Last updated on April 2019

Natural Killer Cells in Acute Leukaemia and Myelodysplastic Syndrome


Brief description of study

A novel method has been developed to expand natural (NK) cells and enhance their cytotoxicity against cancer cells while maintaining low killing capacity against non-transformed cells. In this method, donor NK cells are expanded by co-culture with the irradiated K562 cell line modified to express membrane bound IL-15 and 41BB ligand (K562-mb15-41BBL). Expression of these proteins in conjunction with unknown stimuli provided by K562 cells promotes selective growth of NK cells. Then, the expanded NK cell population is depleted of T cells to prevent graft versus host disease (GVHD). Expanded and activated NK cells showed powerful anti-leukemic activity against acute myeloid leukemia (AML) cells in vitro and in animal models of leukemia.Unpublished laboratory results also demonstrated that T-cell acute lymphoblastic leukaemia (T-ALL) is extremely sensitive to the cytotoxicity exerted by the expanded and activated NK cells.

The present study represents the translation of the laboratory findings into clinical application. The study proposes to determine the feasibility, safety and efficacy of infusing expanded NK cells into patients who have AML or T-lineage ALL which is resistant to standard therapy as demonstrated by persistent minimal residual disease (MRD). Patients with myelodysplastic syndrome (MDS), who are at high risk to develop AML will also be eligible for the study. In this patient cohort, the study will also investigate the in vivo lifespan and phenotype of the expanded NK cells.

The main hypothesis to be tested in this study is that infusion of expanded activated NK cells can produce measurable clinical responses in patients with AML or T-ALL.

Detailed Study Description

The study will enroll 20 eligible subjects who will receive NK cell infusion to test whether infusion of expanded activated NK cells can produce measurable clinical responses in patients with AML/MDS or T-ALL.The study aims to infuse a target dose of 10 x 107 CD56+ cells/kg, however, as the actual cell dose obtained will vary depending on the donor harvest, the accepted range for cell infusion will be 0.5-20 x 107 CD56+ cells/kg. On day -10, eligible donors (adult family member of recipient) will undergo apheresis once. A second apheresis procedure may be needed to obtain the required cell count from the donor. NK cells will be expanded in co-culture with irradiated (100 Gy) K562-mb15-41BBL cells in closed culture containers for 10 days. Prior to NK cell infusion on Day 0, recipients will undergo screening evaluations and will receive cyclophosphamide, Fludarabine, IL-2, and supportive medications (e.g. mesna). Cytokine regimen of IL-2 will be initiated on the evening of day -1 (dose 1 of 6). IL-2 will be continued at a dose of 1 million units/m2 subcutaneously 3 times per week for 2 weeks (6 doses total). Post-infusion follow-up procedures for up to 1 year from the day of NK cell infusion include physical examination, Complete Blood Count, and metabolic/chemistry studies. The effects of NK cell infusion will also be determined by comparing MRD levels before and after treatment. MRD blood and bone marrow levels will be collected at baseline and at specified time points (until 1 year from the day of NK cell infusion). NK cell donors will be recruited from the family members of the patient recipient. Potential donors aged 21 years old will be consented and will undergo the required screening tests and human leukocyte antigen (HLA) typing. Since 20 eligible subjects will be enrolled as NK cell recipients, 20 donors will also be recruited for this study. Ineligible NK cell donors will have to be replaced.

Clinical Study Identifier: NCT02123836

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