Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Bacterium or component thereof or substance produced by said...
Patent
1996-10-25
2000-05-02
Goldberg, Jerome D.
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Bacterium or component thereof or substance produced by said...
A61K 3904
Patent
active
060569646
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/6B95/00715 filed Mar. 29, 1995.
This invention relates to immunotherapeutic agents useful in delaying or preventing the growth of tumours.
It has been suggested that the immune system is capable of preventing or delaying the growth of tumours at least in some cases, and some studies have tended to support this view. Thus Coley (W.B. 1894 "Treatment of Inoperable Malignant Tumours with toxins of erysipelas and the bacillus prodigiosus") described an immunotherapeutic method which appeared to be effective against a restricted range of tumours of mesodermal origin, by inducing a necrotizing mechanism similar to that induced by Koch's immunotherapy against tuberculosis. Since that time, most attempts at immunotherapy for cancer have aimed at inducing rapid tissue necrosis similar to that achieved in some cases by Coley.
It is known that there are at least 2 patterns of maturation of helper T cells, called TH1 and TH2. The former is associated with production of interleukin 2 (IL2), gamma interferon (IFN-.gamma.), cytotoxic T cells (CTLs), reduced antibody production and down-regulation of production of TH2 cells. The latter produce IL4, IL5, enhance antibody production and down-regulate TH1 cells. The Koch phenomenon, probably induced by Coley's toxin, is thought to be the result of a mixture of TH1+TH2 matured cells.
It has been found that there are two categories of immune reactivity that can be harnessed for the control of tumours, and both can be evoked by Bacillus Calmette-Guerin vaccine (BCG). One is mechanism is tissue-destructive, as exemplified by Koch's and Coley's immunotherapies and by tumour immunotherapy with TNF.alpha., and probably involves cytokine-mediated tissue damage in inflammatory sites appropriately prepared by the T cell-dependent Koch phenomenon. This mechanism appears to be effective against tumours of mesodermal origin. The second mechanism, based on immune recognition of the tumour cells themselves, might be effective against tumours of any origin. Indirect evidence for the existence of a non-specific TH1 based antitumour mechanism comes from the success of recombinant interleukin 12, a powerful TH1 inducer, in experimental cancers.
It is thought that Mycobacteria, if used in a way that avoids the induction of the Koch phenomenon, may be able to prime recognition of stressed autologous cells via heat shock protein (HSP) epitopes and epitopes of other proteins with highly conserved sequences, and so lead to selective tumour cell destruction. We conclude that the variable efficacy of BCG immunotherapy in the past was due to a failure to realise that BCG tends to boost the pattern of response already primed, as is emerging from studies of its efficacy in protection against tuberculosis and leprosy.
BCG as a vaccine against mycobacterial disease (both tuberculosis and leprosy) is very variable, giving anything from 80% protection to 0% protection in different studies. It is therefore significant that BCG given at birth appears in general to protect against childhood leukaemias only in those geographical locations where it protects against tuberculosis (Grange J M, Stanford J L. BCG vaccination and cancer. Tubercle. (1990); 71: 61-64). That is to say, it protects against both conditions in those places where it evokes a response to mycobacterial antigens that is not tissue-necrotising, and is not the Koch phenomenon.
Many tumour cells may present on their surfaces bacteriomimetic, carbohydrate, antigens and epitopes of stress proteins and other highly conserved proteins in relation to class 1 and class 2 major histocompatibility complex (MHC). Under circumstances of high antibody production, anti-carbohydrate antibodies originally raised against bacterial sugars, and perhaps IgA in type, could cover the tumour cells and block their surface components from cellular immune attack.
As we have shown in our International Application PCT/GB93/00463, immunotherapy with M. vaccae induces a predominantly TH1 pattern of response with macrophage activation by IFN-.
REFERENCES:
International Journal of Immunopharmacology, vol. 7, No. 4, 1985 Aberdeen GB, pp. 515-524, Luisa MO (Moras et al).
Rook Graham Arthur William
Stanford John Lawson
Goldberg Jerome D.
Stanford Rook Limited
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