Five PD-1-Related Questions for Suzanne L. Topalian, MD

Suzanne L. Topalian, MD

Professor, Surgery and Oncology, John Hopkins University School of Medicine Director, Melanoma Program, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD

In her laboratory, Suzanne L. Topalian, MD, focuses on cancer immunology and immunotherapy. She also has led clinical development of monoclonal antibodies to treat patients with melanoma and other solid tumors, including those targeting the programmed death-1 (PD-1) T cell co-receptor.

1

What is the role of the PD-1 pathway in normal cells?

The PD-1 pathway has two major components: PD-1, an inhibitory receptor expressed on activated T cells, and its ligands PD-L1 and PD-L2. PD-L1 (also known as B7- H1) is expressed by many human cancers and by normal cells in an inflammatory environment, while PD-L2 (or B7-DC) is expressed selectively on dendritic cells. When PD-1 binds either of these ligands, it transmits a negative signal into the T cells that essentially turns them off. In the setting of inflammation or infection, the PD-1 pathway protects normal tissues from collateral damage during an immune response.

2

How is it implicated in the development of human cancer?

We believe that activated T cells that are poised to attack cancer cells express PD-1 on their surface. If they encounter a cancer cell expressing PD-L1, it creates a shield protecting the cancer cell from immune attack.

3

What PD-1 agents are currently available or under development?

The idea behind drugs that block the PD-1 pathway is to liberate T cells from the negative influence exerted by tumor cells expressing PD-L1 and allow the T cells to do their job in eliminating cancer. A variety of agents are currently in the clinic that block either PD-1 or PD-L1. Most of them are monoclonal antibodies; some are fully human, some humanized. One agent is a fusion protein. All have the effect of blocking the interaction between PD-1 and its ligands. There is a lot of interest in the pharmaceutical sector in these agents.

4

What has been the most significant advance in the field of PD-1 research in recent years?

To me, the most significant finding is the complementary activity of anti-PD-1 and anti-PD-L1 agents. We have been encouraged so far, from clinical testing, to see that blocking either PD-1 or PD-L1 seems able to halt the progression or mediate the regression of established treatment-refractory metastatic cancers. It appears that this pathway is very important in cancer biology and that interrupting it in a variety of different ways can promote tumor regression. This validates the PD-1 pathway as a target for cancer therapy.

5

What is the future of PD-1-targeted cancer therapy?

So far, PD-1 blocking agents have been tested only in certain kinds of cancers, and the full spectrum of activity of these agents is not yet known. One goal for the future will be to further define which cancers are susceptible to this kind of therapy.

Another very important goal is to develop biomarkers that would help us to select patients who are most likely to benefit from this therapy and least likely to develop side effects. We have reported some preliminary evidence for a molecular marker for clinical response to anti-PD-1 therapy: In a subset of patients from an anti- PD-1 trial, we found a highly significant correlation between pretreatment tumor expression of the ligand PD-L1 and clinical response of patients to PD-1 blockade. A lot more work obviously needs to be done to further assess this potential biomarker, but this is an example of the kind of research that I think will be front and center over the next couple of years.