April 27, 2023
Chimeric antigen receptor (CAR)-T cell therapy has become a safe and effective treatment option for a growing number of indications. While initially posed as a third line course of treatment, recent research has shown CAR-T cell therapy to be an option for more indications earlier in the treatment plan.
Currently, CAR-T cell therapy is FDA approved for:
- Relapsed, refractory B-cell acute lymphoblastic leukemia.
- Relapsed, refractory B-cell non-Hodgkin's lymphoma.
- Relapsed, refractory mantle cell lymphoma.
- Relapsed, refractory follicular lymphoma.
- Relapsed, refractory multiple myeloma.
More indications are being studied each day, and experts are learning new ways to use CAR-T cell products with fewer toxicities and at new points along a patient's care journey.
Clinical trials for new manufacturing
With the rapid growth of knowledge of and available uses for CAR-T cell therapy, questions have arisen around manufacturing processes and how to ensure consistent access to the products needed for this breakthrough therapy. The field is currently experiencing manufacturing shortages for CAR-T cell products related to multiple myeloma.
Researchers at Mayo Clinic are studying ways to manufacture CAR-T products on-site and have developed a biomanufacturing lab to do just that. This unique approach to CAR-T cell therapy is now in clinical trials for B cell malignancies in lymphoma and leukemia. Few centers have the capability to manufacture CAR-T cell products on site. There are a plethora of considerations including good manufacturing practice regulations, the need for clinical-grade DNA and virus, and the complexities around manufacturing systematic layout planning.
"The FDA does not approve a process. It approves a drug," says Saad J. Kenderian, M.B., Ch.B., a hematologist and oncologist at Mayo Clinic Comprehensive Cancer Center in Rochester, Minnesota. "We do have societies working on proposals to change those policies, but it does present a challenge for a trial like this."
Dr. Kenderian notes that allowing patients access to CAR-T cell products manufactured on-site at academic medical centers comes with a host of benefits. The time needed to manufacture the products on-site is much shorter than when sending out to a centralized manufacturing company, and the cost is much lower. While the products manufactured at Mayo Clinic are similar in nature to those centrally manufactured, they ultimately are a unique CAR-T cell product.
"We treated our first patient last year, and we're very encouraged by the feasibility of this approach," says Dr. Kenderian. "It's really a unique trial opportunity."
Rapid advancements for CAR-T cell therapy
Dr. Kenderian and his colleagues have been involved with a variety of other industry-sponsored clinical trials and preclinical research as well. This research is moving the field forward, allowing more patients with a wider variety of indications to receive CAR-T cell therapy.
One such trial is a multicenter study called ZUMA-19. Results of the phase 1 trial were published in Blood in November 2022. The trial evaluated the use of axicabtagene ciloleucel, an approved CAR-T cell therapy for patients with large B-cell lymphoma, in combination with lenzilumab, a monoclonal antibody, to decrease dose-reducing toxicities. In the phase 1 trial, researchers observed reduced markers of toxicities and no new safety issues. The research is moving into phase 2 trials that should open later in 2023.
Dr. Kenderian and his colleagues also are working on the clinical-grade materials to move another piece of research into clinical trials. Many patients with multiple myeloma do not have a durable response to treatment with CAR-T cell therapy. In preclinical studies, Dr. Kenderian and his team observed improved efficacy by also targeting cancer-associated fibroblasts. This research is in the IND-enabling phase.
The CAR-T cell therapy referral process
With the rapid changes in the landscape of CAR-T cell therapy, it's important for all patients with approved indications to be evaluated at a center specialized in the therapy. This improves opportunities for access to treatment and clinical trials.
At Mayo Clinic, Dr. Kenderian works with a team of experts specially trained in CAR-T cell therapy as well as a variety of disease areas. After patients are screened, a personalized care team is assembled for each patient's unique care plan.
Although patients need to stay near the facility for 5 to 6 weeks during their treatment, remote patient monitoring tools have made it possible for patients to receive CAR-T cell therapy as an outpatient treatment at Mayo Clinic.
"We have converted an entire hospital floor into an outpatient unit," says Dr. Kenderian. "It's an incredible reflection of the innovative approach our teams are taking to CAR-T cell therapy."
The team at Mayo Clinic uses wearable devices to help remotely monitor patients, who then return to the outpatient unit for follow-up care as needed. Following the initial treatment period, patients follow up with their CAR-T cell therapy team for up to three years. All CAR-T cell therapy and follow-up is coordinated with the patient's local care team as well.
For more information
Oluwole OO, et al. ZUMA-19: A phase 1/2 study of axicabtagene ciloleucel plus lenzilumab in patients with relapsed or refractory large B-cell lymphoma. Blood. 2022;140(suppl);10318.
Refer a patient to Mayo Clinic.