Immunotherapy—An Increasingly Important Role in Oncology

Current Immunotherapy Options

The use of cancer immunotherapies has evolved. The latest immunotherapies are not only effective, but also accessible enough to be administered not just by expert immunologists, but by general oncologists. Immune-checkpoint modulators known as anti-programmed cell death-1 (PD-1) and anti-programmed cell death ligand-1 (anti-PD-L1) antibodies are still in late-stage clinical trials, but may be approved in the US for at least a few tumor types within the next several years. Other immunotherapy approaches, including extracting and culturing the patient’s own immune cells (called adoptive cell therapy), as well as combination therapy with other immunotherapies or targeted therapies, are also being developed and explored.A decade ago, only a small fraction of patients were eligible for the few immunotherapy options available at that time. An even smaller fraction of those eligible patients responded to treatment, but many of those who did had durable, long-term responses. Among the only Food and Drug Administration (FDA) approved immunotherapy options available to cancer patients was interleukin-2 (IL-2) and interferon-alpha. Interleukin-2 has been approved for renal cell carcinoma since 1992 and for melanoma since 1998. This cytokine must be administered in a hospital setting because of potentially dangerous side effects. Moreover, only otherwise healthy patients are eligible and only a small fraction—about 3% to 5%—of patients respond. These types of immunotherapies are nonspecific and work by generally stimulating the immune system.

New Immune-Checkpoint Inhibitors

Hallmark of Cancer: Avoidance of the Immune System

Several novel immunotherapy approaches have been developed over the last 15 years. Among these is another type of nonspecific immune stimulation: inhibition of pathways that block immune system activity, known as ‘putting a break on the break.’ The first antibody that works by this mechanism, ipilimumab, an anti-CTLA-4 antibody, was first approved in 2011 for treatment of metastatic melanoma. Approximately 10% to 15% of patients respond and can have long-term regression or stability of their disease. Ipilimumab can cause high-grade autoimmune side effects that require careful monitoring. Still, approval of this antibody demonstrated that immune therapy can be safely administered, and patients can be managed in an outpatient setting.The next set of immune-checkpoint blockade antibodies, called anti-PD1 and anti-PD-L1 antibodies, work on a T-cell modulation pathway distinct from the one that involves CTLA-4. Many tumors express PD-L1, a ligand for PD-1. PD-1 is expressed on antigen-presenting immune cells. The interaction of the two molecules results in inhibitory signaling that dampens the immune response.In vitroexperiments have shown that this interaction leads to programmed cell death of T-cells specific to tumors. Patients treated with antibodies against either PD-1 or PD-L1 have thus far demonstrated relatively high response rates on the order of 25% to 30% in metastatic melanoma and renal cell cancer and in non-small cell lung cancer, a tumor type that has not previously responded well to immunotherapies.^1-3Among the most advanced antibodies in this class are an anti-PD-1 agent, nivolumab from Bristol Myers Squibb, MK-3475 from Merck, and the anti-PD-L1 antibody MPDL3280A from Roche. These antibodies have so far resulted in not only high response rates, but also long-term durable responses of several years in the longest treated patients. The toxicity profile of these antibodies is unlike that of any other immune therapy—side effects are manageable and generally mild, allowing for safe administration by not only expert immunologists, but also by general, practicing oncologists. Early phase clinical trials are now testing the activity of these antibodies in other tumor types such as breast and ovarian cancers.Researchers continue to make progress in their understanding of the important role of the immune system in fighting cancer and the ways by which tumors can avoid being seen by immune cells or block the effects of these immune cells. When Douglas Hanahan and Robert Weinberg published their now seminal “Hallmarks of Cancer” review in the journal Cell in 2000, the six hallmarks did not include the tumor-immune system interaction. Eleven years later, an accumulating body of literature showed two additional hallmarks of most, if not all, cancers: the ability to deregulate cellular metabolism and the ability to evade the immune system.⁴

While it is thought that the immune system continuously monitors, finds, and destroys emerging cancer cells before the formation of most tumors, the tumors that do emerge have a way to bypass this system of detection. Evidence for this comes from both clinical studies as well as from preclinical animal models. For example, mouse models lacking specific components of the immune system are more prone to cancer when exposed to cancer-causing substances compared with mice with an intact immune system. The immune system components identified to be particularly important for curbing tumor initiation are part of both the innate and adaptive branches of the immune system—cytotoxic T lymphocytes (CTLs), helper T-cells, and natural killer cells.

Evidence from the clinic bolsters results from these mouse model studies. Researchers are studying different tumor types to understand whether or not certain tumors are more likely to have higher levels of natural killer cells and CTLs, a phenomenon associated with a better prognosis.

Daniel S. Chen, MD, PhD

The Cancer Immunity Cycle

Studies have elucidated the signaling pathways used to modulate immune responses that result in activation or deactivation of T-cell responses. This has led to the identification of the previously mentioned checkpoint signaling molecules such as CTLA-4 and PD-1.Daniel S. Chen, MD, PhD, of Stanford University Medical School and Ira Mellman, of the University of California, San Francisco School of Medicine describe the latest research on anticancer immunity, in their July 2013 review, ‘Cancer-Immunity Cycle.’ First, dendritic cells need to recognize tumor antigens as foreign. The abundance of tumor-specific antigens vary based on the tumor and the patient and are usually released as a result of tumor cell death. These captured antigens must then be presented to T-cells which prime T-cell effector responses against these cancer-specific antigens. These activated T-cells must then travel to the tumor site and infiltrate the tumor, specifically recognizing and binding the cancer cells that express the cancer antigen, leading to cancer cell death. The killed cancer cells then release other antigens, thus restimulating the cycle.

References

Current and future directions in immune-based cancer therapy include understanding which patients are more likely to respond to treatment as well as identifying biomarkers that can indicate whether or not a patient is responding to therapy. “Multiple approaches to cancer therapy exist, and few are as complicated as immune-based therapy,” state Chen and Mellman. Novel immune therapy approaches are also in development, both in the preclinical phases as well as in early-stage clinical trials. What the anti-PD-1 and anti-PD-L1 antibodies have demonstrated is that relatively safe immunotherapies can be used to treat a relatively large cancer patient population that have not previously responded to immune system stimulation. Further understanding the biology of how the immune system attacks tumors and ways by which tumors can evade the immune system may lead to tailored immune therapies and the establishment of a new era of cancer immunotherapy.

1. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer.NEJM. 2012;366:2443-2454.
2. Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma.NEJM. 2013;Jul 11;369(2):122-133.
3. Hamid O, Robert C, Daud A, et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma.NEJM. 2013;Jul 11;369(2):134-144.
4. Hanahan D, Weinberg RA, Hallmarks of Cancer: The Next Generation.Cell. 2011; 144: 646-674.