Agarwala Discusses Role of Cytokines in Changing Immunotherapy Landscape

Sanjiv S. Agarwala, MD

Cytokine signaling proteins, such as interferon and interleukin, have long been utilized to manipulate the immune system for the treatment of cancer. However, as checkpoint inhibitors rise as novel immunotherapy agents, the role that cytokines will play going forward is becoming less clear.

To further understand how cytokines are used in today’s landscape and what their role will be in the future, OncLive interviewed Sanjiv S. Agarwala, MD, Section Chief of Hematology/Oncology, St. Luke's Cancer Center, and professor of Medicine, Temple University.

OncLive: With the increasing availability of novel immunotherapeutic agents, where do cytokines fit into the oncology armamentarium?

Dr Agarwala: Cytokines are proteins that work through cells in the immune system on other cells in the immune system, so they are a really good communicator between cells. We have had cytokines around for a while, and there have been a couple of drugs approved in that area. Obviously, with some of the new immunotherapies out there, cytokines are starting to take a little bit of a backseat. However, cytokines like interferon and interleukin 2 (IL-2) are still important. We still use them and they are still approved for indications in certain diseases like melanoma and kidney cancer.

What are the biggest differences between using cytokines and newer immunotherapies, such as checkpoint inhibitors?

I look at the immune system almost like a seesaw. On the one side, you are starting the immune system, and on the other side, there are breaks on the immune system pushing it the opposite way. Cytokines are a way to start the immune system while the newer therapies, the checkpoint inhibitors, take the breaks off. They take advantage of the fact that when the immune system is already started and these breaks are naturally coming on, checkpoint inhibitors can take the breaks away. That seems to have been a much more successful and powerful approach, at least clinically. However, this lends a logical conclusion to combine cytokines and checkpoint inhibitors.

Are there specific combination therapies with cytokines and checkpoint inhibitors that have the most potential?

There are studies in melanoma where pegylated interferon is being combined with pembrolizumab. Because these are just starting out, we will have to wait a while for the results. However, there is potential synergy with these two mechanisms of action.

I think it would also be interesting to do a triple combination, perhaps a cytokine such as pegylated interferon, an anti—PD-1 agent and an anti–CTLA-4. However, the disadvantage of putting things together is that you get more toxicity, but there is some science behind it.

What some of the advantages and disadvantages to using cytokines?

Cytokines actually have more toxicity, which force us to give it only in specialized centers, but it can be managed. However, if you get through that, you do have a 5% to 7% long-term durable remission rate. Those are often complete responses. Cytokines, such as IL-2, are still the only immunotherapies that produce complete responses. That is a very small number, but you don’t get a lot of complete responses with checkpoint inhibitors. You get a lot partial responses, stable disease, and long-term benefit; they have a lot of advantages, but you don’t get those complete responses in most cases.

Cytokines are also still very well established in adjuvant therapy. In melanoma, interferon is well established because we still don’t have data with checkpoint inhibitors that show a proven benefit and FDA approval for the adjuvant setting. If you were giving a patient adjuvant therapy, you would start with a cytokine; if they relapsed, you would give them an anti—PD-1 or anti–CTLA-4. We will have to wait and see if that continues to be the case.

Do you see cytokines ever becoming irrelevant in the treatment paradigm?

No matter how good the new immunotherapies are, we have to admit that most patients are still not cured. We have good results, long-term remissions, and benefits that can last several years, but we don’t have a 100% response rate. We don’t have even close to a 100% cure rate. We are always going to need other options. We need the cytokines around because if you do well on an anti—PD-1 inhibitor but then you progress, there might be a cytokine in your future.