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.”
Study Details
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
KEY POINTS
- Response was observed in 8 of 11 patients.
- No cases of cytokine-release syndrome, neurotoxicity, or graft-vs-host disease were observed.
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.
