First CAR Therapy Receives FDA Breakthrough Designation


The investigational CD19-targeted CAR therapy CTL019 has received a breakthrough therapy designation from the FDA as a potential treatment for pediatric and adult patients with relapsed/refractory ALL.

Carl H. June, MD

The investigational CD19-targeted chimeric antigen receptor (CAR) therapy CTL019 has received a breakthrough therapy designation from the FDA as a potential treatment for pediatric and adult patients with relapsed/refractory acute lymphoblastic leukemia (ALL).

The novel therapy, which generated excitement at the 2013 ASH Annual Meeting, showed a complete remission (CR) rate of 86% in pediatric patients and 100% in adult patients with relapsed/refractory CD19-positive ALL in an early phase clinical study. The personalized cell therapy is being developed through an agreement between the University of Pennsylvania and Novartis.

“Our early findings reveal tremendous promise for a desperate group of patients, many of whom have been able to return to their normal lives at school and work after receiving this new, personalized immunotherapy,” lead investigator Carl H. June, MD, a Richard W. Vague Professor in Immunotherapy in the department of Pathology and Laboratory Medicine in the Perelman School of Medicine and director of Translational Research in the Abramson Cancer Center of the University of Pennsylvania, said in a statement. “Receiving the FDA’s Breakthrough Designation is an essential step in our work with Novartis to expand this therapy to patients across the world who desperately need new options to help them fight this disease.”

CTL019 is an autologous T cell therapy engineered through lentiviral transduction to express a CD19-specific CAR. The treatment is manufactured using autologous T cells collected through leukapheresis, which are modified and then activated ex vivo using anti-CD3/CD28 beads. Once infused into the patient, CTL019 continues to undergo robust in vivo expansion that can persist for 15 months or longer.

In the study that was the basis for the breakthrough designation, 5 adults and 22 pediatric patients with CD19-positive ALL received treatment with CTL019. T cells were collected from the patients, regardless of past stem cell transplantation. Allogeneic donors were not utilized in the trial.

In pediatric patients, the treatment dose ranged from 107 to 108 cells/kg with a transduction efficiency of 11-45%. Adult patients received CTL019 at 5x109 total cells split over three days with a transduction efficiency of 6-31%.

Overall, 19 of the 22 pediatric patients treated with the therapy experienced a CR (86%), with the first patient who received treatment remaining in remission at the 20-month follow-up. All 5 adult patients treated with CTL019 experienced a CR, with the longest duration continuing past 6 months. One adult patient treated with the T cell therapy became eligible to receive bone marrow transplant.

Treatment was halted for 5 patients who experienced fevers within the first 24 hours of infusions. Cytokine release syndrome (CRS) was evident in all patients who responded to CTL019. CRS appeared concurrently with peak T cell expansion, fever, and variable degrees of myalgias, nausea, and anorexia. However, researchers noted that patients who developed CRS responded rapidly to IL-6-targeted anti-cytokine treatment.

"This is a major milestone as we are now one step closer in helping address the high unmet needs of this patient population,” June said. "We are excited about the strength of the positive early data seen in pediatric and adult patients with relapsed/refractory acute lymphoblastic leukemia and look forward to building upon these findings as we continue advancing the CTL019 clinical program in phase II trials."

In addition to the promising results demonstrated in ALL, treatment with CTL019 also showed promise in adult patients with chronic lymphocytic leukemia (CLL). In a study presented at the 2013 ASH Annual Meeting, 47% of patients with CLL responded to therapy, with 7 experiencing a CR.

The University of Pennsylvania is currently conducting a single-arm, open-label phase II study examining CTL019 in adult patients with ALL. The estimated enrollment for the study was 67 and the total duration of the primary follow-up is 1 year from cell infusion. The study is ongoing but not actively recruiting (NCT02167360).

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