Targeting the Tumor Microenvironment in Lymphoma

Stephen M. Ansell, MD, PhD

Ahead of the American Society of Hematology (ASH) Annual Meeting, held in Orlando, Florida, from December 5–8, we are speaking with Stephen Ansell, MD, PhD, professor of medicine who specializes in non-Hodgkin and Hodgkin lymphoma at the Mayo Clinic in Rochester, Minnesota, about targeting the tumor microenvironment in lymphoid malignancies. Dr. Ansell’s talk, “Re-educating the Tumor Microenvironment in the Clinic,” will be held on both December 5 and 6 at the meeting.

- Interviewed by Anna Azvolinsky 

Cancer Network: First, can we talk about what is meant by the tumor microenvironment in lymphoid cancers, such as Hodgkin lymphoma and non-Hodgkin lymphoma?

Dr. Ansell: Yes, thank you. The interesting thing is that when one does a biopsy of a patient who has either Hodgkin or non-Hodgkin lymphoma, within the tumor, not every cell that is present there is actually a cancer cell. There are many cancer, or malignant, cells present, but there are also a lot of other cells that are present. Remember, of course, that Hodgkin lymphoma and non-Hodgkin lymphoma typically occur in lymph nodes. Lymph nodes are very active areas of the immune system, so there are a substantial number of immune cells present within the tumor. These other cells, the non-cancer cells, are what we call the tumor microenvironment. What is very interesting is that over time, we have learned that the cancer cells actually recruit some of these cells to the area of the tumor and these cells may provide support for the growth of the cancer cells.

The tumor microenvironment is really important because many times it is actually promoting the cancer growth and if we can disrupt that tumor microenvironment, we could have a better outcome for patients. What is also important to know is that within Hodgkin lymphoma, it is even more unusual-the tumor microenvironment is almost 95% non-cancer cells and only a small percentage of the cells are Reed–Sternberg cells, or cancer cells. The tumor microenvironment is probably even more important and relevant in Hodgkin lymphoma than in non-Hodgkin lymphoma, although it is important in both.

Cancer Network: How is the tumor microenvironment related to a potential anti-immune response?

Dr. Ansell: Many of the cells present within the tumor and in this tumor microenvironment are immune cells, and many of them are lymphocytes, particularly T lymphocytes. Many of them are macrophages and other cells that are all part of the normal immune mechanism. What is interesting is to know whether those cells are actually targeting the cancer cells and are trying to eradicate them, or instead are just recruited there to provide some help. Remember, of course, that both Hodgkin and non-Hodgkin lymphoma cancer cells are part of the immune system. They are typically B lymphocytes, and they actually interact with the tumor microenvironment and particularly with the immune cells within the tumor microenvironment.

What is a really important strategy for treating patients is to turn this immune response on the cancer cells and actually get it to be more targeted, more directed, and more focused on the malignant cells specifically. And so the goal of many of these treatments is to take away things that are suppressing a good effective immune response and promote it in a way that it would actually target the cancer cells specifically. There have been a number of studies that have shown that even the immune cells that are trying to target the cancer cells are often very suppressed. If there are ways to remove the suppression and get the cells to be really switched on, as it were, that is really what we would like to achieve.

Cancer Network: What are some of the ways that these microenvironment cells are being targeted for potential treatments for these types of lymphomas?

Dr. Ansell: Interestingly, there are actually a variety of different ways. As I mentioned a minute ago, sometimes there is an immune response going on but that immune response is being significantly suppressed or switched off by mechanisms from the cancer cell to the immune cells to tell them to stop reacting and to slow down. There have been antibody treatments developed that block this negative signal and keep the [immune] cells in an activated state. There are treatments including anti–PD-1 [programmed death 1] treatments, agents such as nivolumab and pembrolizumab. There are treatments that target a different mechanism called CTLA-4 [cytotoxic T-lymphocyte–associated protein 4], such as ipilimumab. These treatments are being used to keep the immune system active.

A second way to do it is to take the immune system and directly stimulate it-not just take away a negative signal but actually provide a positive active signal. The active signal can include targeting a variety of other messaging systems, receptors that are on the immune cells to switch them on. These include treatments that target areas such as CD40 or CD27, and these are ways, as it were, to activate or kick-start the immune system.

Then there is a final way and that is to try to circumvent everything by artificially activating the immune system. There are chimeric antigen receptor T cells, known as CAR T cells, which are T cells that have been engineered to directly go off to the cancer cells. There are bi-specific, or BiTE, antibodies, proteins that pull the cancer and immune cells into very close proximity, which causes the immune system to get activated without needing to have either an activating signal or a suppressive signal removed. These are probably the three main ways to activate the immune system and to get the cancer cells targeted by the immune system.

Cancer Network: Thank you so much for joining us today, Dr. Ansell, and enjoy the meeting.

Dr. Ansell: Thank you.