ANTILEUKEMIA ACTIVITY OF A NATURAL-KILLER-CELL LINE AGAINST HUMAN LEUKEMIAS

We describe here the in vitro and in vivo antileukemia activity of a r ecently described natural killer (NK) cell line (NK-92), which has fea tures of human activated NK cells. The cytotoxic activity of rhIL2-dep endent cultured NK-92 cells against primary patient-derived leukemic t arget cells [12 acute myelogenous leukemias (AMLs), 7 T acute lympbobl astic leukemias (T-ALLs), 14 B-lineage-ALLs, and 13 chronic myelogenou s leukemias (CMLs)], human leukemic cell lines (K562, KG1, HL60, Raji, NALM6, TALL-104, CEM-S, and CEM-T) and normal bone marrow cells was m easured in Cr-51-release assay (CRA), The patient-derived leukemias co uld be subdivided into three groups based on their sensitivity to NK-9 2 cells: insensitive (less than or equal to 19% lysis), sensitive (20- 49% lysis), and highly sensitive (greater than or equal to 50% lysis) at an E:T ratio of 9:1, Of 46 patient-derived samples, 24 (52.2%) were sensitive or highly sensitive to NK-92-mediated in vitro cytotoxicity (6 of 12 AMLs, 7 of 7 T-ALLs, 5 of 14 B-lineage-ALLs, and 6 of 13 CML s). NK-92 cells were highly cytotoxic against all of the eight leukemi c cell lines tested in a standard 4-h CRA, Normal human bone marrow he matopoietic cells derived from 18 normal donors were insensitive to NK -92-mediated cytolysis, In comparison with human lymphokine-activated killer cells, normal NK cells, and T cells, NK-92 cells displayed more powerful antileukemia activity against a patient-derived T-ALL as wel l as K562 and HL60 cells, both in in vitro CRA and in a xenografted hu man leukemia SCID mouse model. The NK-92 cells did not induce the deve lopment of leukemia in SCID mice after i.v., i.p., or s.c. inoculation . In adoptive transfer experiments, SCID mice receiving i.p. inoculati ons of human leukemias derived from a T-ALL (TA27) and an AML (MA26) t hat were highly sensitive to the cytolysis of NK-92 cells in vitro, as well as a pre-B-ALL (BA31) that was insensitive to the in vitro cytol ysis of NK-92 cells, were treated by administration of NK-92 cells wit h or without rhIL2 (2 x 10(7) NK-92 cells i.p.; one dose or five doses ). Survival times of SCID mice bearing the sensitive TA27 and MA26 leu kemias were significantly prolonged by adoptive cell therapy with NK-9 2 cells. Some of the animals who received five doses of NK-92 cells wi th or without rhIL2 administration were still alive without any signs of leukemia development 6 months after leukemia inoculation. In contra st, survival of mice bearing the insensitive BA31 leukemia were not af fected by this treatment. This in vitro and in vivo antileukemia effec t of NK-92 cells suggests that cytotoxic NK cells of this type may hav e potential as effecters of leukemia control.