Expert Discusses CAR T-Cell Advances in ALL

Stephan Grupp, MD, PhD

Data from the phase II ELIANA study presented at the 2016 ASH Annual Meeting showed that the CAR T-cell therapy CTL019 induced an 83% complete remission (CR) or CR with incomplete blood count recovery (CRi) rate in pediatric and young adult patients with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL).

Patients were enrolled in the study at 25 centers in the United States, Europe, Asia, and Australia. Among the first 50 patients enrolled, the 6-month overall survival rate was 89% (95% CI, 76-95) and the disease-free survival rate was 60%.

OncLive: Can you discuss the breakthroughs with CAR T cells?

In an interview with OncLive, lead study investigator Stephan Grupp, MD, PhD, the Yetta Deitch Novotny Professor of Pediatrics at the Perelman School of Medicine at the University of Pennsylvania, discussed the study results and the next steps with CAR T-cell therapy in ALL.Grupp: The whole idea of CAR T cells is engineering T cells to be able to attack cancer. This has been the most successful in patients with a specific type of leukemia. ALL is the most common childhood cancer. We're using CD19-targeted cells and there are several other groups that are doing this as well. Several groups have come out with beneficial short-term clinical results and now we’re getting longer term clinical results.

The big question is whether this can be FDA approved. There is data from a global registration trial for a specific CD19-targeted CAR product, called CTL019, which has been licensed to the drug company, Novartis. Novartis has completed a global registration trial for this drug, which has been tested in 25 centers across 11 countries.

Two important questions to consider are can you do this safely in multiple institutions and can you still have the same outcome as a single dedicated institution that’s done a lot of CAR T cell work. Fortunately, the answer to both of those questions is, “Yes.” The registration trial reported that for the first 50 patients that received CTL019 showed an 83% complete response rate in these patients with relapsed/refractory ALL. That compares very favorably to the broad data and to our specific data previously.

CAR T cells are a little bit different than other cancer treatment modalities, and certainly have unique toxicities that are familiar to a bone marrow transplant. A principal toxicity is cytokine release syndrome (CRS). In the process of doing this global trial, we were able to create an algorithm for treating cytokine release syndrome to hopefully get all the physicians aligned on this, do the appropriate training, and be able to treat these patients with exactly the same safety that we saw in the single institution trial, which included no deaths from CRS.

Please expand on the long-term data that you are seeing.

A logistical issue is if you can take these cells and ship them all over the world because you must make that an individual product for each patient. You have to collect cells from the patient, send them to a factory in the United States, and then send it back to the center. We found that it is possible from a logistical standpoint. We have some long-term results. At 1 year, the event-free survival rates were in the 50% to 60% range, depending on the study. Also at 1 year, we have overall survival rates around 79% to 80%, and this is across several studies of CTL019. That shows that there is a substantial number of patients who do have long-term disease control.

We’ve also been following these patients for a longer period of time on the single institution trial, but we don’t yet have this follow-up on the registration trial. We’re not seeing a lot of events after a year, and so we’re hoping that patients who reach their year have a much higher likelihood of staying in remission at that point.

What are the next steps regarding this drug?

What are some of the differences when you are treating pediatric patients versus adult patients?

The other thing that is very exciting to me as a bone marrow transplanter is that we’re able to achieve this without many of the patients going on to subsequent bone marrow transplant. For a large fraction of the patients that we treated, CTL019 is definitive therapy.FDA approval is the next step. Novartis is on record saying that they intend to submit a biologics license application, which is the drug application for this product, sometime soon. The exact timing isn’t clear to me, but they have been saying that we should expect this in the first couple months in 2017. Then that enters a process where we would hopefully hear within 6 months about potential FDA approval. I am very hopeful that this will be FDA approved. I think there are a couple of things that we think about. The first is most kids with ALL do just fine with regular chemotherapy, but 10% to 15% of those kids relapse. The upfront therapy is so good that the patients who are left behind by that therapy have a bad case of the disease so they need other treatments.

What about the long-term safety considerations with pediatric patients?

We are starting to have a conversation about what it might look like to roll this treatment out earlier in ALL therapy. If you can identify patients who are at high risk for relapse and think about giving CTL019 to those patients after a couple months of chemotherapy, it is an exciting idea and that trial is being designed right now. In general, younger patients certainly have fewer comorbidities than elderly patients, which is a positive for the younger side and does make it easier to treat these patients, especially if they have significant cytokine release syndrome.

However, the principal long-term side effect of CTL019 is B-cell aplasia, which causes low antibodies and hypogammaglobulinemia, which requires intravenous immunoglobulin (IVIG) replacement. We don't know how long it's going to last because we haven't followed people long enough to be sure about that.

Is there anything else you would like to highlight?

The impact on the patient is that they have to receive a medication. The IVIG provides excellent replacement for those patients, the infection risk returns to the baseline for the population, but they do need to get either intravenous hemoglobin monthly in the clinic or get a product they can get administered at home, which is a lot more convenient.There are several groups, such as Kite Pharma, Juno Therapeutics, and Novartis, that have very promising products. I think what everyone wants to know is can you make this work the same way in solid tumors, especially adult solid tumors. The answer to that question is, “Not yet.” We're not at the point where we have high efficacy with CAR T cells in these solid tumors. In a solid tumor, there is the ability to exclude T cells and in that situation, we need an additional strategy to get the CAR T cells bootstrapped up within the tumors. It is something people are actively working on in multiple centers with multiple approaches, but we’re not there yet.

Grupp SA, Laetsch TW, Buechner J, et al. Analysis of a global registration trial of the efficacy and safety of CTL019 in pediatric and young adults with relapsed/refractory acute lymphoblastic leukemia. 58th ASH Annual Meeting and Exposition; San Diego, California; December 2-6, 2016. Abstract 221.