Early-phase clinical trial to test new CAR T-cell therapy for multiple myeloma
Sample of bone marrow with multiple myeloma cells stained in blue.
Photo courtesy of Wikipedia
The Center for Cancer Research is a leading center for chimeric antigen receptor (CAR) T-cell research. In fact, James Kochenderfer, M.D., Investigator, Experimental Transplantation and Immunology Branch, and Steve Rosenberg, M.D., Ph.D., Chief, Surgery Branch, were the first to show that CAR T-cell therapies targeting the CD19 protein were effective against lymphoma, which led to FDA approval last year of a CAR T-cell therapy for certain types of large B-cell lymphoma.
The encouraging results of CD19-targeted CAR T-cell therapy largely motivated a new phase I clinical trial of an anti-B-cell maturation antigen (BCMA)-targeted CAR T-cell therapy for multiple myeloma. The hope is that this could, in turn, inform CAR T-cell therapy for other blood cancers. “CAR T-cell therapies are very promising for these types of cancer,” Kochenderfer says. “I think this trial could definitely help further the field.”
The trial will test a novel CAR T-cell immunotherapy in patients whose multiple myeloma has persisted or relapsed after at least three prior courses of therapy. The trial uses a fully human molecule as part of the therapy, unlike a similar trial earlier this summer which used some components derived from mouse genes. This trial is currently open and recruiting patients.
Multiple myeloma is a type of cancer where white blood cells, known as plasma cells, multiply uncontrollably in the bone marrow. “The disease is almost always incurable,” says Kochenderfer, the leader of the trial. “It’s very resistant to treatment. Patients will get a temporary response and then relapse.” Indeed, even with treatment, life expectancy for those diagnosed with early-stage multiple myeloma is only about five years.
Currently, multiple myeloma treatment involves medication (such as drugs that adjust the immune response), chemotherapy or a stem-cell transplant. In a stem-cell transplant, cells from the patient’s bone marrow are removed and replaced with healthy donor stem cells, some of which mature into T-cells, another class of disease-fighting white blood cells, in hopes that they will destroy the cancer cells. Although stem-cell transplants can lead to long-term remissions, they often result in a potentially fatal condition in which donor stem cells destroy healthy tissue.
CAR T-cell therapy sidesteps this problem since it doesn’t require donor cells. Instead, it involves collecting patients’ own T-cells, inserting a gene in them for a receptor that targets specific proteins on cancer cells, and then coaxing them to multiply in the clinic before infusing the new cells back into patients. Ideally, the new cells will further expand their numbers in patients, zero in on cancer cells that express the protein target, and destroy them.
The type of CAR T that Kochenderfer and colleagues have developed is a construct that targets the BCMA protein, expressed only on multiple myeloma cells and normal plasma cells. “We can target multiple myeloma without hurting any of the other organs by using this construct,” Kochenderfer says.
Kochenderfer and his lab were the first to develop a BCMA-targeted CAR construct. They tested an early version in a phase I clinical trial involving 16 patients. Thirteen patients responded to treatment, and three are experiencing ongoing responses of over a year. This new construct may be more effective than an earlier construct that contained an artificial molecule. The new version is fully human, making the patient’s immune system less likely to recognize it as foreign and destroy it. Preclinical work led by Norris Lam, a biologist in Kochenderfer’s lab, has conducted extensive experiments to develop the new fully human CAR. These experiments have shown that the new construct performs better in mice than the anti-BCMA CAR used in the earlier NCI anti-BCMA CAR trial.
In the phase I trial of the new CAR construct, the researchers will first treat three patients with a very low dose of CAR T cells. Once that dose proves to be safe, they will treat another three patients with a higher dose, and so on until they determine the maximum dose patients can tolerate. If Kochenderfer and his team can demonstrate that treating multiple myeloma with their new CAR construct is safe and feasible, and at least as effective as the early construct, they will proceed with a phase II trial. “Our goal is to develop T-cell therapies that give long-term, lasting remissions,” Kochenderfer says.
NCI Protocol ID: NCI-18-C-0125
Protocol Title: T Cells Expressing a Novel Fully-Human Anti-BCMA CAR for Treating Multiple Myeloma
Clinicaltrials.gov identifier: NCT03602612
The Center for Cancer Research is NCI’s internal cancer center, a publicly funded organization working to improve the lives of cancer patients by solving important, challenging and neglected problems in cancer research and patient care. Highly trained physician-scientists develop and carry out clinical trials to create the medicines of tomorrow treating patients at the world’s largest dedicated research hospital on the campus of the National Institutes of Health in Bethesda, Maryland.Sat, 09/01/2018