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CAR T-cell Therapies Effective Across Hematologic Malignancies

Silas Inman @silasinman
Published: Wednesday, Mar 02, 2016

Dr. Stephan Grupp

Stephan Grupp, MD, PhD

Chimeric antigen receptor (CAR)-modified T-cell therapies continue to demonstrate promising signs of efficacy for patients with hematologic malignancies, including those with acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL), according to data from several early phase trials.

For patients with ALL, CD19-targeted CAR-modified T-cells have demonstrated complete response (CR) rates ranging from 90% to 100%.1,2 Additionally, for those with NHL, the CR rates are approximately 60% for patients treated with anti–CD19 CAR T cell therapies.4,5 Moreover, studies are beginning to identify effective management techniques for cytokine release syndrome (CRS), which is an indicator of effectiveness for this class of medication.

There are currently a number of therapies in development, including CTL019, which is furthest along in development and has received a breakthrough therapy designation from that FDA for its potential as a treatment for pediatric and adult patients with relapsed/refractory ALL. This therapy has been assessed across numerous settings, including ALL, NHL, and multiple myeloma.

High Response Rates in ALL

In a phase II study exploring CTL019,1 which is being developed by the University of Pennsylvania and Novartis, 59 patients with CD19-positive ALL received treatment with the modified T-cells at a median 4.3x106 cells/kg over 1 to 3 days. One week prior to treatment with CTL019, a majority of patients received lymphodepleting chemotherapy.

In this study, CTL019 demonstrated a 93% CR rate in pediatric patients with relapsed/refractory ALL. After a median follow-up of 12 months, 79% of patients enrolled in the trial remained alive. Additionally, the relapse-free survival rate was 76% and 55% at 6 and 12 months, respectively.

Of those who responded, 6 went on to receive subsequent stem cell transplantation and 18 patients remained in CR for more than 1 year. There were no relapses past the 1-year mark.

“This clinical trial of CTL019 is the largest study of a CAR-T therapy in pediatric patients with relapsed or refractory acute lymphoblastic leukemia, and it is helping us better understand the therapy's potential to achieve durable responses in this patient population,” said lead investigator Stephan Grupp, MD, PhD, the Yetta Deitch Novotny Professor of Pediatrics at the Perelman School of Medicine at the University of Pennsylvania.

Overall, 88% of patients experienced grade 1 to 4 CRS with CTL019. The severity of CRS was related to tumor burden and coincided with response. Overall, 27% of patients with CRS developed hemodynamic or respiratory instability that was reversed by IL-6 receptor antagonist.

“With each child we treat as part of this trial, we learn more about the potential of CTL019 to help patients whose cancers cannot be controlled with conventional therapies,” said Grupp. “The response rate and durability we are seeing are unprecedented, and gives us hope that personalized cellular therapies will be a powerful key to long-term control of this difficult cancer.”

In a second trial,2 which was conducted by the National Cancer Institute (NCI) and Kite Pharma, a CD19 CAR T-cell therapy showed a 100% CR rate in 9 patients with primary refractory ALL and for 5 patients with CNS ALL. All patients who achieved a CR also tested negative for minimal residual disease (MRD). Those with Philadelphia chromosome-positive and downs syndrome-related ALL experienced an MRD-negative CR rate of 60% and 67%, respectively.

All patients responding with primary refractory ALL went on to receive a stem cell transplant. At the time of the analysis, all patients remained alive and 88.9% remained disease-free (range 5-28 months). A response was not seen for patients with MLL rearranged ALL (n = 2).

“There was a 60% complete response rate in this ultra-high risk ALL population and a 100% MRD-negative response rate in primary refractory and CNS leukemia," said lead investigator Daniel W. Lee III, MD, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute. “This treatment was a bridge to transplant in refractory patients.”

An early intervention algorithm developed by the NCI was utilized to prevent CRS. Under this grade-driven system, those with grade 1 CRS received vigilant supportive care. For grade 2 CRS, if the patient had extensive comorbidities or an older age, and for those with grade 3 or 4 CRS, tocilizumab was initiated with or without corticosteroids along with supportive care.


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