Safety With CAR T-Cell Therapy

Stephan A. Grupp, MD, PhD


August 30, 2017

Editorial Collaboration

Medscape &

Hi. My name is Dr Stephan Grupp. I am the director of the Cancer Immunotherapy Program at the Children's Hospital of Philadelphia. I am also a professor of pediatrics at the University of Pennsylvania School of Medicine. I'm here today to talk about some news that has come across in the chimeric antigen receptor (CAR) T-cell field. It's been an exciting couple of weeks because we have had the first presentation to the US Food and Drug Administration (FDA) about an engineered CAR T-cell therapy. We went before the Oncology Drug Advisory Committee (ODAC) with the group from Novartis, which is the drug company that is seeking approval for CTL019, the CD19-directed CAR T-cell therapy that has been designed for pediatric and young adult patients with acute lymphoblastic leukemia (ALL).

This therapy is certainly going to have other uses, but this is the first time that it has gone in front of the FDA. We were excited to present the data, and we were even more excited at the end of the day when the advisory panel voted 10-0 to recommend approval to the FDA. At this point, we are waiting for the next steps.

We spent a lot of time talking about the issue of risk-benefit in these patients. These were patients with refractory disease in many cases (relapsed in all, or primary refractory) who had no other treatment options available to them. The data across multiple trials have shown efficacy ranging from 83% to 95% complete response rates, and the vast majority of these patients are also minimal residual disease negative. Those are all real positives in terms of the risk-benefit.

Of course, there are unique toxicities associated with CAR T-cell therapy, the most notable of which is cytokine release syndrome. However, in our global registration trial, we showed that we could do this safely across 25 centers in 11 countries. Many centers hadn't treated patients with cell therapy before, but they were very good centers that had significant transplant and intensive care unit experience. So, we were able to do this safely across the globe in a way that was comparable to the results that we had locally in a single-institution trial.

There was also a lot of discussion at the FDA about long-term safety. This is a gene therapy, and for the first time, these patients have the potential to survive for many years after receiving this treatment. The safety follow-up that would be required was something the agency was really focused on. Is it necessary to do genetic testing for replication-competent lentivirus? The sense was that it probably was not, because it didn't seem to be a realistic risk in the absence of many clinical events that would suggest otherwise. There also were concerns about oncogenicity—in other words, activation of T-cell proliferation with the CAR T-cell gene that has been inserted into these T cells. We don't see any evidence of that at all across many hundreds of patients, so that was actually quite reassuring.

This is a cellular immunotherapy—a brand-new way of treating cancer and of applying immunotherapy. All of the really striking results, including this trial, which led to this successful ODAC vote, have been in patients with hematologic malignancies, specifically ALL, non-Hodgkin's lymphoma, and to a certain extent, chronic lymphoblastic leukemia as well. These are all CD19-positive malignancies. Data are also emerging in multiple myeloma.

The key question for all of us is whether this therapy will be applicable to solid tumors. It will be the work of the next 5 years to see whether we can apply what we've learned in hematologic malignancies to the solid tumor world. That's another level of understanding that we will need. More technological development will be required before this is successful, but this is something we are all very excited about.

And, of course, most exciting is the fact that if the FDA approves this [Editor's note: FDA approved CTL019 (tisagenlecleucel) on August 30, 2017] then it would be the first engineered cell therapy available for prescription in the United States. Novartis intends a very careful rollout to specific trained centers, and there will be a certification process. This is a new approach to delivering this brand-new therapy, but we've learned a lot from the registration trials that will allow us to figure out how to do this safely across multiple centers.