA-4 and PD-1, but they could add to the effectiveness of immunotherapies for cancer.
“We are on the verge of clinical trials involving a lot of combinations,” he said. “The goal from now on should be to work with combinations to move the tail of the survival curve up; not necessarily to increase the median survival, but to get the tail of the survival curve up as high as we can get it.”