In the past 2 years, cancer treatments known as immune therapies have become all the rage. However, they have actually been explored for decades, particularly in melanoma, and have produced some notable successes. Now, immune therapies are showing more and more promise for lung cancer.
A person’s immune system fights all kinds of ‘intruders’ in his or her body, from viruses that cause the common cold to cancer cells. Immune therapies improve the ability of the immune system to recognize cancer cells in the body and kill them. For a long time, it was thought that the immune system was unable to recognize and kill lung cancer cells. But new promising results show that some people with lung cancer may actually benefit from therapies that boost their immune system.
The road to immune therapies for lung cancer has been a bumpy one. A lot of effort has gone into testing various ‘cancer vaccines,’ which work a lot like familiar vaccines, such as the flu vaccine. In this approach, patients with lung cancer are injected with some of the proteins that are found on cancer cells, with the hope of triggering the immune system to recognize and attack cancer cells. However, in spite of many clinical trials testing them in patients, lung cancer vaccines have generally not been successful. Just recently, one of the most advanced vaccination protocols for lung cancer, MAGE-A3, fell short of success against melanoma in a pivotal phase III clinical trial. The results of a phase II trial in non-small cell lung cancer (NSCLC) were not impressive, but a phase III trial in NSCLC is still ongoing. Another one, belagenpumatucel-L (Lucanix), failed to meet the endpoints of a clinical trial. But hope remains for Lucanix because NSCLC patients in the trial who started vaccination earlier after completing radiation or chemotherapy treatment showed an increase in overall survival.
Researchers have also been looking for ways to stimulate T cells, the ‘killer’ cells of the immune system, to attack cancers. In a healthy immune system, T cells only attack abnormal cells or viruses. But the immune system can become a dangerous weapon if its controls go awry and it turns on normal cells, provoking a host of ‘autoimmune diseases.’ Therefore, immune cells are outfitted with control molecules that serve as brakes to prevent attacks on ‘self.’ Some of these brakes may prevent T cells from attacking tumors. A number of brakes have been identified, and now drugs have been developed that successfully target them, forcing them to release their hold on T cells.
One brake molecule, CTLA4, is targeted by the drugs ipilimumab and tremelimumab. Another, PD-1, is deactivated by the investigational (still being tested) drugs nivolumab (BMS-936558) from Bristol-Myers Squibb and MK-3475 from Merck. These drugs, known as ‘immune checkpoint antibodies,’ are capable of unleashing the killing power of T cells that is directed toward tumor cells. They have shown significant success in melanoma, and are now showing promise for lung cancer (see below).
To add to the complexity of immune regulation in cancer, tumors can evolve to escape immune responses by making proteins that prevent recognition by T cells. PD-L1 is the best known of these protective proteins. When PD-L1 is present on tumor cells, it binds to the brake molecule PD-1 on T cells, and thus protects the tumor cells from T cell attack. Therefore, drugs have been developed that target PD-L1. These drugs, MPDL3280A from Genentech and MEDI4736 from MedImmune, are in clinical testing for several cancer types, including lung cancer (see below).
The remarkable point about immune therapies is that, so far, they appear to provide long-lasting results, especially considering the relative novelty of immune checkpoint antibodies. This is a winning feature of immune therapy compared to chemotherapy and targeted therapies, which are often associated with short-lived responses and the return of tumors.
Immune checkpoint antibodies are already known to induce side effects, some of them not too serious, such as rash, fatigue, and diarrhea, and some more serious, such as pneumonitis. However, these can be controlled and, so far, the observed effectiveness of these drugs far outweighs the potential risks. It remains to be seen if more promising results of clinical trials will result in faster U.S. Food and Drug Administration (FDA) approval of the immune checkpoint antibodies; we hope that trials exploring combinations of these drugs will produce even more encouraging results in lung cancer patients.
Clinical trials testing anti-CTLA4 and anti-PD-L1 treatments for lung cancer
In an ongoing clinical trial, nivolumab caused long-lasting tumor shrinkage in 24% of patients with NSCLC. Some patients in the trial continue to respond well, even after stopping treatment for various reasons. Other ongoing trials for nivolumab in lung cancer include the phase I trial NCT01454102 for NSCLC, which is testing nivolumab in combination with several other drugs including ipilimumab (nivolumab + ipilimumab is a winning combination in melanoma treatment). The phase II trial NCT01928576 will examine whether pretreatment with a certain class of drugs will improve responses to nivolumab. Patients with small cell lung cancer (SCLC) can enroll in the phase I/II trial NCT01928394, which also tests the nivolumab/ipilimumab combination. Phase I trial NCT01714739 combines nivolumab with another drug that targets the KIR protein, which is found on immune system cells called natural killer cells. This might stimulate natural killer cells to attack cancer cells.
Preliminary results from an ongoing study testing MPDL3280A, which targets PD-L1, were reported recently: tumors shrank or disappeared in 26% of smokers in the trial, compared to only 10% of patients who never smoked (NCT01846416). MPDL3280A is currently being tested in two additional clinical trials for NSCLC: the phase II trial NCT01903993, which compares MPDL3280A treatment to the chemotherapy docetaxel in patients who failed to respond to platinum-based therapy; and NCT01375842, a phase I trial that is enrolling patients with several different cancer types including lung cancer. The phase I trial NCT01633970 is currently evaluating a combination of MDLP3280A with bevacizumab and chemotherapy in patients with advanced cancers. The relatively new anti-PD-L1 drug MEDI4736 recently entered early clinical testing in the phase I trial NCT01693562.
Results from a clinical trial testing MK-3475 have also been impressive. Thirty-eight patients with squamous and nonsquamous NSCLC who had received two prior chemotherapy treatments were treated with MK-3475 in a phase I trial. Twenty-four percent of patients experienced tumor shrinkage. The presence of PD-L1 on tumor cells was found to correlate with a positive response to treatment. MK-3475 is currently in three recruiting trials for NSCLC: the phase I-II trial NCT01840579A, the phase II/III study NCT01905657 (which will enroll 920 patients whose tumors express PD-L1 and whose cancers progressed after platinum-based therapy), and the phase I trial NCT01295827 for patients with NSCLC and melanoma.
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