Use of CAR-Transduced Natural Killer Cells in CD19-Positive Lymphoid Tumors
Enli Liu 1, David Marin 1, Pinaki Banerjee 1, Homer A Macapinlac 1, Philip Thompson 1, Rafet Basar 1, Lucila Nassif Kerbauy 1, Bethany Overman 1, Peter Thall 1, Mecit Kaplan 1, Vandana Nandivada 1, Indresh Kaur 1, Ana Nunez Cortes 1, Kai Cao 1, May Daher 1, Chitra Hosing 1, Evan N Cohen 1, Partow Kebriaei 1, Rohtesh Mehta 1, Sattva Neelapu 1, Yago Nieto 1, Michael Wang 1, William Wierda 1, Michael Keating 1, Richard Champlin 1, Elizabeth J Shpall 1, Katayoun Rezvani 1
• 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.).