Drug – bio-affecting and body treating compositions – Lymphokine
Patent
1989-12-28
1993-12-28
Wityshyn, Michael G.
Drug, bio-affecting and body treating compositions
Lymphokine
424 88, 4352351, 435236, 435237, 435239, A61K 3912, C12N 700
Patent
active
052737454
DESCRIPTION:
BRIEF SUMMARY
The invention relates to the preparation of virus-modified tumour-vaccines, and their use in immunotherapy of tumour metastases.
Even after extensive removal of the primary tumour it is still a problem to prevent the formation of metastases either due to growing out of micrometastases already present at the time of surgery, or to the formation of new metastases by tumour cells sown out during the operation.
In addition to classical chemotherapeutic approaches, more recently it has been tried to activate the patient's own immune-system such that it prevents the formation of micrometastases or eliminates metastases already formed, resp., by the formation of T killer cells which are as tumour-specific as possible. So called oncolysates, i.e. lysates of tumour cells, mostly from tumour cell-lines, have been used for the immunization of the patient with varying success. In doing this the problem arises that such cell lysates, which, in addition, are usually not isolated from the actual tumour cells, but from tumour cell-lines grown in cell culture, are not sufficiently immunogenic, and therefore do not lead to sufficient stimulation of the immune defence of the patients as to effectively prevent the formation of metastases.
It was now the object of the present invention to prepare tumour-specific vaccines improved with respect to their immunogenicity and tumour-specificity, which upon active immunization can selectively induce a specific immune response in the immune system of the patient, and thereby build a systemic immunity against tumour metastases, as well as to use such vaccines in the therapy of malignant tumours.
It can be assumed that tumour-specific immune T lymphocytes, when they are present, only occur at low frequency among the lymphocytes, because the antigenicity and immunogenicity of tumour antigens is generally only weak. In an animal model studied the frequency of such cells is only one in 15 000 spleen lymphocytes. These tumours-specific cells are usually not fully activated in tumour-bearing animals, and need additional activation signals.
It was now found that the activation of the immune system can be crucially improved by combining a specific and an unspecific immunogenic component. The specific component in this case is represented by the autologous tumour cells isolated from the resected tumour by mechanical and enzymatical methods. The unspecific component is represented by a virus, in particular Newcastle Disease Virus (NDV), contributing to the activation of an inflammatory reaction. NDV is suited for this purpose, because it is a good activator of interferon, and, according to studies, can activate tumour-specific T cells. Moreover, the virus is also particularily well tolerated.
To prepare the vaccine the virus is incubated with irradiated tumour cells, which leads to adsorption of the virus to the tumour cells. The virus-modified tumour cells are inactivated by irradiation, so they cannot grow out as tumours, and are then used as a vaccine. By immunization with this vaccine, sensitized tumour-specific T cells are meant to be activated selectively in situ, and these cells, circulating in the blood and in the lymph, are to be used for a systemic therapy against micrometastases. After intradermal vaccination with such a vaccine, it is intended in the first place to trigger a cutaneous reaction of the delayed type. This reaction, which is specific for cellular immune reactions, indicates that a specific antigen has been recognized, and has resulted in an inflammatory reaction at the site of the vaccination. This could be confirmed by experiments. Due to the presence of the corresponding antigen, the tumour-specific T cells are to be concentrated at the site of the vaccination, and activated to become cytotoxic T lymphocytes with the help of additional activation signals mediated by the virus. When the activated tumour-specific T cells come back in circulation again, i.e. into the blood and into the lymphatic system, they are able to migrate into the organs, and there they can exert th
REFERENCES:
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Schirrmacher et al., in Cancer Metastasis, Schirrmacher et al., Eds., Springer-Verlag, Berlin, pp. 157-170, 1989.
Schirrmacher et al., Clin. Expl. Metastasis, vol. 5, No. 2, pp. 147-156, 1986.
"Prevention of Metastatic Spread by Postoperative Immunotherapy with Virally Modified Autologous Tumor Cells. I. Parameters for Optimal Therapeutic Effects", R. Heicappell et al., Int. J. Cancer, 37, 569-577 (1986).
"Modification of Tumor Cells by a Low Dose of Newcastle Disease Virus. Augmentation of the Tumor-Specific T Cell Response in the Absence of an Anti-Viral Response", Paul Von Hoegen et al., Eur. J. Immunol., 18, 1159-1166 (1988).
"Natural Killer Cell Cytotoxic Potential of Patients with Ovarian Carcinoma and its Modulation with Virus-Modified Tumor Cell Extract", Eva Lotzova et al., Cancer Immunol Immunother, 17, 124-129 (1984).
Mohamed Abdel A.
Schirrmacher Volker R.
Wityshyn Michael G.
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