Among 11 patients with relapsed or refractory CD19-positive lymphoid tumours, a majority had a response to treatment with chimeric antigen receptor (CAR) natural killer (NK) cells without the development of major toxic effects. Allogeneic CAR-NK cells can be delivered in adoptive transfer without the serious cytokine release syndrome and neurologic toxic effects according to study findings published online on 6 February 2020 in The New England Journal of Medicine.
CARs have been used to redirect the specificity of T-cells against a number of haematologic malignancies, but despite notable clinical responses, autologous CAR-modified T-cells have some logistic and clinical limitations. They are produced on an individual patient basis, which makes their production complex and expensive. Furthermore, in a number of patients, treatment with CAR T-cells has been associated with cytokine release syndrome and neurotoxicity, which require treatment in specialised care units.
NK cells that have been engineered to express a CAR are candidate effectors for cancer treatment. NK cells from an allogeneic source, such as cord blood, can be safely administered without the need for full HLA matching, which eliminates the need to produce a unique CAR product for each patient. Furthermore, allogeneic NK cells have a proven track record of safety after infusion for adoptive immunotherapy in patients with cancer.
In a preclinical model of lymphoma in mice, a group of investigators of the University of Texas M.D. Anderson Cancer Center in Houston, TX, US, previously found that NK cells that had been derived from cord blood and transduced with anti-CD19 CAR, interleukin-15, and inducible caspase 9 had better anti-tumour activity than non-transduced control NK cells. Therefore, they undertook a phase I and II trial to assess the safety and efficacy of escalating doses of CAR-NK cells for the treatment of relapsed or refractory CD19-positive non-Hodgkin’s lymphoma or chronic lymphocytic leukaemia (CLL).
They administered HLA-mismatched anti-CD19 CAR-NK cells derived from cord blood to 11 patients with relapsed or refractory CD19-positive tumours. 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.
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.
These preliminary results show that CAR-NK cells can induce responses in patients with high-risk CD19-positive tumours with relatively few adverse events aside from transient myelotoxicity.
The study was funded by by the M.D. Anderson Cancer Center CLL and Lymphoma Moonshot and the US National Institutes of Health grants.
Liu E, Marin D, Banerjee P, et al. Use of CAR-Transduced Natural Killer Cells in CD19-Positive Lymphoid Tumors. NEJM 2020; 382(6):545-553. doi: 10.1056/NEJMoa1910607.