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

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?

There are many. This is ongoing work in our laboratory, as well as many cancer immunology laboratories around the world. There are a large family of immune checkpoint molecules that are related and yet have distinct functions. These other checkpoints are being looked at as potential biomarkers for response to anti­—PD-1 therapy. In addition, tumors may or may not be infiltrated by immune cells, and some researchers have proposed that tumors that do not contain immune cells are not likely to respond to anti-PD-1. There is evidence for this. There is also evidence that a certain type of T-cell or immune cell is needed to respond to anti­–PD-1 therapies. It is generally thought that CD8-positive killer T cells are the most important T cell in the PD-1 pathway response. These are just some ideas, there are many others. Looking at immunological markers is just the beginning of the story.

Another story that has emerged in the past year or 2 is the notion that tumors that contain higher mutational burdens might be more likely to respond to anti­—PD-1 therapy. The idea is that these mutations lead to the expression of abnormal proteins that have never been seen before by the immune system and so they can create a strong immune stimulant.

There is a subtype of colon cancer that is very highly mutated, and it turns out that this subtype, which represents about 10% to 15% of all colon cancers, is highly responsive to anti­—PD-1 therapy. The garden variety colon cancer, which only has a modest mutational burden, is not responsive to anti­–PD-1 therapies. This is an example where 2 different very active fields of cancer research—cancer genetics and cancer immunology—have a direct point of intersection.

It is very possible that the microsatellite instability test, which identifies a genetic abnormality associated with a higher mutational burden in the tumor, could become a biomarker to select patients with cancer for anti-PD-1 therapy.

Biomarker research has the potential to reveal many of these markers or molecules that could be targeted. It could provide markers of patients more likely to respond to immunotherapy monotherapy, or the markers themselves could become targets for new drugs or combination therapies. Really biomarkers are intimately associated with the developmment of combination therapies.

Are there particular combinations of anti­—PD-1/PD-L1 agents for which you see a lot of potential?

The first FDA-approved immunotherapy combination is the combination of drugs blocking 2 distinct immune checkpoints—anti­—PD-1 plus anti­–CTLA-4. That was approved in melanoma. The response rate in patients with advanced melanoma to the combination is higher than the response to either drug alone. The progression-free survival with the combination is substantial, and that was the basis for approving this combination in melanoma.

But a lot of work still needs to be done, because the combination has a high rate of serious side effects. Ongoing work is now looking at different doses of these drugs, either given at the same time or given in sequence, the hope being that maybe a dosing regimen can be found that would still have the therapeutic impact but with fewer serious side effects. I think research is well on its way in that area.

Do you see potential for combining chemotherapy with anti­—PD-1 therapies?

This is where the combinations really need to be thought about in terms of the different cancer types. For instance, in melanoma, chemotherapy is not really effective. The idea of combining anti­—PD-1 with a standard melanoma chemotherapy is not really appealing. But in melanoma, a very big story is the BRAF inhibitors. So combinations of anti­–PD-1 with BRAF and MEK inhibitors are looking very interesting.

In lung cancer, where platinum-based chemotherapy is a mainstay for treatment, that chemotherapy is being combined with anti­—PD-1 therapies. We are looking to see if those effects might be additive or even synergistic. We’ve developed a common-denominator approach by applying anti­–PD-1 as a single drug in various forms of cancer. Now, the next step is going to be considering individual tumor types and how other treatments that are known to be effective in different cancer types might be combined with anti­–PD-1 therapy.