Checkpoint Inhibitors

At Fred Hutchinson Cancer Center, researchers have found a way to put your immune system back in control. Checkpoint inhibitor immunotherapy has led to impressive immune responses, even with cancers that were difficult to treat until now, such as lung cancer and melanoma (skin cancer). This science fuels Fred Hutch’s mission to provide our patients better, longer, richer lives.

With checkpoint inhibitors showing great promise for many different cancer types, Fred Hutch continues to study what makes this therapy work best and when it is the right option for each patient. Our immunotherapy leaders have years of experience turning research into real-world therapies. Other cancer care centers just administer these drugs — Fred Hutch’s science is the backbone behind them.

Dr. Shailender Bhatia

“Fred Hutchinson Cancer Center continues to be at the forefront of groundbreaking clinical trials for checkpoint inhibitors. That’s because our team has long held a strong belief that the immune system has the power to eradicate cancer cells completely.”

— Shailender Bhatia, MD, Medical Oncologist

What Are Checkpoint Inhibitors?

Your immune system has built-in checkpoints that help it find invaders to attack, like bacteria or tumors. Cancer cells can trick these checkpoints by sending false signals. This disguises the tumors so that they appear harmless, which puts the brakes on T cells — your immune system’s anti-infection troops — and keeps them from attacking tumors.

Antibodies are Y-shaped proteins that the immune system uses to identify and fight antigens (foreign objects like viruses and tumors). Immune checkpoint inhibitors are designed to release these brakes. They block cancer’s false signals, restarting the immune system’s engines so it can attack cancer.

How It Works

Checkpoint inhibitor therapy is moving at a skyrocketing pace. A growing number of clinical trials and commercially available drugs are bringing this therapy to more patients and more cancer types. They can also be combined with other treatments, like adoptive T-cell therapy, to work even better together.

“I feel incredibly lucky to have been treated at an organization committed to moving the needle in research. Because of clinical trials at Fred Hutch, we are getting to a point where they are yielding amazing results for patients like me.”
— David Dunnington, Melanoma patient

Antibody Therapies and Checkpoint Inhibitors

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 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 Fred Hutch 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.

What Kind of Cancers Can Be Treated with Antibody Therapy?

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.

Checkpoint Inhibitors Block Antibodies that Hide Cancer Cells from the Immune System

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. Fred Hutch was one of the first institutions in the world to research checkpoint inhibitor immunotherapy in patients. Dr. Shailender Bhatia and Dr. John Thompson were instrumental in the clinical trials of two checkpoint inhibitors, anti-PD-1 and anti-PD-L1, to treat melanoma. This research helped to develop two recent FDA-approved checkpoint inhibitor drugs — pembrolizumab (Keytruda®) and nivolumab (Opdivo®) — that are now used to treat melanoma, lung cancer, head and neck cancers and other cancers.

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 Fred Hutch Phase I clinical trials program.

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