Areas of Research
- Lymphoma Research
- Targeted Therapy Research
The Wang Laboratory research program aims to elucidate the mechanisms underlying therapeutic resistance in B-cell lymphoma and to translate these findings to the clinic to improve patient outcomes. The research group has utilized genomics and molecular analysis, patient-derived xenograft (PDX) mouse models and state-of-the-art molecular tools to understand the cellular mechanisms responsible for therapeutic resistance and disease progression in mantle cell lymphoma (MCL), with rapid expansion into diffuse large B-cell lymphoma (DLBCL).
About our lymphoma research
The EXPLORE Trial
This trial is the world’s first personalized clinical trial for mantle cell lymphoma (MCL) using patient-derived xenograft (PDX) mouse models. This study is designed for patients who have achieved remission from frontline therapy but are facing relapse. The beauty of using PDX models in the clinic is that numerous agents and drug combinations can be tested to determine the most beneficial therapy for each individual patient. Moreover, we can identify and administer effective personalized therapies in real-time to halt disease progression in patients, making this a truly adaptive form of treatment.
The MATCH Trial
We are also pursuing personalized therapy for MCL by conducting an MCL-MATCH trial. This clinical trial analyzes patients’ own tumor samples to identify gene abnormalities that can be targeted with existing drugs and agents. This approach encompasses the basic tenet of precision medicine: treatment based on a patient’s own genetic mutations that drive cancer progression and growth.
The founding and current director of our laboratory is Michael Wang, M.D. Since founding the lab, he has mentored three assistant professors, two instructors, three post-doctoral fellows, four graduate research assistants, and ten visiting students. The lab is under the additional leadership of Assistant Professors Liang Zhang, M.D., Ph.D. and Vivian Jiang, Ph.D.; and Scientific Manager Krystle Nomie, Ph.D.
Meet the Wang Lab
The Wang Lab is comprised of assistant professors, postdoctoral fellows, graduate researchers and research assistants.
Mantle cell lymphoma (MCL) accounts for 7% of all non-Hodgkin lymphoma cases and is a rare and incurable subtype of B-cell lymphoma. The majority of B-cell lymphoma patients (70%) cannot be cured by current treatment strategies. Patients may initially respond to treatment, but the lymphoma then returns, eventually leading to death for the majority of patients. Unfortunately, 90% of MCL patients have not been cured. Although modern, successful therapies have been developed, they are often applied to common lymphomas such as large-cell lymphoma and follicular lymphoma. Applications in MCL often fall behind because MCL is rare, and there is less public demand for MCL research.
Ibrutinib, a first-in-class Bruton’s tyrosine kinase (BTK), was recently approved by the FDA based on the treatment’s unprecedented single-agent activity in relapsed/refractory MCL. However, despite dramatic responses to ibrutinib, patients inevitably develop resistance to it, generally within one to two years. The vast majority of MCL patients who experience disease progression after ibrutinib treatment die within 12 months. This demonstrates that standard-of-care approaches are failing, and overcoming ibrutinib resistance remains an urgent unmet clinical need. Additionally, diversity in genetic alterations and pathways contributing to disease progression and resistance makes it impossible to overcome this disease with uniform treatment regimens.
Our lab aims to develop personalized therapies to overcome drug resistance and ultimately cure MCL.
In the News
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
lymphomas, develop in the lymphatic system. Approximately 85
percent of cases are B-cell lymphomas, meaning they arise in B
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’s Moon Shots Program™, a collaborative effort to accelerate the development of scientific discoveries into clinical advances that save patients’ lives.
Michael Wang, M.D., professor of Lymphoma and Myeloma and a co-leader of the Moon Shot™, spoke with Cancer Frontline about the team’s efforts to more quickly bring innovative new treatment options forward for patients.
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.
Mantle cell lymphoma (MCL) is a rare disease that is seldom encountered by the average community oncologist and infrequently studied independently of other B cell lymphomas. Especially lacking have been studies of treatment for newly diagnosed MCL patients, many of whom develop resistance to or cannot tolerate cytotoxic first-line treatments. The University of Texas MD Anderson Cancer Center, however, is now evaluating a noncytotoxic combination of targeted and immunotherapy agents for first-line treatment of MCL in clinical trials.
As a tertiary care center, MD Anderson sees more patients with MCL than does any other hospital in the country, and researchers saw this as an opportunity. “We have attracted a critical mass of patients with MCL, and this enabled us to design clinical trials that are purely for MCL; so we are now regarded as the authority in this disease,” said Michael Wang, M.D., a professor in the Department of Lymphoma and Myeloma and the co-leader of MD Anderson’s B Cell Lymphoma Moon Shot Program.
Most MCL trials test novel interventions in patients with relapsed disease, but two ongoing trials from MD Anderson are focusing on previously untreated patients. “For MCL, the first therapy is the most important,” Dr. Wang said. “If you do well with the first-line therapy, you can eliminate almost all of the MCL cells. They won’t have the opportunity to develop resistance, and the remission can last longer.”
Standard first-line therapy
Standard first-line treatments for MCL include high-dose chemotherapy regimens such as hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD) with or without stem cell transplant. Such intensive therapies given up front lead to low rates of recurrence and to overall survival times of several years.
However, these intensive regimens can be too toxic for many patients, especially older patients. Thus, the standard first-line therapy for elderly MCL patients is bendamustine plus rituximab. This combination is less toxic than intensive therapies, but the response rate is lower and the responses less durable than those from more intensive regimens.
Even young patients, who often can tolerate intensive therapies, experience acute or long-term adverse effects from cytotoxic therapies. “For every 10 patients we treat with standard intensive therapy, we lose one patient to toxicity. That is not acceptable,” Dr. Wang said.
Also, remissions in MCL patients are not always durable. One reason for this may be that the cytotoxic drugs given intravenously as standard first-line therapy sometimes cannot eliminate the many MCL cells that reside in the bone marrow and lymphatic tissues.
Ibrutinib plus rituximab
The surviving MCL cells could potentially be eliminated by exploiting a phenomenon called compartmental shift, in which a drug induces a transient migration of cancer cells to the peripheral blood from other parts of the body, such as the bone marrow or lymph nodes. Once in the peripheral blood, the cancer cells are more vulnerable to intravenous anticancer drugs.
The oral targeted agent ibrutinib, which inhibits B cell receptor signaling by targeting Bruton tyrosine kinase, has been observed to induce compartmental shift in MCL. Furthermore, Dr. Wang and his colleagues have shown that combining ibrutinib with intravenous rituximab, which destroys B cells by binding to CD20 on the cells’ surface, improves the activity of both drugs in patients with relapsed or refractory MCL. On the basis of these findings, Dr. Wang’s group hypothesized that the drug combination would be effective against newly diagnosed MCL. This targeted–immunotherapy drug combination also represents a less toxic alternative to standard treatment regimens for MCL.
Trial for younger patients
To exploit the potential of ibrutinib plus rituximab as a first-line therapy that can allow patients to undergo fewer cycles of cytotoxic drugs, Dr. Wang and his colleagues are currently enrolling patients aged 65 years or younger with newly diagnosed MCL in a single-center phase II clinical trial (No. 2014-0559). Most patients treated thus far have had advanced disease, and all had good performance status and organ function.
The patients are treated in two steps: first, during a chemotherapy-free “window,” they receive oral ibrutinib and intravenous rituximab; then, they receive consolidation chemotherapy comprising rituximab plus hyper-CVAD alternating with rituximab, methotrexate, and cytarabine. The ibrutinib and rituximab are given for two to 12 cycles, depending on response; and consolidation chemotherapy is given for four to eight cycles, depending on whether complete remission is achieved at the end of the chemotherapy-free step.
“If we take advantage of the window of time before the start of cytotoxic chemotherapy to administer targeted, biological therapy, then less chemotherapy will be needed. This could both decrease the toxicity of treatment and increase survival time,” said Dr. Wang, the trial’s principal investigator.
The preliminary results have affirmed expectations. Among patients treated thus far with ibrutinib and rituximab, the overall response rate (complete plus partial responses) has been 100%, and the complete response rate has been 73% and is still rising, allowing most of the patients to undergo only four cycles of consolidation chemotherapy. The most common adverse events due to the targeted therapy have been fatigue, myalgia, diarrhea, and oral mucositis, all at low grades; and common adverse events due to the chemotherapy have included anemia, lymphocytopenia, thrombocytopenia, and leukopenia. Further follow-up is needed to determine survival outcomes, but after a median follow-up of 9 months, no patient has died or had disease progression or recurrence.
“This has been the first time a first-line chemotherapy-free regimen has had an overall response rate of 100% in young patients with MCL,” Dr. Wang said. The early success of the trial led to the addition of another 50 patients to the trial’s projected recruitment.
Trial for older patients
Older patients with MCL typically receive less intensive—and thus less effective—therapy than younger patients. As a result, survival times in these older patients are usually shorter, only 3–5 years. To prolong survival without compromising safety in this older group, Dr. Wang and colleagues designed an international randomized controlled phase III trial for 550 patients 65 years or older with newly diagnosed MCL (No. 2013-0056). Jorge Romaguera, M.D., a professor in the Department of Lymphoma and Myeloma, said, “Because of its low toxicity and high efficacy profile, ibrutinib is the perfect drug to add to the established first-line therapy for elderly patients with newly diagnosed MCL.”
The patients in the double-blind trial received six cycles of a standard regimen of bendamustine and rituximab plus either ibrutinib or placebo. The objective of the trial was to prolong progression-free survival and, potentially, overall survival.
Results of the trial, which has completed enrollment, could lead to the approval of ibrutinib as a first-line treatment for MCL. Dr. Wang said, “If the primary objective is achieved, this will be the new standard for elderly MCL patients around the world.”
Although the trial of ibrutinib and rituximab in younger patients has achieved excellent responses, even the patients who received only four cycles of consolidation chemotherapy experienced some significant adverse effects. Another trial aimed at reducing this remaining toxicity is being planned. Also, laboratory studies are planned to identify molecular correlates of the outcomes in the trial of ibrutinib plus rituximab in younger patients, and long-term follow-up is needed to ensure that the patients’ responses are durable.
The use of ibrutinib plus rituximab will, Dr. Wang expects, change practices in MCL treatment. “This approach reduces the use of first-line cytotoxic chemotherapy while improving efficacy and greatly reducing toxicity,” he said. And in the longer term, he anticipates that the impact of these MCL trials on cure rates and survival outcomes will contribute to MD Anderson’s goal of dramatically increasing the cure rate for B cell lymphomas.
For more information, contact Dr. Jorge Romaguera at 713-745-4247 or Dr. Michael Wang at 713-792-2860. For more information about clinical trials for patients with lymphoma, visit www.clinicaltrials.org.
OncoLog, April 2017, Volume 62, Issue 4
Liang (Leo) Zhang, M.D., Ph.D.
Laboratory of M. Wang, M.D.
Department of Lymphoma/Myeloma, Division of Cancer Medicine
1515 Holcombe Blvd #853
Houston, TX 77030