While most people living with follicular lymphoma—the most common subtype of slow-growing indolent non-Hodgkin’s lymphoma—respond to treatment, studies conclude that approximately 20 percent of patients relapse within two years of receiving first-line therapy. One area of research to understand this is the tumor microenvironment, which researchers have recognized as a significant driver of this blood cancer.
At the University of Texas MD Anderson Cancer Center in Houston, Dr. Loretta J. Nastoupil leads the Lymphoma Phase I Drug Development team, which is exploring the role of the tumor microenvironment in lymphoma. In this Q&A, she discusses how targeting the microenvironment may change how we treat follicular lymphoma and why treatment combinations may be helping to eliminate these tumor cells.
What is the tumor microenvironment?
“Recently, researchers have been paying increased attention to the tumor microenvironment—the cells, molecules and pathways that surround and support the growth of tumor cells.
When B-cells, a type of white blood cell, become cancerous in follicular lymphoma, they have migrated from the bone marrow, where they are produced, to the lymph node. The microenvironment within the lymph node is essential in maintaining this disease. Complex interactions between cells in the nodes keep the cancerous B-cells growing.”
Why is targeting the microenvironment in follicular lymphoma worth studying?
“We tend to consider follicular lymphoma as more of a chronic disease than a fatal one. Patients generally do well with treatment, but we can’t cure it. Current therapies can put most people in remission, when there are no signs of cancer, but it usually comes back. If we can understand the tumor biology better, we hope to develop treatments that lead to a more durable remission.
We know that the microenvironment plays a critical role in maintaining this disease, helping it to thrive and to resist treatment. Right now, characterizing the microenvironment is our best predictor of how well someone with follicular lymphoma is going to do. If we can figure out better ways to target whatever structures support the lymphoma, instead of helping to stop DNA replication like some current therapies do, we might progress how we treat patients with follicular lymphoma.”
Why can’t we just target the genetic drivers of follicular lymphoma?
“With solid tumors, immune cells infiltrate in small numbers. If you can target or block that mutation, you can stop or slow that tumor from growing. But in follicular lymphoma, it’s not the same.
About 90 percent of patients with follicular lymphoma have an abnormal rearrangement between parts of two chromosomes, called a translocation. But you can’t target that abnormality for treatment. Acquiring the translocation is just the first in a multi-step process that leads to follicular lymphoma. The other steps lead to more genetic alterations, which provide some survival advantage to that cancer cell, including masking them from the immune system’s search-and-destroy process.”
Do any current therapies target the microenvironment?
“People with follicular lymphoma are often treated with anti-CD20 antibodies that interact with effector cells of the immune microenvironment. Essentially, you’re putting a flag on the follicular cancer cells, which express the CD20 proteins on their surface, and hope the other key immune system players see those flags and eliminate the cancer cells. Significant developments in treatment over the last two decades have led to an improvement in the relative five-year survival rate for patients with follicular lymphoma, which increased from 70 percent in 1990 to 89 percent in 2010.
Therapies that target the microenvironment offer a promising approach that has the potential to improve outcomes in follicular lymphoma.”
How important is combination therapy in helping the immune system to eliminate follicular lymphoma cells?
“With follicular lymphoma, when you block one pathway, usually cancer cells find another way to escape the immune system.
Now, it’s critical to be more rational about the combinations we’re studying. We could do a better job selecting combinations if we understood the key players in the microenvironment and their roles in maintaining the lymphoma.”
We want 100 percent of patients with follicular lymphoma to be looking at an average life expectancy, and we want to achieve that with as little impact on their quality of life as possible.
How important is targeting the microenvironment to the future of treating patients with follicular lymphoma?
“With follicular lymphoma, many patients do well with the current standard of care treatment options. So why do we focus so much on the 20 percent that relapse early, within the first couple years? Why do we talk about it so much at our meetings and in our research? It’s because we want 100 percent of patients with follicular lymphoma to be looking at an average life expectancy, and we want to achieve that with as little impact on their quality of life as possible. Targeting the tumor microenvironment is the next step forward towards accomplishing this goal.”
To learn more about novel combination approaches for some patients with lymphoma, read “The Goal to Treat Lymphoma without Chemotherapy.”