In the last three years, the treatment of lymphoma has progressed dramatically. The Food and Drug Administration has approved three new drugs — nivolumab (Opdivo®) and pembrolizumab (Keytruda®) for Hodgkin lymphoma and ibrutinib (Imbruvica™) for marginal cell lymphoma. Memorial Sloan Kettering has played an essential role in the clinical trials resulting in these approvals.
Here, I’ll explain MSK’s ambitious strategy to continue advancing the field by developing new therapies, combining existing therapies, and investigating other novel approaches.
Outlining a Strategy
In 2015, a large group of us went on a retreat in New Paltz, New York, about 90 miles north of Manhattan. We were there to plan a research strategy to improve the lymphoma cure rate. In addition to lymphoma doctors like me, the group also included scientists from the Sloan Kettering Institute and specialists in immunology, radiation therapy, stem cell transplantation, and hematopathology. We had an intensive, wide-ranging discussion about unmet medical needs, how to leverage MSK’s outstanding resources, and how to organize our priorities for making a difference in the lives of people with lymphoma.
Out of this discussion, we identified four major research areas to focus on.Back to top
Divide and Conquer: Genomics
Our program is among the best in the world at incorporating genomic analysis into our approach to treating people with lymphoma. MSK was one of the centers that helped design the Foundation One Heme panel. This diagnostic test identifies genetic alterations in blood cancers. It is now a standard part of care for these diseases. We’re also fingerprinting the tumor genome by performing DNA and RNA sequencing on tumor samples. This allows us to better understand the biology of the disease, to better classify different lymphoma types, and to identify new treatment opportunities.
Armed with information from these tests, we’re taking a divide-and-conquer approach, slicing large groups of lymphoma types into smaller subsets defined by genomic makeup. This helps us better select people for receiving specific treatments. In many cases, the best option for a patient is a clinical trial.
Genomic testing also provides valuable information about the biology of the disease, especially how resistance develops. Let’s say we select a group of people to receive a specific drug because it targets a certain mutation. If half of those people respond to the drug and half do not, we can compare the genomic makeup of the two groups. The findings can guide the design of the next generation of clinical trials.Back to top
Double Shot: Combination Strategies
We know a lot about the molecular pathways that control how lymphoma cells grow and survive. We’re using this information to identify combinations of small-molecule drugs that kill lymphoma cells more effectively than either drug would alone. Our strategy in this area is guided by two principles. First, even when a drug targets a specific pathway, the disease will develop resistance. We need additional drugs to block those secondary resistance pathways. We are designing new combination treatments based on our understanding of the causes of tumor cell resistance.
Second, there are so many potential cancer drugs available to test — somewhere around 600 or more — that it’s impossible to try every combination. Even if you had just ten drugs and wanted to test every two-drug combination in clinical trials, it would take 90 years. The key is to prioritize the most-effective and safest combinations. How do we prioritize? It’s more logical to test multiple drug combinations in the lab and in animal models to pick the combinations with the best chance of success in patients.Back to top
Rallying the Immune System
MSK has one of the most active programs investigating immunotherapy for the treatment of lymphoma. There are three approaches showing great promise: checkpoint inhibitor drugs, chimeric antigen receptor (CAR) T cell therapy, and bispecific antibodies.
Checkpoint inhibitor drugs, such as nivolumab and pembrolizumab, have demonstrated response rates as high as 70% in Hodgkin lymphoma. We’re trying to understand why Hodgkin lymphoma has such a high response rate so we can use that information for success with other cancers. We are also combining checkpoint inhibitors with other drugs to further improve their effectiveness.
CAR T cell therapy involves removing some of a patient’s immune T cells and genetically modifying them to find and kill lymphoma cells. We then grow the modified cells in a laboratory and return them to the patient. We are investigating this treatment for follicular lymphoma, diffuse large B cell lymphoma, mantle cell lymphoma, and other types.
Bispecific antibody treatment involves removing T cells from patients and coating them with antibodies that have two parts. One part guides T cells to the cancer cells. The other targets a surface protein that kills the cancer cells. The approach somewhat resembles CAR T cell therapy but in a more artificial way. The antibodies attract the patient’s own T cells to the site of the tumor to facilitate their killing effect.
We are also actively investigating combinations of immunotherapies with each other and with other treatments, such as chemotherapy or small-molecule drugs.Back to top
Preventing Relapse: Circulating Tumor DNA
When cancer cells die, some of the DNA they shed ends up in the blood. Detection methods have advanced to the point that we can isolate this circulating tumor DNA. We can then use it to study the genetic makeup of the cancer cells that may remain in the body. We hope that we can connect the presence or absence of circulating tumor DNA with a patient’s chance of cure. We think some cases of relapse are due to the persistence of cancer cells in the blood at very low levels, detectable only by very sensitive molecular test.
Traditionally, we did not subject patients in remission to additional treatment. If only a fraction of people relapse, we could not justify treating them all. But if the presence of circulating tumor DNA predicts relapse, we may want to preemptively treat those at risk to improve their chance for a cure. In coming years, I believe we will have clinical trials specifically designed to eradicate these last remaining cancer cells.Back to top
A Broad, Lasting Impact
This all sounds ambitious, but we have extraordinarily talented researchers dedicated to improving the cure rate of people with lymphoma. They are collaborating with fellow MSK researchers as well as with scientists and doctors at other institutions, pharmaceutical companies, and the National Cancer Institute. We also are reaching out to people with lymphoma and their caregivers and referring doctors to make them aware of our clinical trials. With so many promising treatments becoming available, our patients are the true pioneers in changing the landscape for this disease. Our mission is not just to treat patients at MSK, but to advance cancer care worldwide.Back to top