Drug – bio-affecting and body treating compositions – Whole live micro-organism – cell – or virus containing – Genetically modified micro-organism – cell – or virus
Patent
1997-11-14
1999-08-10
Hutzell, Paula K.
Drug, bio-affecting and body treating compositions
Whole live micro-organism, cell, or virus containing
Genetically modified micro-organism, cell, or virus
435325, 4353201, 435 6952, 424 933, 4242771, 424 852, A01N 6300, C12N 1585, C12N 1563
Patent
active
059355697
DESCRIPTION:
BRIEF SUMMARY
The objective of the invention is genetic anticancer vaccine for gene therapy of human neoplastic diseases particularly malignant melanoma.
Concept of so called genetic cellular vaccines is based on genetic modification of autologous (patient's own) or antigenetically related (allogeneic) cancer cells in order to activate patient's imnmunologic system to eliminate cancer. Autologous (obtained from each patient to be treated) and/or allogeneic (established cancer cell lines) genetically modified cancer cells are irradiated and injected subcutaneously to the patient. Until now cancer (autologous or allogeneic) cells in order to provide costimulatory signal for patient's own immune system have been genetically modified by insertion of various genes encoding: interleukin Immunization with Interleukin-2 Transfected Melanoma Cells. A Phase I-II Study in Patients with Metastatic Melanoma. Human Gene Therapy, 4:323-330, 1993. Fibroblasts Admixed with Autologous Tumor to Elicit an Immune Response. Human Gene Therapy, 5:41-56, 1994. Colon Carcinoma, Renal Cell Carcinoma, Melanoma or Lymphoma. Human Gene Therapy 5:1161-1168, 1994. Cells Modified by Insertion of the Gene for Tumor Necrosis Factor (TNF). Human Gene Therapy, 3:57-73, 1991. Autologous Tumor Cells in Patients with Disseminated Malignant Melanoma. Human Gene Therapy, 5:761-773, 1994. for producing immunomolecule--interleukin 2, interferon gamma, colony stimulating factor, adhesion molecule, tumor-associated antigen, etc., antisense RNA expression by packaging cell culture for eg tumor gene therapy.
The objective of the invention is genetic modification of human malignant melanoma cell line which is HLA-A1 and HLA-A2 positive by introduction into the cells two genes (cDNA) coding human IL-6 and soluble IL-6 receptor (sIL-6R).
SIL-6R was constructed by replacement of cytoplasmic and transmembrane domains of the membrane receptor by translational stop codon using polymerase chain reaction (PCR). Moreover, signal peptide was replaced by translational start codon ATG using PCR and introducing methionine as a first aminoacid of sIL-6R.
Another objective of the invention is a vaccine containing autologous cancer cells and genetically modified allogeneic cancer cells. Combination of autologous and allogeneic cells will increase immunogenicity and effectiveness of the vaccine. In this variant of the vaccine autologous cells do not require genetic modification. Products of introduced genes will be supplied by allogeneic cells and their biological effect will be provided by "by stander effect".
EXAMPLES OF APPLICATION OF THE INVENTION
metastatic focus will be surgically excised. Obtained tissue will be minced, cells enzymatically isolated and either frozen in liquid nitrogen or cultured in vitro in typical conditions. After obtaining in culture required number of cells they will be mixed (1:1) with genetically modified allogeneic cells. If propagation of autologous cells in vitro will not be possible cells frozen in liquid nitrogen will be thawed and used. Then the mixture (5.times.10.sup.7 cells per injection) will be irradiated using a total dose of 100 Gy and subcutanousely administered to the patient. Four injections will be administered in two weeks intervals followed by three injections once a month. If necessary injections will be continued in two months intervals. due to the advancement of the disease or localization of lesions. In such cases allogeneic vaccine will be applied. Genetically modified cells (5.times.10.sup.7) will be irradiated and administered as described above.
1. Genetic anticancer vaccine, comprising with two genes (cDNA), one encoding interleukin 6 (IL-6), and the other encoding interleukin 6 soluble receptor (sIL-6R), while content of allogeneic cells cannot be lower than 50% and cannot exceed 70%.
DESCRIPTION
EXAMPLES OF APPLICATION OF THE INVENTION
metastatic focus will be surgically excised. Obtained tissue will be minced, cells enzymatically isolated and either frozen in liquid nitrogen or cultured in vitro in typical conditions.
Mackiewicz Andrzej
Rose-John Stefan
Akademia Medyczna IM. K. Marcinkowskiego
Bansal Geetha P.
Hutzell Paula K.
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