A new chimeric antigen receptor (CAR) T-cell therapy to treat mantle cell lymphoma, a cancer in the blood, has been approved by the U.S. Food and Drug Administration as a treatment for patients with relapsed or resistant disease. This is the only approved CAR T-cell therapy for this type of lymphoma.
The cell therapy brexucabtagene autoleucel, which is marketed under the brand name Tecartus, is the third CAR T-cell therapy to be approved by the FDA and UCLA Health is one of the few institutions to provide all three therapies. The others are Kymriah and Yescarta for the treatment of certain types of non-Hodgkin’s lymphoma and diffuse large B-cell lymphoma.
CAR T-cell therapy works by training a person’s own immune system to fight cancer cells by genetically modifying the T-cells to recognize and attack the cancer. It’s a “living therapy” that stays inside the body to keep killing tumor cells long after the cells are infused in the body.
“CAR T-cell therapy is a game-changer for mantle cell lymphoma since just a single treatment yields an excellent response rate,” said John Timmerman, MD, a professor of hematology/oncology in the David Geffen School of Medicine at UCLA and investigator on the trial. “While it is too early to know if some of these patients have been cured, it is likely that the combination of CAR T cells with other treatments will lead to even better results, with even more durable remissions.”
Timmerman, along with Sarah Larson, MD, assistant professor of hematology/oncology at the David Geffen School of Medicine and the UCLA Jonsson Comprehensive Cancer Center, breaks down the significance of the FDA approval and what it means for patients diagnosed with mantle cell lymphoma.
How common is mantle cell lymphoma and what are the current treatment options for this cancer?
Timmerman: Mantle cell lymphoma is a distinct subtype of lymphoma, representing 6% of all non-Hodgkin’s lymphomas, or about 4,500 patients per year in the U.S. While most cases are viewed as incurable, there are still many standard therapies, so treatment is aimed at obtaining long remissions with each line of available therapy. Initial treatment usually includes chemotherapy plus an anti-CD20 monoclonal antibody, oftentimes followed by high-dose chemotherapy and an autologous stem cell transplant, which often keeps patients in remission for five or more years. For relapsed disease, options include targeted agents or immunomodulatory drugs. Allogeneic stem cell transplantation can be effective, and even curative in some selected patients, but carries risks of substantial morbidity and mortality.
How is this new treatment an improvement over past treatments for mantle cell lymphoma?
Timmerman: Most treatments require many months of therapy to achieve tumor shrinkage. But just one infusion of Tecartus CAR T cells leads to remission in most patients.
Larson: With Tecartus, patients go into remission and stay in remission longer when compared to the clinical trials of the other available treatments.
UCLA participated in the ZUMA-2 clinical trial that led to the approval of Tecartus. What were the main results?
Timmerman: The ZUMA-2 pivotal trial included 74 adult patients with relapsed or refractory mantle cell lymphoma who had previously received chemotherapy, an anti-CD20 antibody, and a BTK inhibitor. Patients had blood T-cells collected, and a CAR T-cell product was successfully manufactured for 96% of cases. Most patient’s tumors regressed rapidly, with 87% having at least some shrinkage and 62% having complete tumor regression. That response rate is higher than other available therapies for mantle cell lymphoma. After a year of follow-up, 61% of patients remained in remission. The in the New England Journal of Medicine on April 2, 2020.
What is significant about this FDA approval?
Larson: These are very exciting results for mantle cell lymphoma because of the high remission rate and lasting remissions. This treatment provides a lasting response in the majority of patients after a single infusion. Similar to the previous FDA approval for Yescarta, we can use these promising data to continue to improve the outcome for patients with mantle cell lymphoma.
Timmerman: We are still just beginning to understand this technology, so there is a huge potential to improve this form of treatment.
What are the side effects of this treatment?
Timmerman: Cytokine release syndrome, a result of immune messenger molecules being released by the activated immune cells, is seen to varying degrees in 91% of patients, and is manifested as fevers, chills, malaise and potentially low blood pressure and organ toxicity. This can usually be managed with supportive measures and a drug that blocks the cytokine interleukin-6. Another potential side effect is neurotoxicity, seen in up to 63% of patients, with symptoms of confusion, drowsiness and speaking difficulties, and in severe cases, seizures and coma. Our group at UCLA has designed a unique trial using the interleukin-1 antagonist Anakinra to mitigate neurotoxicity, and recently treated our first patients. So overall, side effects of CAR T-cell therapies are manageable, and ongoing research is teaching us how to make this novel treatment easier to tolerate.
How far has CAR T-cell therapy come since the first two FDA approvals in 2018 for lymphoma?
Larson: Due to the success of CAR T cells, we are implementing them earlier in treatment and testing them in combination therapies as part of new clinical trials. We routinely give CAR T cells to patients treated in the lymphoma program.
Timmerman: Since we first started treating patients with CAR T cells at UCLA in early 2016, the field has progressed rapidly, with several CAR T-cell products now FDA-approved for types of non-Hodgkin’s lymphoma and acute leukemia. We now administer CAR T cells every week in our transplant unit as standard-of-care, and have over a dozen new clinical trials. Patients who have run out of other treatment options are often put into remission with CAR T-cell therapy. But unfortunately, most still eventually relapse, so there is still much work to be done.
Any other exciting research with CAR T-cell therapy happening at UCLA
Larson: UCLA has been at the forefront of engineered cell therapy. In addition to industry-sponsored trials and commercially available products, we also design, develop and manufacture our own CAR T cells to improve patient outcomes.
Timmerman: CAR T-cell therapy research continues to grow at UCLA, both on the laboratory and clinical sides. In addition to industry-sponsored clinical trials, we now have a homegrown trial of “dual targeting” CAR T cells designed by Dr. Yvonne Chen and Dr. Sarah Larson that simultaneously attacks to antigens on the surface of lymphoma cells (CD19 and CD20). They are next preparing to launch a second related trial of dual-targeted CAR T cells for multiple myeloma. This strategy may be more potent than traditional CAR T cells that target a single antigen, and reduce the capacity for immune escape by tumor cells.
In the laboratory, we are searching for ways to make CAR T cells more effective at killing tumor cells. One approach has been to first attack lymphoma cells with an antibody-interferon-alpha fusion protein that weakens the tumor cell, while strengthening the incoming T-cells. This project is now moving into new mouse models we are building in our translational research laboratories. Further efforts in our group include analysis of patient lymphoma cells pre- and post-CAR T-cell treatment to determine the immunologic and genetic factors that lead to resistance to this therapy. Our multipronged efforts here at UCLA to improve both the efficacy and safety of CAR T-cell therapy are aimed at making a continued impact on this fast-evolving field.
