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Innovative Immunotherapy for Lymphoma
Led by: David Maloney,MD, PhD, Oliver Press, MD, PhD, Stan Riddell, MD, Brian Till, MD and Cameron Turtle, MBBS, PhD, FRACP, FRCPA

Dr. Maloney
Dr. Press
Dr. Riddell
Dr. Till
Dr. Turtle

Immunotherapy is emerging as a new and effective method for cancer therapy. One of the most promising approaches is to engineer the patient's T cells (immune cells) to express a marker that instructs the T cell to seek out and eliminate cancer cells. Studies of small numbers of patients with advanced B cell lymphomas and leukemias have shown promising antitumor effects on T cells that are genetically modified to recognize a specific protein on tumor cells (such as CD19 or CD 20). 

In April 2016, Drs. David Maloney, Cameron Turtle and their colleagues at the Fred Hutch published the first set of results from a clinical trial testing their targeted T-cell therapy: 93 percent of participants with B-cell acute lymphocytic leukemia went into complete remission after their T cells were engineered to target CD19-bearing cancer cells — even though multiple other treatments had already failed them.

 Earlier this year, Dr. Stan Riddell shared preliminary data from a clinical trial at the American Association for the Advancement of Science’s annual meeting. He noted that 19 of 30 non-Hodgkin lymphoma patients experienced partial or complete responses to treatment. In some patients, pounds of cancer were eliminated after a single dose of the engineered T cells. As the CD19 trial continues, another CAR T-cell therapy trial is also helping patients. It involves a CAR the Riddell Lab has designed that targets a molecule called ROR1. This basket trial — so-called because it groups patients not by the organ in which their cancers originated but by the molecular target their cancers share — will enroll patients with ROR1-positive mantle cell lymphoma, chronic lymphocytic leukemia, and acute lymphoid leukemia as well as triple negative breast cancer and non-small cell lung cancer. 

These trials have helped carve a path that Drs. Press and Till and their colleagues can now build upon with their own clinical study. Dr. Oliver Press and his colleagues have just launched the first groundbreaking trial of CD20-specific CAR T-cell therapy for lymphoma patients. This is the first trial of this type of CAR T-cell therapy aimed at CD20. CAR T-cell therapies for lymphoma patients have so far targeted the CD19 molecule, and there are now dozens of such trials open worldwide. Dr. Till noted, however, that “this is the first time that anyone in our country has targeted CD20 using potent CAR T cells … Nobody has seen yet how well that will work.” Drs. Till and Press are hopeful their approach will work as well as, if not better than, the CD19 CAR T-cell therapy currently being tested at Fred Hutch. In the broader context of CAR T-cell therapy for lymphoma patients, they look forward to offering an alternative either for individuals whose lymphomas do not express CD19 or perhaps as part of a combination therapy that targets multiple markers to even more effectively overwhelm — and eliminate — a patient’s cancer.

Immunotherapy techniques hold great promise for those with B cell lymphomas and leukemias. Prior work in CAR T cell therapy has been successful, and it is crucial to demonstrate the safety and effectiveness of this treatment. This work hopes to establish the benefit of these therapies and establish a new, more effective treatment for patients.

Improving survival and reducing side effects in Hodgkin lymphoma

For many years, the standard chemotherapy regimen for Hodgkin lymphoma in the U.S. has been a four-drug combination called ABVD, which cures seven of every 10 patients with advanced (stage 3 or 4) disease. The more toxic chemo regimen, known as eBEACOPP, was developed in Germany in the 1990s. Results from studies in that country suggested that it might cure more patients than ABVD — but at a cost. Many patients who receive eBEACOPP become infertile, a huge blow to the young adults who make up the bulk of Hodgkin patients. Heart damage and even second cancers are other possible side effects of the eBEACOPP regimen. This places Hodgkin lymphoma in a special situation, requiring researchers to develop a response-adapted therapy that both improves cure rates and decreases toxicities by directing aggressive therapy to only those patients who need it.

As part of a collaboration in a national cooperative study, Fred Hutch researchers have identified a strategy with less toxic side effects by guiding treatment decisions with imaging. The study used a type of imaging, a PET scan, that visualizes a molecule with a radioactive label as it’s taken up by cells in the lymph nodes. Highly metabolically active tissues — like aggressively growing tumors — take up a large amount of the molecule and glow brightly on a scan and would indicate a more high-risk patient class. The aim would then be for these high-risk patients to be treated with eBEACOPP instead of ABVD to increase their chances of survival. For patients whose imaging suggested they had more low-risk tumors, they can be treated by the standard ABVD and spared the negative side effects of eBEACOPP.

Of the 319 participants who went through the trial, 79 percent saw progression-free survival of 2 years or more. Among patients in the higher-risk group, 64 percent saw two-year progression-free survival. This study has demonstrated that only about 20 percent of patients benefit from the toxic regimen.

This work is making important strides in the successful treatment and management of patients with Hodgkin lymphoma.  This work would not be possible without the cooperation of researchers around the country working together to find a less toxic and more effective treatment for this disease.

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