In a phase I/II trial reported in The New England Journal of Medicine, Liu et al found that anti-CD19 chimeric antigen receptor (CAR) natural killer (NK) cells produced rapid responses in patients with CD19-positive lymphoid tumors, without the toxicities associated with CAR T-cell therapy in this setting.
“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.”— Liu et al
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As stated by the investigators, “Anti-CD19 … 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. NK cells that have been modified to express an anti-CD19 CAR have the potential to overcome these limitations.”
In the trial, 11 patients at The University of Texas MD Anderson Cancer Center with relapsed or refractory non-Hodgkin lymphoma (n = 6) or chronic lymphocytic leukemia (CLL, n = 5) received HLA-mismatched anti-CD19 CAR-NK cells derived from cord blood. NK cells were transduced with a retroviral vector expressing genes encoding anti-CD19 CAR, interleukin-15, and inducible caspase 9 as a safety switch. After ex vivo expansion, the cells were administered in a single infusion at 1×105, 1×106, or 1×107 CAR-NK cells/kg following lymphodepleting chemotherapy.
Patients had received a median of four lines of prior therapy. All patients with CLL had disease progression while receiving ibrutinib, plus a minimum of three other lines of therapy. Among the patients with lymphoma, four had disease progression after autologous hematopoietic stem cell transplant.
Toxicity and Responses
No maximum tolerated dose was reached. No cases of cytokine-release syndrome, neurotoxicity, or graft-vs-host disease were observed, and no increases from baseline in levels of inflammatory cytokines, including interleukin-6, were observed. Grade 3 or 4 lymphopenia and neutropenia were observed in 10 patients. No grade 3 or 4 nonhematologic adverse events or tumor lysis syndrome were observed. Grade 1 or 2 tachycardia was observed in four patients, and one patient had grade 3 electrolyte abnormalities.
Among the 11 patients, 8 (73%) had objective response. Among the eight responders, four with lymphoma and three with CLL had complete remission; the remaining responder had remission of the Richter’s transformation disease component but persistent CLL. Responses were observed within 30 days after infusion at all dose levels. The CAR-NK cells expanded after administration and were observed to persist at low levels for ≥ 12 months.
The investigators concluded, “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.”
Disclosure: The study was funded by the MD Anderson Cancer Center CLL and Lymphoma Moonshot and the National Institutes of Health. For full disclosures of the study authors, visit nejm.org.