The Promise of CAR T-Cell Therapy: Q+A with Ran Reshef, MD

For decades, cancer treatment relied on the three pillars of surgery, chemotherapy, and radiation therapy. In recent years, the emergence of immunotherapy has added a whole new set of unique tools that enhance the body’s own immune system to fight cancer.

Among these is a promising type of treatment called chimeric antigen receptor (CAR) T-cell therapy, which re-engineers a patient’s white blood cells to recognize and kill tumor cells. For patients with certain types of lymphoma and leukemia who have exhausted all other options, including chemotherapy and bone marrow transplantation, CAR T-cell therapy has worked when nothing else has.

“CAR T-cell therapy is the most modern and innovative form of cancer immunotherapy that we have right now,” said Dr. Ran Reshef, medical director for the CAR-T Cell Program at Columbia University Irving Medical Center (CUIMC). “We at Columbia have been administering CAR T-cells routinely for close to three years now, with more than 40 patients treated so far on our campus, and many of them have had tremendous treatment success.”

Along with caring for patients with leukemia, lymphoma, and other blood cancers, Dr. Reshef studies innovative ways to improve the outcome of patients undergoing stem-cell transplants and novel cell therapies. He is a principal investigator at the Columbia Center for Translational Immunology and a member of the Herbert Irving Comprehensive Cancer Center.

Recently, Dr. Reshef took part in a multi-center, phase 2 clinical trial (ZUMA-5) that investigated CAR T-cell therapy for patients with relapsed or refractory indolent non-Hodgkin lymphoma (NHL), a slow-progressing lymphoma that makes up about 40 percent of all NHL cases in the U.S. ZUMA-5 is the first completed study to evaluate CAR T-cell therapy exclusively in these high-risk patients, who all had progressive disease despite undergoing multiple previous treatments. The results, which demonstrated complete remissions in 80 percent of patients after CAR T-cell therapy, were presented at the 62nd Annual Meeting of the American Society of Hematology in December.

What is CAR T-cell therapy and in what cancers is it used?

CAR T-cell therapy uses genetic modification to train the patient’s own T-cells, a type of immune cell, to recognize cancer cells. The initial approvals of CAR T-cells have been in highly aggressive diseases like large B-cell lymphoma in adults and acute lymphoblastic leukemia in children and young adults up to age 25. Those have been the first two diseases where CAR T-cells have shown great success, with patients surviving many years after treatment without cancer relapse. More recently, there has been an approval of CAR T-cells in mantle cell lymphoma, which is an uncommon form of lymphoma typical to male patients over age 60. We at Columbia have already successfully treated a patient with mantle cell lymphoma shortly after FDA approval.

How common are indolent non-Hodgkin lymphomas, and what are the current treatment options?

Indolent lymphomas are very common. They primarily occur in older individuals, but we occasionally see them even in younger individuals. Treatment has evolved over the years to include chemotherapy-free options. However, we have patients who seem to be refractory to the standard therapies, or patients who respond to them and recur after a fairly short period of time. In essence, it remains an incurable disease and we don’t have definitive or curative options for it.

What is exciting about this new trial? Can CAR T-cells be given to patients earlier, rather than exhausting all other treatment options first?

The ZUMA-5 trial, which we participated in, represents the first major success of CAR T-cells in indolent lymphomas. The pivotal results show that more 90 percent of patients responded and 80 percent of the patients achieved a complete remission with a single infusion of CAR T-cells. That is by far better than what we can get with most other therapies in cancer, and it justifies moving CAR T-cells to an earlier line of therapy. 

Along with the high response rates, it also seems that these responses are very durable, and more than two-thirds of patients who achieve a complete response would remain that way in the long run. Of course, in an indolent disease, we need longer follow-up, but the majority of patients that we treated on the trial remain in remission today, which is extremely encouraging.

We also saw fewer side effects than what we’ve seen in aggressive lymphomas, with some patients being monitored in the hospital without ever developing fever or any other side effect. This suggests that, for indolent lymphoma, we might even be able to administer CAR T-cells in an outpatient setting, taking away the burden of admission to the hospital and of course the high costs associated with that. 

When will CAR T-cell therapy become available for patients with indolent lymphomas?

The results for this specific type of CAR T-cell therapy that was used in the ZUMA-5 study have already been submitted to the FDA and are under review. We hope that during the first half of 2021, this treatment will be approved by the FDA, and we will be able to start using it in patients outside clinical trials.