Antibodies selectively target a particular molecule, either on the tumor itself or another strategic location.
Unfortunately, few of the body’s 100 million naturally occurring antibodies are able to recognize cancer cells. To overcome this problem, researchers have developed ways of finding antibodies that have a specific receptor needed to work against different cancers. These are called “monoclonal antibodies” because they are of a single type that is grown in large quantities for cancer therapy.
Some antibodies target the cancer directly to kill tumor cells. This approach works best against blood cancers, where rituximab (Rituxan®) is probably the most widely used antibody therapy. Rituxan kills B-cell-derived cancers such as non-Hodgkin’s lymphoma or chronic lymphocytic leukemia.
Radioimmunotherapy is a technique developed at Seattle Cancer Care Alliance (SCCA) over the last 20 years to help blood cancer patients who don’t respond to chemotherapy or who, more recently, may have stopped getting benefit from Rituxan. In the 1990s, Oliver W. Press, MD, PhD, and Frederick R. Appelbaum, MD, among others, pioneered the idea of using antibodies as biological vehicles to target radiation directly to cancer cells and thereby limit the amount of radiation that goes to healthy organs. Their work led to the subsequent development of two FDA-approved radioimmunotherapy drugs, Zevalin and Bexxar.
John M. Pagel, MD, PhD, a leukemia specialist at SCCA, says that the impact of radioimmunotherapy has been profound. “Our approach using high-dose radioimmunotherapy combined with a stem cell transplant has cured many people who had little chance of long-term survival with standard approaches. Radioimmunotherapy reduces toxicities, and improves responses and outcomes. That’s why people have come here from all over the world—because they can’t get these treatments anywhere else."
While the use of radioimmunotherapy is presently confined to blood cancers, researchers have found that monoclonal antibodies selected to block key growth signals for cancer cells can be effective against solid tumors. Well-known monoclonal antibody drugs in this category include trastuzumab (Herceptin®), used to treat breast cancer, and bevacizumab (Avastin®), which is used to treat colorectal, lung, brain, kidney, and ovarian cancers.
More recently, monoclonal antibodies have been developed that manipulate anti-tumor T-cell responses by blocking negative regulatory proteins on T-cells. These monoclonal antibodies are called immune checkpoint inhibitors. In 2011, the FDA approved ipilimumab (Yervoy®) for use in late-stage melanoma patients. Commonly known as “ipi,” this drug blocks an “off signal” on T-lymphocytes. In other words, it allows the body to mount an enhanced anti-tumor immune response. Celestia Higano, MD, has led clinical trials with ipi to treat prostate cancer since the early 2000s. There are currently two international trials that have completed enrollment and will determine whether ipi is superior to placebo in metastatic, castration-resistant prostate cancer.
And in 2012, clinical trials of two related antibodies, anti-PD-1 and anti-PD-L1, produced results versus melanoma that are potentially even better than ipi’s. The responses that anti-PD-1 and anti-PD-L1 have produced in lung cancer patients represent a potential breakthrough: Non-small cell lung cancer had never before responded so positively to immunotherapy.
Finally, monoclonal antibodies can be modified to carry a toxic substance directly to targeted tumor cells. These are called antibody-drug conjugates (ADCs). The conjugates are the attached poisons, which can be a chemotherapy drug or cell toxin. In this manner, drugs that might be toxic to normal cells can be delivered only to tumor cells without the side effects that would be caused by the drug alone. Several experimental antibody-drug conjugates are currently under study in ongoing clinical trials that are part of the SCCA Phase I clinical trials program.
What to Expect
Antibody-based cancer therapies serve diverse roles in many different cancer types. Antibody treatments are typically well tolerated and administered on an outpatient basis. Complications, such as fevers, do occur. But most patients receive the treatment and go home the same day.
Another recent breakthrough is the growing knowledge about the linkage between different genetic mutations in a patient’s tumor tissue and the specific antibodies or other small molecule drugs that are most effective in treating them. A new test called UW-OncoPlex is increasingly used to single out the most effective treatment that may be available for each individual.