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Topalian Discusses the Evolution of PD-1/PD-L1 Inhibitors in Cancer Care

Laura Panjwani
Published: Monday, Oct 24, 2016

Suzanne L.Topalian, MD

Suzanne L.Topalian, MD

The identification of the PD-1/PD-L1 pathway and the development of therapies targeting it transformed the field of immunotherapy and brought decades of work to the forefront, of cancer care, said Suzanne L. Topalian, MD.

“The development path for these drugs has been a long one, and has involved many investigators around the world,” said Topalian, director, Melanoma Program, professor of Surgery and Oncology, Johns Hopkins Medicine.

 “This development really brought immunotherapy into the mainstream. We’ve moved information from bench to bedside, developing new treatments based on this scientific knowledge, which has now proved to be effective in several different types of cancers.”

With anti­–PD-1 therapies rapidly gaining FDA approval across tumor types, the focus now needs to shift to identifying effective biomarkers to guide treatment decisions and determining which combination regimens will be the most effective with the least amount of toxicity, said Topalian.

“There is a lot on the horizon,” she said. “Clearly it will take a global team of researchers to address issues this broad and it will pull in people from all different areas of science and cancer biology.”

In an interview with OncLive, Topalian discussed key topics from her presentation, including the evolution of PD-1, emerging biomarkers, and why a precision medicine approach is necessary to identify effective immunotherapy combination regimens.

OncLive: Looking back, how has the role of PD-1 and other checkpoint molecules evolved to where we are today?

Topalian: For a long time—and depending on whom you talk to it could go back decades or a century or even further than that—we’ve known that the immune system can recognize cancer and can sometimes play a role in combating cancer. But it was only more recently through basic discovery in immunology laboratories that people realized there are several different mechanisms by which tumors can escape immune attack.

The overriding balance between the immune system and cancer is what we call tolerance, where the immune system tolerates the presence and growth of cancer cells, because cancer cells can masquerade as normal cells. All the signals that the immune system uses to detect cells that are not normal—for example cells that are infected with viruses—those mechanisms are turned off by various other mechanisms that cancers have for immune evasion.

PD-1 is a so-called immune checkpoint molecules that is expressed on activated immune cells, but when it interacts with its major ligand PD-L1, expressed on cancer cells, then the immune attack is turned off. Once this pathway was identified, which was a result of many years of research in a variety of different laboratories, then this became a very attractive target to move into the clinic for cancer immunotherapy.

The role of PD-L1 as a biomarker has been debated. How do you see it being utilized across the various tumor types?

The first evidence for PD-L1 as a potential biomarker was published from our group here at Johns Hopkins. Since then, many other groups and pharmaceutical companies have made their own versions of the PD-L1 immunohistochemistry test. This test has been used to look at tumor specimens from patients being treated on many different trials, such that many thousands of patients’ tumors have been tested for PD-L1 expression, and those results were correlated with the clinical outcomes  after treatment with anti­–PD-1 or anti–PD-L1 drugs.

The story that emerged was that for several different kinds of cancers, if the tumor expresses PD-L1, those patients are more likely to respond to anti­–PD-1 therapies, but it is not an absolute correlation. It is a greater likelihood of response, but it’s not a guarantee of response.

Then on the other side, there are a small number of patients whose tumors are PD-L1–negative on these tests, who can still respond to anti­–PD-1 therapy. So it’s not a perfect test, but it can be used to guide treatment decisions for patients who might be candidates to receive these drugs.

 The FDA has now approved 3 different commercial PD-L1 immunohistochemistry tests to be used in patients with melanoma, non­–small cell lung cancer, or bladder cancer, to help physicians and patients discuss what the appropriate treatment options might be.

Besides PD-L1, what other biomarkers are emerging for use with PD-1/PD-L1 agents?


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