Under the Microscope: Making the Most of a Breakthrough Cancer Therapy

David Gerber, MD, calls immunotherapy one of the greatest advances in cancer treatment in the last 50 to 100 years. But even the most important breakthroughs have downsides. Gerber has made it his mission to understand—and minimize—the risks associated with these revolutionary cancer treatments.

“Immunotherapy is a game changer,” says Gerber, who specializes in lung cancer research and treatment at Harold C. Simmons Comprehensive Cancer Center at The University of Texas Southwestern in Dallas. “But it doesn’t work in everyone and can cause toxicities. In fact, one of the risks of immunotherapy can be disappointment, because of all the attention directed at it.”

Today’s immunotherapies cause some form of toxicity in about 25 to 40 percent of patients. The most serious toxicities, called immune-related adverse events, occur when immunotherapy causes the patient’s own immune system to attack normal organs in the body. These toxicities can occur at any point in treatment. They can be severe and can cause side effects that result in permanent damage, affecting a person’s quality of life even after their cancer is cured.

To better understand these risks, Gerber and his team are conducting research aimed at understanding which patients are most likely to develop immunotherapy toxicities and when during treatment they are likely to occur. With funding from Bristol-Myers Squibb, the V Foundation supports a component of the work aimed at identifying early on who is most likely to develop toxicity and immune-related adverse events.

Illuminating the unknown

Immunotherapy generally falls into two categories. Checkpoint inhibitor therapy essentially takes the brakes off the immune system in a controlled way to enhance the patient’s immune system response to cancer. CAR-T immunotherapy modifies T-cells, the cells that attack infections, by adding a new component that allows the T-cells to recognize and attack certain cancers.

With chemotherapy, the side effects are known, and doctors know when to look for them and how to treat them if needed. With immunotherapy, doctors and patients don’t yet know who will develop toxic side effects, what they will be or when they will happen.

“The fact is, when you take the breaks off the immune system, it can attack the body,” says Gerber. “It can attack the skin, liver, thyroid, lungs, pituitary or adrenal glands, joints, muscles, and in rare cases, the brain or heart.”

To understand what drives these problems, Gerber and his multidisciplinary team of experts in cancer treatment, immunology and genetics are studying blood samples from 400 cancer patients undergoing immunotherapy—200 who developed toxicities and 200 who did not. The researchers are testing samples of patients’ immune cells taken before and after their first immunotherapy treatments. Looking at the levels of cytokines (proteins that play a role in cell signaling), the team has already identified patterns that could mean a predisposition to developing toxicity.

Empowering doctors and patients—with data

Immune-related adverse events are mostly treatable, but they can be tricky to diagnose. Gerber says accurate and timely diagnoses of toxicities can be hard, in part because there often are no straightforward blood tests or radiology studies to characterize them. “We also need to understand the timing of these effects,” he adds. “It could be after the first dose of immunotherapy or it could be toward the end of therapy.”

In their previous work, the research team identified blood-based tests that may predict the future development of immune-related adverse events based on the levels of certain cytokines in blood cells. Gerber hopes the current work will lead to genetic tests that identify an underlying predisposition to these types of reactions.

Ultimately, the work could help clinicians customize therapies based on an individual patient’s risk, potentially expand the safe use of immunotherapies, and prevent toxicities whenever possible. In this way, the researchers hope to allow more people to safely benefit from immunotherapy—and thrive for years to come. “We want to be able to predict which patients are likely to develop what problems and when, and then monitor and treat them better,” says Gerber. “These are critical questions, and although not all the pieces of the puzzle are in place, we think we’ve started to make headway.”