Q1 · MEDICINE
Article
Author: Wang, Michael ; Keating, Michael ; Shpall, Elizabeth J. ; Wierda, William ; Liu, Enli ; Kaur, Indresh ; Cohen, Evan N. ; Banerjee, Pinaki ; Macapinlac, Homer A. ; Champlin, Richard ; Cao, Kai ; Daher, May ; Nassif Kerbauy, Lucila ; Nunez Cortes, Ana ; Rezvani, Katayoun ; Marin, David ; Thall, Peter ; Hosing, Chitra ; Kebriaei, Partow ; Mehta, Rohtesh ; Nieto, Yago ; Kaplan, Mecit ; Nandivada, Vandana ; Neelapu, Sattva ; Overman, Bethany ; Basar, Rafet ; Thompson, Philip
BACKGROUND:Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy has shown remarkable clinical efficacy in B-cell cancers. However, CAR T cells can induce substantial toxic effects, and the manufacture of the cells is complex. Natural killer (NK) cells that have been modified to express an anti-CD19 CAR have the potential to overcome these limitations.
METHODS:In this phase 1 and 2 trial, we administered HLA-mismatched anti-CD19 CAR-NK cells derived from cord blood to 11 patients with relapsed or refractory CD19-positive cancers (non-Hodgkin's lymphoma or chronic lymphocytic leukemia [CLL]). NK cells were transduced with a retroviral vector expressing genes that encode anti-CD19 CAR, interleukin-15, and inducible caspase 9 as a safety switch. The cells were expanded ex vivo and administered in a single infusion at one of three doses (1×105, 1×106, or 1×107 CAR-NK cells per kilogram of body weight) after lymphodepleting chemotherapy.
RESULTS:The administration of CAR-NK cells was not associated with the development of cytokine release syndrome, neurotoxicity, or graft-versus-host disease, and there was no increase in the levels of inflammatory cytokines, including interleukin-6, over baseline. The maximum tolerated dose was not reached. Of the 11 patients who were treated, 8 (73%) had a response; of these patients, 7 (4 with lymphoma and 3 with CLL) had a complete remission, and 1 had remission of the Richter's transformation component but had persistent CLL. Responses were rapid and seen within 30 days after infusion at all dose levels. The infused CAR-NK cells expanded and persisted at low levels for at least 12 months.
CONCLUSIONS:Among 11 patients with relapsed or refractory CD19-positive cancers, a majority had a response to treatment with CAR-NK cells without the development of major toxic effects. (Funded by the M.D. Anderson Cancer Center CLL and Lymphoma Moonshot and the National Institutes of Health; ClinicalTrials.gov number, NCT03056339.).