Drug – bio-affecting and body treating compositions – Whole live micro-organism – cell – or virus containing – Genetically modified micro-organism – cell – or virus
Patent
1997-05-20
2000-03-21
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
424 937, 514 44, 4353201, 435325, A01N 6300, A61K 4800, C12N 1563, C12N 1585
Patent
active
060399414
DESCRIPTION:
BRIEF SUMMARY
DESCRIPTION
The invention concerns a live vaccine against tumour diseases, its production and its use. Fields of application are medicine and genetic engineering.
Vaccines against tumour diseases have been known for a long time. The classical vaccines that have been used very often clinically are composed of a mixture of irradiated tumour cells and adjuvants such as for example lysates of Bacillus Calmette-Guerin (BCG) or Corynebacterium parvum. After two decades of clinical evaluation it may be summarized that these vaccines do not have a reproducible effect (cf review article: Oettgen, H. and Old, L., The History of Cancer Immunotherapy, in: Biological Therapy of Cancer, Eds. V. deVita, S. Hellman and S. Rosenberg, J. B. Lippincott Company 1991, p. 87-119). Recent results from animal models have shown that the transfer and expression of some cytokine genes (e.g. IL2, IL4, IL7, TNF, IFN.gamma.) can suppress the growth of gene-modified tumour cells in vivo but not in vitro. This inhibition of the tumour growth is the result of an immune response induced by the transfected cytokine. In many cases the gene-transfected tumour is completely rejected (cf. review article: Blankenstein, Eur. J. Cancer, 1994, in press). In a similar manner the expression of the B7 molecule a cell surface protein with costimulatory activity for T-lymphocytes, can inhibit tumour growth. However, the therapeutically important question is whether the rejection of the gene-transfected tumour leads to a long-term persistent immunological memory for the tumour cells. This would be recognized by the fact that animals that had rejected the gene-transfected tumour could later also reject tumour cells that had not been administered by gene transfection. This is also the case to a limited extent and at present several clinical studies are being carried out based on this finding in which irradiated tumour cells provided with a single cytokine gene are being used as vaccines (cf review article: Tepper, R. and Mule, J., 1994 Hum. Gene Therapy 5, 153-164). These studies are referred to as gene therapy studies.
A virus-modified, tumour-specific vaccine is described in DE-OS 38 06 565 which is composed of tumour cells from an operation preparation of a patient who was to be treated later which have been inactivated by irradiation and with NDV virus under sterile conditions. The application of this vaccine was improved according to DE-OS 39 22 444 by using it together with systemically administered cytokines and optionally with haematopoesis-stimulating factors and/or antisuppressive agents.
A disadvantage of the previously used vaccines is their low effectivity. This assertion is based on the one hand on one of the earlier findings that have shown that the vaccine effect of a tumour cell transfected with a single cytokine gene is no better than that which can be achieved by a tumour cell/adjuvant mixture (Hock et al., 1993, Cancer Res. 53, 714-716). As mentioned above tumour cell/adjuvant mixtures have been shown clinically to be not effective. On the other hand neither the expression of a single cytokine nor the expression of the B7 molecule alone leads to a reliable rejection of the tumour. I.e. a certain percentage of the mice which have been injected with gene transfected cells develop a tumour after a latency period which is often associated with loss of the cytokine production (Hock et al., 1993, PNAS 90, 2774-2778). This prohibits tumour cells which have been transfected with a single gene coding for immuno-stimulatory activity from being used as live tumour cell vaccines.
The object of the invention is to eliminate the disadvantages of the known vaccines i.e. their inadequate effectiveness together with the necessity of having to inject tumour cells that are incapable of proliferation. It is intended to develop a live vaccine by genetic engineering which stimulates the immune system towards tumour cells that are already in the body.
This object is achieved by a vaccine according to claim 1; the subclaims are preferred variants.
It is produ
REFERENCES:
A. Porgador et al., Natural Immunity, "Immunotherapy of Tumor Metastasis Via Gene Therapy", Mar. 1994 & May 1994, pp. 113-130, vol. 13, Nr 2-3.
R. Costello et al., Immunology, "Interleukin-7 is a Potent Co-stimulus of the Adhesion Pathway Involving CD2 and CD28 Molecules", Nov. 1993, pp. 451-457, vol. 80, Nr. 3.
L. Chen et al., Cell, "Immunotheraphy of Tumor Metastasis Via Gene Therapy", Dec. 24, 1992, pp. 1093-1102, vol. 71.
A. Belldegrun et al. Journal of the National Cancer Institute, "Human Renal Carcinoma Line Transfected With Interleukin-2 and/or Interferon Alpha Gene(s): Implications for Live Cancer Vaccines", Feb. 3, 1993 pp. 207-216, vol. 85, Nr 3.
D. Pardoll, Current Opinion in Immunology, "New Strategies for Active Immunotherapy with Genetically Engineered Tumor Cells", Dec. 1992, pp. 619-623, vol. 4, Nr. 6.
S. Cayeux et al. European Journal of Immunology, "Tumor Cells Co-transfected with Interleukin-7 and B7.1 Genes Induce CD25 and CD28 on Tumor-infiltrating T Lymphocytes and are Strong Vaccines", Aug. 1995, pp. 2325-2331, vol. 25, Nr. 8.
S. Cayeux et al., Immunobiology, "Analysis of the Vaccination-efficiency of Cytokine/B7-transfected Tumor Cells", Sep. 1994, pp. 208-209, vol. 191, Nr. 2-3.
Blankenstein Thomas
Cayeux-Pezzutto Sophie
Bansal Geetha P.
Hutzell Paula K.
Max-Delbruck-Centrum Fur Molekulare Medizin
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