Improving B-cell lymphoma treatment with immunotherapies and more
Clayton R. Boldt, Ph.D.
Lymphomas are the most common hematological malignancy in the U.S., accounting for an estimated 80,000 new cancer diagnoses and 21,000 deaths each year. These cancers, broadly classified as either Hodgkin lymphomas or non-Hodgkin lymphomas, develop in the lymphatic system. Approximately 85 percent of cases are B-cell lymphomas, meaning they arise in B lymphocytes.
MD Anderson’s B-Cell Lymphoma Moon Shot™ is working toward the goal of doubling the cure rate for patients with B-cell lymphomas within this decade. The effort is part of MD Anderson’sMoon Shots Program™, a collaborative effort to accelerate the development of scientific discoveries into clinical advances that save patients’ lives.
Why is there a need for a Moon Shot devoted to B-cell lymphomas?
Wang: We started the B-Cell Lymphoma Moon Shot to double the cure rate for our patients within five to 10 years — from about 30 to 60 percent. The Moon Shot is needed in order to make those significant advancements possible.
For many years, MD Anderson has been one of the largest referral centers for lymphomas in the world. We have championed many therapies currently in use for treating lymphomas, including the chemotherapies R-CHOP, R-ESHAP, R-MINE and R-HyperCVAD. Our department was instrumental in bringing forward rituximab, a monoclonal antibody, for the treatment of lymphomas.
However, if a patient is not cured by frontline therapies, they often develop resistant disease and ultimately die. The Moon Shot is working to bring forward the future of lymphoma treatments and improve the lives of our patients.
What do you see in the future for patients with B-cell lymphomas?
Wang: I really think that the 21st century is the century for biomedical science, and we are right in the heart of this era. Our generation has the best science and technology combined, more than any other generation in the history of mankind. We are really blessed with a lot, and we have a responsibility to take advantage of these opportunities as best we can to bring good results to our patients.
In terms of oncology, we have moved beyond just chemotherapies. We now have chemo-free targeted therapies and we are entering very quickly into the cell therapy and immunotherapy era. Coming in the future is the precision medicine or genomic medicine era, with treatments specific to each patient. We need to anticipate these changes, think about barriers ahead of us, and develop a good strategy to take advantage of what’s coming.
How has the B-Cell Lymphoma Moon Shot made it possible to work toward that future?
Wang: We’ve been fortunate to receive funding support from grants and industry partnerships, but these funds usually are for a particular project or a particular clinical trial. Many of our forward thinking, exciting ideas aren’t supported by those mechanisms. When we do solve the funding issue, we often collaborate nationally or internationally across long distances, making it challenging to move forward quickly.
Our institution has become a leader in some areas of lymphoma treatment, like mantle cell lymphoma (MCL) treatment and cell therapy, but we are less prolific in other correlational and translational therapies. The Moon Shot has enabled us to turn our weaknesses into strengths.
The Moon Shot has concentrated the best technologies of our time, provided funding support and valuable infrastructure in the platforms, and provided a scientifically robust environment to develop our innovative ideas quickly. The Moon Shots Program provides the best environment for working as an organized team. This is exactly what the Moon Shots Program was designed for.
While we continue to perfect treatments in each therapeutic category — chemotherapy, targeted therapies, cell-based therapies and immunotherapy — we need to be prepared for the precision medicine era. Our center has exceptional clinical care and clinical trials, but we also need to conduct laboratory research to bring forward new therapies and new trials.
Unfortunately, once we get new therapies approved, they won’t last forever. No therapies last forever. While we cure a fraction of patients, there will be another fraction of patients we can't cure. We need to know why these patients become resistant to treatments.
Now, with the support of the Moon Shot, we have the ability to do in-depth analysis of samples from these trials. We can analyze the sequencing, find new genetic lesions, study these in the lab, and come back with innovative solutions for treating these patients.
What successes have you seen so far?
Wang: I have been proud to lead this Moon Shot with Dr. Richard Champlin. The Moon Shot has propelled us to a new level. We’ve achieved clinical outcomes, pioneered scientific advances, and secured multiple grants. We’ve even seen passion from the community — people have been inspired by our work to contribute further to the Moon Shots Program.
In the past five years, our team’s work has led to approvals for several drugs, most recently the FDA approval of ibrutinib and acalabrutinib in MCL and CD19 CAR T cells in large cell lymphoma.
We led the FDA approval for acalabrutinib with correlative science. We have developed chemo-free therapy combinations. We have been able to unite several companies together through the Moon Shot with window-of-opportunity clinical trials and were able to determine that chemo-free targeted therapy was very effective and durable in patients with fewer side effects. As part of the Moon Shot, we have designed the Window study for MCL, which I lead, SMART studies led by Dr. Jason Westin for large cell lymphoma, and we have championed chemo-free combination therapies led by Drs. Loretta Nastoupil and Nathan Fowler for indolent lymphoma.
We’ve found that oxidative phosphorylation is mediating one of the major drug resistance mechanisms in MCL, and we want to counter that pathway to fight the resistance. We didn’t have a drug corresponding to the pathway, but through collaboration with the Institute for Applied Cancer Science and our Therapeutics Discovery platforms, we were able to use their oxidative phosphorylation inhibitor, IACS-10759. It’s now in clinical trials at MD Anderson for lymphomas. This would not be possible without the Moon Shot.
Dr. Sattva Neelapu, a leader in CAR T-cell therapy, not only led the pivotal trial for FDA approval but is also leading many resistance mechanism studies powered by continued Moon Shot support. And while CAR T-cell therapy is very effective, there is the price of high toxicity. Therefore, we’re working with the Adoptive Cell Therapy platform and Drs. Elizabeth Shpall and Katy Rezvani to use cord blood-derived natural killer (NK) cells to generate CAR-modified NK cells. So far, they don’t have the same toxic effects, and the efficacy is superb. The ACT platform is instrumental to our work.
Is there a project you’re particularly excited about at the moment?
Wang: I’m very excited about our MCL-MATCH project. This project will help us enter the precision medicine era and overcome the limitations of the current clinical trial system. In the past, clinical trials have compared one or two therapies in a large number of patients. However, now that we’ve made so much progress, one patient may have ten choices. How do we know which one to use?
We're helping solve that question with MCL-MATCH. Using in vitro tumor samples, we use bio-pathway data to marry the dysregulation of signaling pathways with massive in vitro screening to select the best three choices of therapy for any one patient. That way, the patient will be treated, in a combination manner, with the best therapies that exist.
MCL-MATCH is the first of its kind in the field of lymphoma. While we are initially focusing on MCL, we are quickly broadening to other lymphoma variants. If this trial is successful in the first phase, we will try this approach for patients with diffuse large B-cell lymphoma, follicular lymphoma, marginal zone lymphoma – every high-risk patient could take part in this trial if it’s initially proven to be safe and effective.
MCL-MATCH is an example of the new clinical trial design that integrates pathway information with efficacy in a personalized manner. This would not be possible without the Moon Shot’s support.