CAR T-Cell Therapy Elicits High Response Rate in Pediatric ALL

Stephan Grupp, MD, PhD

The anti-CD19 chimeric antigen receptor (CAR)-modified T-cell therapy CTL019 demonstrated an impressive 92% complete response (CR) rate in pediatric patients with relapsed/refractory acute lymphoblastic leukemia (ALL), according to a presentation by Stephan Grupp, MD, PhD, at the 2014 ASH Annual Meeting.

“What we really have now that we didn’t have before is longer follow-up. A lot of kids are now a year out. We’re seeing the possibility of longer term disease control without further treatment, especially without bone marrow transplant, so I am very excited about that,” said lead study author Stephan Grupp, MD, PhD, of the Children’s Hospital of Philadelphia, in an interview with OncLive. “I am excited about the prospect of having a pediatric multisite trial to see how well these cells are going to work in broader application.”

CTL019 is an autologous T-cell therapy engineered through lentiviral transduction to express a CD19-specific CAR. Once infused into the patient, CTL019 continues to undergo robust in vivo expansion that can persist for longer than 2 years in some patients. In July 2014, CTL019 received a breakthrough therapy designation from the FDA for its potential as a treatment for pediatric and adult patients with relapsed/refractory ALL.

In the updated findings from the phase I study, 39 patients with CD19-positive ALL received treatment with CTL019 at a median 3.6x10⁶ cells/kg over 1 to 3 days. One week prior to treatment with CTL019, 87% of patients received lymphodepleting chemotherapy. The day prior to the infusion of CTL019, five patients tested minimal residual disease (MRD)-negative.

Of the patients who achieved a CR (n = 36), 85% tested MRD-negative by flow cytometry. The event-free survival was 70% and overall survival was 75%. At a median follow-up of 6 months, 76% of patients continued to respond to therapy.

“Although the median follow-up is 6 months, there are patients who are out a year and even as far as 31 months. Fifteen patients are out a year or more,” Grupp said.

In patients with a large burden of disease, with >50% blasts by MRD, the overall response rate (ORR) was 82%. In patients with blasts >5%, the ORR was 88%. Patients with low levels of disease experienced an ORR of 100%.

Flow cytometry analysis within the study revealed that CTL019 cells are persistent over time. Additionally, further study showed that CTL019 cells were found in the cerebrospinal fluid of 90% of patients, with two patients with central nervous system involvement experiencing a CR.

“Persistence of the cells is a key point here. Once we give these cells, they stick around for many months for many patients,” Grupp said. “About two-thirds of patients retain their T cells for 6 months or longer, which is a key point for maintaining remission in these patients.”

There were ten relapses in the study, half of which occurred following a loss of CD19 expression. At the time of the analysis, few patients had required subsequent therapy, with three going on to receive a stem cell transplant. Forty percent of patients who relapsed with CD19-negative disease after achieving a CR were also refractory to prior treatment with blinatumomab (Blincyto).

“Some of the patients that we have treated have relapsed. If you go into remission, the likelihood that you'll remain in remission 6 months later is 76%. That’s pretty good,” said Grupp. “Some of those patients recur because their leukemia cells learn how to hide the target and then the T cells can’t see the leukemia anymore. In that situation, the T cells aren’t going to work.”

All patients enrolled in the study experienced cytokine release syndrome (CRS), at the point of peak T-cell expansion. In 37% of patients, CRS was rapidly reversed using the IL-6 inhibitor tocilizumab (Actemra), a treatment that is currently approved for patients with rheumatoid arthritis.

The incidence of severe CRS was found to correlate with disease burden, suggesting this side effect could effectively be predicted and prevented. Overall, patients with a high disease burden prior to treatment with CTL019 were significantly more likely to experience CRS (P <.002).

“You can control cytokine release syndrome with tocilizumab, which targets IL-6," said Grupp. “In the patients who have enough T-cell proliferation to require this drug, they have a 100% likelihood of going into clinical response. I think if we try to control the T cells using steroids, we’d start to see limitations in efficacy.”

Overall, 21 patients had relapsed on an allogeneic stem cell transplant prior to entering the study. As a result, cells collected to manufacture CTL019 were 100% of donor origin. Despite this, graft-versus-host disease was not apparent in the trial. Other side effects with CTL019 include B cell aplasia, macrophage activation syndromes, and neurotoxicity.

Grupp SA, Maude, SL, Shaw P, et al. T cells engineered with a chimeric antigen receptor (CAR) targeting CD19 (CTL019) have long term persistence and induce durable remissions in children with relapsed, refractory ALL. Presented at: 2014 ASH Annual Meeting; December 6-9, 2014; San Francisco, CA. Abstract 380.

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