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ASCO kicks off with promising immunotherapy studies

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Is it safe to say the age of immunotherapy in cancer treatment has arrived? If so, it's had a few sputtering starts and disappointments. The promise of training the body to recognize and kill cancer cells--without the damaging side effects of traditional cancer therapy--has intrigued us for years. But we now have a handful of immunotherapy drugs approved for cancer treatment, and many more on the horizon, it seems, from the studies released in anticipation of the annual meeting of the American Society of Clinical Oncology (ASCO).Information released today in preparation of the meeting highlights several studies, including two new immunotherapy approaches for a variety of cancers, including melanoma.Programmed Cell Death

The two studies zero in on the functions of a protein called PD-1 (programmed cell death 1), which lives on the surface of certain immune cells called T cells. In normal situations, T cells express PD-1 to down-regulate the immune system, preventing it from staging an over-the-top immune response to healthy cells. Ideally, T cells recognize and attack cancer cells. However, cancer cells can be sneaky. And some cancer cells express a protein on their surface called PD-L1 (PD-ligand 1), which binds to T cells' PD-1. Once they bind, the cancer cells become somewhat invisible to the immune system, evading recognition and death. Scientists have developed a new class of drugs that blocks this interaction. MPDL3280A

An experimental drug called MPDL3280A (if it moves forward, it will ultimately receive a new name) binds to PD-L1 on cancer cells, which prevents it from binding to the T cell. In the study, patients with metastatic or incurable cancers, including melanoma, lung, kidney, head and neck, colorectal and gastric cancers, were given the antibody drug intravenously every three weeks. Because it was a phase 1 study, the goal was to discover the highest, but safest dose. Because side effects were infrequent, a maximum tolerated dose was not found--which is a good thing. Moderate side effects seen during the trial included hyperglycemia, fatigue and increased liver enzymes. An interesting note is that PD-L1 doesn't occur in all cancers. Tumors that expressed PD-L1 responded more favorably to the drug, which may present an opportunity to use the protein as a biomarker for treatment. A third of patients who had PD-L1-positive tumors responded to MPDL3280A, as opposed to only 13 percent of patients with PD-L1-negative tumors. The duration of the response also appears favorable, with 26 of 29 responders still seeing benefit at their last appointment (which ranged from 3 to 15 months). The study has been expanded to include even more cancer types and hematologic (blood) cancers. Randomized phase 2 and 3 studies are planned to confirm the drug's activity and the diagnostic test for PD-L1. Additional studies include a phase 2 study in lung cancer and combining the drug with Zelboraf in a phase 2 melanoma study. Nivolumab

In the second immunotherapy study, the phase 1 trial combined the melanoma drug Yervoy with a PD-1 inhibitor, nivolumab. This drug blocks the protein found on the T cell, not the cancer cell. When combined with Yervoy, which helps with T cell activation in a different way, the result may create a synergistic effect. Patients in the trial had stage 3 or metastatic melanoma and had been treated with several different types of therapy.The study contained several study arms, which helps researchers determine the best and safest dose of both drugs. Of the three combination arms, which varied in dose, researchers found that patients treated with the highest doses responded best, with about half seeing tumor shrinkage. As with other newer therapies for melanoma, the response was rapid, with patients seeing a reduction in tumor size within the first three months of treatment. A third of patients saw at least 80 percent tumor shrinkage. The response also appeared durable, which has been an issue with other immunotherapies, but only time will tell if it sticks. Of the two arms that received nivolumab alone, patients entered the trial after progressing on Yervoy. Researchers said that although these patients did not respond well to Yervoy, some patients did see tumor shrinkage with nivolumab.Side effect are said to be manageable, but 53 percent of patients who received concurrent therapy reported moderate to severe (grade 3 or 4) side effects, mostly due to inflammation, a concern with immunotherapy. About 18 percent of patients who received each drug alone had a grade 3 or 4 side effect. A phase 3 combination study for newly diagnosed patients with advanced melanoma is now in the works and is scheduled to begin this summer. This isn't the first time we've heard of this class of drugs. At last year's ASCO meeting, study data from another PD-1 inhibitor called MDX-1106 (BMS-936558) showed it could shrink tumors in a variety of cancers, including melanoma, kidney and lung cancers. We'll be sure to hear more during this year's meeting about this trial and many others. Because these drugs are targeting certain aspects of the immune systems, researchers are very aware of the possibility of inflammation or other immune-related side effects, such as rash, pneumonitis and diarrhea. It will need to be confirmed in larger trials whether these drugs carry serious side effects, but they appear better tolerated than other immunotherapies that hone in on other targets in the immune system. The annual meeting, which will start May 31, is expected to host more than 30,000 oncologists, researchers, industry representatives and advocates from around the world. About 4,000 abstracts will be presented during the five-day meeting. Most abstracts are released to the public and can be found at asco.org.

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