July 01, 2021
Complex, multifaceted therapy is the name of the game in non-Hodgkin's lymphoma treatment, according to research by Stephen M. Ansell, M.D., PhD., a hematologic oncologist at Mayo Clinic's campus in Rochester, Minnesota. This and other findings were published in February 2021 in the Journal of Clinical Oncology (JCO).
Dr. Ansell had hoped that immune checkpoint blockade might combat immune dysfunction in non-Hodgkin's lymphomas as effectively as in Hodgkin's lymphoma. However, that didn't prove to be the case.
Previously, Dr. Ansell and colleagues discovered in a clinical trial of nivolumab that immune checkpoint blockade is a safe and effective therapy for refractory Hodgkin's lymphoma. The New England Journal of Medicine published their results in 2015.
Dr. Ansell explains that for non-Hodgkin's lymphoma, it was curious to him and others studying tumor microenvironment (TME) that the T cells were not effectively targeting the cancer. What they have discovered is that continuous activation has worn out these cells, exhausting and suppressing them and hindering their readiness to attack tumors.
Therefore, with the exception of a few patient subsets, immune checkpoint blockade alone has proven ineffective as a single therapy for non-Hodgkin's lymphomas. From this study, Dr. Ansell determined the following:
- The immune system needs more support to activate and prevent suppression, targeting tumor cells rather than aiding the development of malignancy.
- A combination approach is necessary to mount a sufficient response to these lymphomas: immune checkpoint blockade plus chemotherapy, or other immune-active agents.
"I think we're coming to realize that one thing alone is not the answer for non-Hodgkin's lymphomas," says Dr. Ansell. "An integrated approach of bringing multiple components together and changing various facets of the immune system is really where we're trying to get to — to create a whole new reprogrammed tumor environment."
Specifically, according to the paper in JCO, an effective non-Hodgkin's lymphoma therapy needs to address these obstacles:
- Inadequate presentation of tumor-associated antigens
- Immunosuppressive cells in the TME
- Cancerous cells overexpressing immunosuppressive ligands
- Cytokine secretion leading to immune exhaustion or immune activation suppression
Background for the JCO findings
Dr. Ansell's lymphoma research program, which focuses on the TME and B cell cancer biology, has produced over 450 journal articles, including the 2021 paper in JCO. A fellowship at Mayo Clinic piqued his interest in this line of research, and during that period, he became interested in lymphoma — particularly lymphoma biology — while working in a B cell malignancy lab. His focus during the fellowship — and since then — has been the TME.
He explains that initially the lymphoma program's research focused on one or two immune checkpoint therapies, but now multiple possibilities have arisen with these therapies. An area of new research that he considers exciting is one that not only exploits the adaptive immune system — the T cell side — but also targets the malignant cells with the innate immune system, the macrophages and monocytes, or the so-called trash collectors of the immune system.
While investigators have made great strides in the last 10 years in treating B-cell lymphomas, progress with T-cell lymphoma has been more modest, according to Dr. Ansell.
Considerations for physicians on reaching a precise diagnosis
As there are numerous non-Hodgkin's lymphoma subtypes, experts may disagree about a precise diagnosis. Dr. Ansell indicates that an adequate biopsy is a crucial component in identifying the exact type of non-Hodgkin's lymphoma.
In addition, expertise in recognizing the various subtypes is critical to an accurate diagnosis, he says. He recommends a second opinion on pathology and also referring a patient to a medical center such as Mayo Clinic with broad experience in distinguishing non-Hodgkin's lymphomas.
Future perspectives on lymphoma research and treatment
Dr. Ansell is positive about the future of non-Hodgkin's lymphoma research and treatment.
"In lymphoma treatment and research, this is a remarkable time with an almost overwhelming amount of riches as regards available novel treatment approaches," says Dr. Ansell. "Twenty years ago, we focused entirely on the tumor cell. But now we understand we can change the environment in which these tumor cells are growing and get the immune system to engage with the tumor in a far greater way. I think the big advance we are likely to see in the future is taking multiple agents that are really promising and utilizing them in combination."
He says patient outcomes now far exceed what they were 10 years ago. "There's a wave of immunotherapies happening across cancer, in part driven by some of the work done here at Mayo Clinic," he says. "So what's really exciting now is to see the biology coming full circle to impact patients and seeing great clinical success, particularly for patients with lymphoma."
Dr. Ansell considers the treatment horizon for lymphoma very promising with novel treatments, novel combinations and the use of these agents in combination with standard treatments to profoundly change patient outcomes.
For more information
Ansell SM. Checkpoint blockade in lymphoma. Journal of Clinical Oncology. 2021;5:525.
Ansell SM, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma. The New England Journal of Medicine. 2015;372:311.