MSK’s Vision to Transform Lymphoma Treatment

By Anas Younes,

Friday, June 16, 2017

Anas Younes, Chief of the Lymphoma Service at MSK
Summary

In 2015, MSK doctors and scientists created an ambitious research strategy organized around four major areas. Anas Younes, Chief of our Lymphoma Service, outlines how these complementary efforts can produce significant progress in lymphoma care.

Highlights
  • MSK experts identified unmet medical needs for people with lymphoma.
  • We prioritized four major research areas.
  • This strategy will continue MSK’s leadership in lymphoma.

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.

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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.

This all sounds ambitious, but we have extraordinarily talented researchers dedicated to improving the cure rate of people with lymphoma.
Anas Younes
Anas Younes Chief of the Lymphoma Service

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.

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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.

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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.

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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.

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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.

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Comments

I know that MSK has been one of the leaders in treating Hodgkin Lymphoma in the elderly. Do any of these research areas hold promise in treating this difficult age group?

Dear Mary, we sent your question to Dr. Younes, who replied, "Our group is one of the most active in the world for managing patients with Hodgkin lymphoma. Over the past year, we led trials resulting in FDA approval of two immune therapy drugs (Nivolumab and Pembrolizumab). We are actively combining these new drugs with other targeted agents, chemotherapy, and radiation. We also have an active survivorship program to council patients who are cured of their disease and monitor them for late toxicity." Thank you for your comment, and best wishes to you.

Are you as effective with Non Hodgkins Lymphoma, as you are with Hodgkins Lymphoma.
Robert Farrell

Dear Robert, our lymphoma team has extensive experience developing the latest protocols for non-Hodgkin as well as Hodgkin lymphoma. If you’re interested in making an appointment for a consultation, you can call 800-525-2225 or go to https://www.mskcc.org/experience/become-patient/appointment for more information on making an appointment. Thank you for your comment.

I need marginal cell lymphoma treatment. I am 86 years old.

How do radiation treatments play a role in treating Hodgkin's Lymphoma today? I have been a Hodgkin's Lymphoma survivor since 1982 and still doing well accept for a few problems that are due to my past radiation treatment. It would be great if they become unnecessary for future patients.

My husband battled with leukemia and lymphoma for 10 years before he passed away in 2009. Everyone at MSK did every thing humanly possible for him. I hope and pray God will continue to bless them with wisdom to find a cure for this terrible disease. Thank you all.

Dear Maria, we're very sorry for your loss, but glad to hear that your family had a good experience at MSK. Thank you for your comment, and best wishes to you.

Hi, does MSK have any current clinical trials for CLL which has transformed (Richter's) into a Classical Hodgkins Lymphoma? I've been told, since there has been a relapse with ABVD, the next step is RICE chemo followed by stem cell transplant.
Thank You,

Dear Mark, we recommend you contact our Patient Access Service to discuss scheduling a consultation with one of our blood cancer experts. They should be able to tell you what trials may be available to you. You can call 800-525-2225 or go to https://www.mskcc.org/experience/become-patient/appointment to learn more. Thank you for your comment, and best wishes to you.

I was treated for non Hodgkins lymphoma in 1995 at MSK. Although I went in remission, high dose of radiation put me at higher risk of breast cancer. I developed breast cancer in 2015 and am doing well thanks to the wonderful doctors once again at Sloan. It's great that research is making impressive strides in the way lymphoma is being treated. Keep up the great work

Dear Lynn, we're sorry to hear that you've been through so much, but are very glad to hear you're doing well. Thank you for your comment, and best wishes to you.

I was misdiagnosed at another institution before I came to Memorial Sloan Kettering for another opinion. They diagnosed me correctly with NHL. All were excellent and caring providers. I continue to travel to NYC for my care. God Bless you all! Thank you!

Dear Frances, we're glad to hear you've been happy with your care at MSK. Thank you for sharing your experiences. Best wishes to you.

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