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Immunotherapy Comes of Age

Universal Monoclonal Antibody Primes Immune System to Fight Off Variety of Tumor Cells—shows potential to fight multiple mutations that may arise in prostate cancer.

April 18, 2012 -- The adage that a good stew needs time to simmer applies to many things outside the kitchen and it almost always applies to the scientific discovery process. One example of such scientific simmering was the trajectory from lab bench to the clinic of a type targeted immune therapy that is now used to treat several cancers—a class of drugs known as monoclonal antibodies.  There are several very successful monoclonal antibody drugs in use today—examples include Herceptin to treat breast cancer, and Rituxan to treat lymphoma—that work by engineering antibodies that bind to a specific target on a specific type of tumor. These drugs act as “marked-for-deletion” red flags, directing the body’s immune system directly to the tumor. Yet to get to the finish line of extending patients’ lives with monoclonal antibody (MA) drugs took upwards of twenty years as scientists tinkered with the drug recipe.

Now, a new generation of monoclonal antibodies is coming of age—borne out of 15 years of research—that are far more universal in nature than the MA drugs targeted to just one tumor type.  Jim Allison MD, a PCF-funded researcher at Memorial Sloan-Kettering in New York, did seminal work on the MA drug ipilimumab that has the potential to expand this therapy universally to cancer patients with different tumor types.

Ipilimumab was approved by the FDA in April of 2010 for the treatment of malignant melanoma but was designed for prostate cancer patients as well; Phase III clinical trials of ipilimumab are underway in patients with metastatic castration-resistant prostate cancer. The drug works by ramping up a patient’s immune system so it can attack tumor cells in a no-holds-barred fashion.

Normally our immune system functions with innate checks and balances: it furiously attacks anything it perceives as foreign, such as bacteria or viruses, but refrains from attacking cells and tissue it recognizes as “self.”  The hope with immune therapy to combat cancer is that drugs can be used to either teach our immune system to see cancer cells as foreign and/or to energize the immune response in general. Ipilimumab does this by removing a normal check on our immune system—a protein fragment called CTLA-4 that sits on the surface of certain immune T cells and acts as a brake on the immune response. Allison and colleagues developed a monoclonal antibody that targets CTLA-4, blocking its action.  This turned out to be like cutting the brake line on a car—it puts the body’s immune response into overdrive.

 “Our drug is no different from other monoclonal antibodies in the way it is made,” says Allison. “But our antibody’s target is on the T cell, not on the surface of a specific cancer cell.”

This fact has important implications in immune therapy.  The fact that the cancer cell has nothing to do with this drug therapy means it can be applied, in theory, to any tumor type, regardless of specific genetic mutation. In essence it has the potential to be a one-size-fits -all MA therapy that will most likely be used as an adjuvant to other therapies. For example, in the current Phase III trial of ipilimumab, a single dose of radiation was given prior to drug therapy.

Additionally, Allison sees the potential of a T-cell enhancing MA drug to help address the problem of the large number of mutations that can be present in any single tumor or distant metastatic sites. He notes that drugs that target testosterone in a prostate cancer tumor, in an effort to limit the hormone’s tumor-growth promoting effects, target only one thing—testosterone. “But [prostate cancer] tumor’s often have dozens, or hundreds, or even thousands of mutations and every one of these has the potential to be the target for a T-cell,” he says, referring to ipilimumab’ s ability to rev up T-cell actions in the body.

Currently Allison’s lab is working out what combinations of drugs might work best in prostate cancer or on what time schedule they might best be delivered. (Other T-cell inhibitors have recently been discovered.)

Dr. Allison’s work was the focus of a recent feature in the New Yorker that details the promise of immunotherapy to fight cancer and ends with this apt quote on the progress of immunotherapy: “The future is about thoughtful combinations, different antibodies, perhaps with targeted therapies. There won’t be a single silver bullet for everyone.” Jedd Wolchok, a colleague of Dr. Allison’s at Memorial Sloan-Kettering who also worked to develop ipilimumab.

The PCF funded early research on Dr. Allison’s work in ipilimumab as well as Provenge, another immunotherapy drug. He is a PCF 2008 Challenge Award recipient, 2006 PCF Competitive Awards Program recipient and has received PCF funding since 1999.

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