A clinically adaptable method to enhance the cytotoxicity of natural killer cells against B-cell malignancies.
Cytotherapy
; 14(7): 830-40, 2012 Aug.
Article
en En
| MEDLINE
| ID: mdl-22458956
ABSTRACT
BACKGROUND AIMS:
Retroviral transduction of anti-CD19 chimeric antigen receptors significantly enhances the cytotoxicity of natural killer (NK) cells against B-cell malignancies. We aimed to validate a more practical, affordable and safe method for this purpose.METHODS:
We tested the expression of a receptor containing CD3ζ and 4-1BB signaling molecules (anti-CD19-BB-ζ) in human NK cells after electroporation with the corresponding mRNA using a clinical-grade electroporator. The cytotoxic capacity of the transfected NK cells was tested in vitro and in a mouse model of leukemia.RESULTS:
Median anti-CD19-BB-ζ expression 24 h after electroporation was 40.3% in freshly purified (n =18) and 61.3% in expanded (n = 31) NK cells; median cell viability was 90%. NK cells expressing anti-CD19-BB-ζ secreted interferon (IFN)-γ in response to CD19-positive target cells and had increased cytotoxicity. Receptor expression was detectable 6 h after electroporation, reaching maximum levels at 24-48 h; specific anti-CD19 cytotoxicity was observed at 96 h. Levels of expression and cytotoxicities were comparable with those achieved by retroviral transduction. A large-scale protocol was developed and applied to expanded NK cells (median NK cell number 2.5 × 10(8), n = 12). Median receptor expression after 24 h was 82.0%; NK cells transfected under these conditions exerted considerable cytotoxicity in xenograft models of B-cell leukemia.CONCLUSIONS:
The method described here represents a practical way to augment the cytotoxicity of NK cells against B-cell malignancies. It has the potential to be extended to other targets beyond CD19 and should facilitate the clinical use of redirected NK cells for cancer therapy.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Linfoma no Hodgkin
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Células Asesinas Naturales
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Antígenos CD19
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Leucemia-Linfoma Linfoblástico de Células Precursoras
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Tratamiento Basado en Trasplante de Células y Tejidos
Tipo de estudio:
Guideline
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Prognostic_studies
Límite:
Animals
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Humans
Idioma:
En
Año:
2012
Tipo del documento:
Article