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Chimeric receptor mRNA transfection as a tool to generate antineoplastic lymphocytes
- Source :
- Human gene therapy. 20(1)
- Publication Year :
- 2008
-
Abstract
- mRNA transfection is a useful approach for temporal cell reprogramming with minimal risk of transgene-mediated mutagenesis. We applied this to redirect lymphocyte cytotoxicity toward malignant cells. Using the chimeric immune receptor (CIR) constructs anti-CD19 CIR and 8H9 CIR, we achieved uniform expression of CIRs on virtually the entire population of lymphocytes. We reprogrammed CD3+ CD8+, CD3+ CD4+, and natural killer (NK ) cells toward autologous and allogeneic targets such as B cells, Daudi lymphoma, primary melanoma, breast ductal carcinoma, breast adenocarcinoma, and rhabdomyosarcoma. The reprogramming procedure is fast. Although most of the experiments were performed on lymphocytes obtained after 7-day activation, only 1-day activation of T cells with anti-CD3, anti-CD28 antibodies, and interleukin-2 is sufficient to develop both lymphocyte cytotoxicity and competence for mRNA transfer. The entire procedure, which includes lymphocyte activation and reprogramming, can be completed in 2 days. The efficiency of mRNA-modified human T cells was tested in a murine xenograft model. Human CD3+CD8+ lymphocytes expressing anti-CD19 CIR mRNA inhibited Daudi lymphoma growth in NOD/SCID mice. These results demonstrate that a mixed population of cytotoxic lymphocytes, including T cells together with NK cells, can be quickly and simultaneously reprogrammed by mRNA against autologous malignancies. With relatively minor modifications the described method of lymphocyte reprogramming can be scaled up for cancer therapy.
- Subjects :
- Cytotoxicity, Immunologic
Lymphoma
Lymphocyte
CD3
Recombinant Fusion Proteins
T-Lymphocytes
Antigens, CD19
Immune receptor
Mice, SCID
Biology
Lymphocyte Activation
Transfection
Mice
Antigen
Mice, Inbred NOD
medicine
Genetics
Scientific Papers
Animals
Humans
RNA, Messenger
Transgenes
Receptors, Immunologic
Cytotoxicity
Molecular Biology
Molecular biology
Xenograft Model Antitumor Assays
medicine.anatomical_structure
biology.protein
Molecular Medicine
Female
Reprogramming
CD8
Subjects
Details
- ISSN :
- 15577422
- Volume :
- 20
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Human gene therapy
- Accession number :
- edsair.doi.dedup.....56e6e95f70ba33b384ef8b1ea4271862