Korean J Lab Med.  2009 Apr;29(2):89-96. 10.3343/kjlm.2009.29.2.89.

Expansion and Activation of Natural Killer Cells for Cancer Immunotherapy

• Cho D
• Campana D

• KMID: 854962
• DOI: http://doi.org/10.3343/kjlm.2009.29.2.89

Abstract

Natural killer (NK) cells can kill a wide range of cancer cells and are a promising tool for cell therapy of cancer. NK cells cytotoxicity is regulated by a balance between stimulatory and inhibitory signals. Interleukin-2 is known to increase NK cell cytotoxicity. Although many cytokines have been studied in efforts to induce durable NK cell expansions, most reports indicate a rather modest effect and the requirement for additional stimuli. We found that contact with the K562 myeloid leukemia cell line, genetically modified to express a membrane-bound form of interleukin-15 and the ligand for the costimulatory molecule 4-1BB, induced vigorous expansion of NK cells from peripheral blood. Based on these findings, we developed a method for large-scale clinical-grade expansion of NK cells. This method is currently used to expand allogeneic NK cells for infusion in patients with leukemia and solid tumors. We here summarize methods for expansion and activation of NK cells from human peripheral blood mononuclear cells as well as clinical-scale methods to produce NK cells for immunotherapy under Current Good Manufacturing Practices (cGMP) conditions.

Keyword

NK cells; Cell therapy; Acute myeloid leukemia; Acute lymphoblastic leukemia; Chimeric receptors

MeSH Terms

Humans
Immunotherapy
Interleukin-2/pharmacology
Killer Cells, Natural/immunology/*transplantation
Leukemia, Myeloid, Acute/therapy
Neoplasms/immunology/*therapy
Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy

Figure

• 

  Fig. 1. Schematic representation of protocols using expanded NK cells at St Jude Children's Research Hospital. The leukapheresis product obtained from a haploidentical donor is mixed with irradiated K562-mb15-41BBL cells. After 7 days of culture, most cells recovered are activated NK cells. After T-cell depletion using the CliniMACS system, NK cells are infused in patients with NK-sensitive malignancies such as acute myeloid leukemia (AML), Ewing sarcoma or rhabdomyosarcoma. For patients whose neoplasia is less sensitive to NK cytotoxicity, such as B-lineage acute lymphoblastic leukemia (ALL) or B-cell non-Hodgkin lymphoma (B-NHL), expanded NK cells are transduced with an anti-CD19 chi-meric receptor before infusion.

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