The study participants included five patients each with these tumor types: acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), and diffuse large B-cell lymphoma (DLBCL).
The allogeneic anti-CD19 CAR therapy appears to be most effective against ALL and CLL, said Kochenderfer. Four of the five patients with ALL initially achieved CRs; among the five patients with CLL, responses included one CR, one PR, and one SD.
Patients with B-cell malignancies that persist after an allogeneic stem cell transplant are often treated with unmanipulated donor lymphocyte infusions, but these treatments have inconsistent efficacy and are associated with significant morbidity and mortality from graft-versus-host disease (GVHD), said Kochenderfer.
“We’re trying to genetically enhance the donor’s own lymphocytes to make the infusion of lymphocytes more effective,” he said. Investigators returned to the original donors, who included siblings and matched donors, for another donation. Each patient’s CAR therapy took eight days to manufacture.
Kochenderfer said none of the patients treated during his study developed new onset of acute GVHD. One patient who had chronic GVHD before receiving the CAR therapy experienced a worsening of the condition, while another patient “developed very mild chronic eye GVHD” more than a year after treatment.
“Patients with high tumor burdens did have severe cytokine-release syndrome with fever, tachycardia, and hypotension,” said Kochenderfer. He said these patients were treated with tocilizumab.
Neurological toxicity was rare, with only one case of mild aphasia, he noted.
Several CAR doses were tested during the study, with 107 total cells/kg as the highest dose administered. Since chemotherapy was not given along with the CAR treatment, patients can receive a higher CAR dose without unacceptable toxicity, Kochenderfer said.
He said one patient with DLBCL who received the highest dose achieved a dramatic response — the tumor mass disappeared within two weeks. That patient is the same participant who started the trial with GVHD and, although that condition has worsened, she remains in complete remission from DLBCL after about 13 months.
Kochenderfer said the next step in his research concerning the use of CAR therapy after allogeneic transplant is exploring different T-cell culturing methods in an effort to produce a less differentiated T cell that would make the agent more effective.
He said that he and Steven A. Rosenberg, head of the NCI’s Tumor Immunology Section, developed the CD-19–targeting agent studied in the posttransplant trial in 2007-2009.
It is the same agent that Kite Pharma, a biopharmaceutical company based in Santa Monica, California, is developing, said Kochenderfer. However, he said the posttransplant study was an academic trial that Kite did not sponsor.
Earlier this month, Kite announced the launch of a phase 1/2 trial of KTE-C19 for the treatment of adult patients with ALL that has relapsed or become refractory following standard chemotherapy or hematopoietic stem cell transplant.2
ZUMA-3 is a single-arm, open-label, multicenter study that seeks to enroll 75 patients; safety measures and the overall CR rate are the primary endpoints.
The study is one of three early-phase trials evaluating KTE-C19 which Kite currently is sponsoring. ZUMA-1 is evaluating the therapy in patients with refractory, aggressive non-Hodgkin lymphomas including refractory DLBCL, primary mediastinal B-cell lymphoma, and transformed follicular lymphoma. ZUMA-2 will test the therapy in patients with relapsed/refractory MCL.