Corynebacterium parvum treatment in normal and tumour bearing hosts

Corynebacterium Parvum is an anaerobic diphtherioid bacterium which suppresses the rate of development and spread of a wide variety of transplantable rodent tumours. It has also been suggested that the bacterium might be of therapeutic benefit to humans suffering from cancer. The experimental work of this thesis discusses some of the effects of C. Parvum on mononuclear phagocyte cells both in normal rats, and rats bearing carcinogen induced cancers of the colon. Particular attention has been paid to this class of cells since it is considered that they are the mediators of the anti tumour effects of the bacterium. In addition, the results of two clinical trials reporting the results of C. Parvum in the treatment of post operative human cancers are presented. Experimental Work The dose of C. Parvum used in the experimental work was calculated from preliminary experiments. C. Parvum was given to adult female Wistar Rats by a variety of routes at different dose rates. Stimulation of the reticuloendothelial system was assessed by measurements of the resulting splenomegaly. It was considered that the optimum dose calculated by this work would also cause stimulation of mononuclear phagocytes. An experimental rat model has been described at the Sir William Dunn School of Pathology in Oxford which enables the continuous collection of effluent gut lymph containing mononuclear phagocytes. It is argued that these cells represent tissue mononuclear phagocytes and lymph collected in this way enables a dynamic assessment of cell traffic in the gut wall. A dose of C. Parvum which caused marked reticuloendothelial stimulation had no measured effect on these gut associated mononuclear cells nor on cells showing the capacity to ingest antibody coated sheep red blood cells. These studies were repeated in rats bearing small colonic cancers induced by dimethylhydrazine. Once again the dose of C. Parvum which was given had no effect on gut associated mononuclear cells or phagocytes. However, the numbers of phagocytic cells were markedly suppressed in all of the tumour bearing rats, whether or not they had been treated with C. Parvum. Since the dose of C. Parvum caused splenomegaly but had no effects on mononuclear phagocytes in effluent gut lymph, other effects of this treatment were studied. The dose of C. Parvum which was used caused; 1. Blood changes : an immediate lymphocytopaenia with a concomittant granulocytosis in peripheral blood. Subsequently the granulocyte level returned to normal levels but the lymphocytes showed a small, but significant increase above the original value by two weeks after treatment. Monocyte numbers in the peripheral blood were not affected. 2. Peritoneal exudates and splenic macerates : esterase positive and phagocytic cells obtained from both of these sources showed a fall one week after treatment followed by a rise by two weeks. 3. Histological changes : there was a marked increase in the area of the white pulp, and probably also the red pulp of the spleen. Both the spleen and caecal lymph nodes showed histological evidence of stimulation of the reticuloendothelial system. It had been hoped to identify tissue macrophages using acid phosphatase, glucuronidase and non specific esterase staining techniques. However, it was not possible to assess post treatment changes by this method. Clinical Two clinical trials are reported describing the use of C. Parvum in the adjuvant treatment of two common human cancers. In the first of these, the bacterium was given in a small intradermal dose along with an inoculum of autologous irradiated tumour cells to post operative patients after resection of Stage 1 and 2 lung cancer. In this trial an attempt was made to stimulate specific immunity against residual tumour cells. In the second trial C. Parvum was given by serial intravenous injections to patients who had undergone resection of Dukes stage B & C colorectal cancers. This approach attempted to non specifically stimulate the reticuloendothelial system with the aim of increasing the destruction of residual tumour cells by "activated" mononuclear phagocytes. In each trial nearly 100 patients were included with an equal distribution between the treatment and the control groups. It was apparent that the median times to recurrence or death were not influenced by the treatment in either trial. Considerable enthusiasm for the use of bacteria in the treatment of human cancers was generated in the early 1970's. This followed reports of improved remission rates notably after the use of B.C.G. in the treatment of acute lymphoblastic leukaemia and malignant melanoma. Carefully constructed clinical trials have failed to support the continued use of this kind of treatment. Both the experimental and clinical work described in this thesis suggest that immune stimulation mediated by bacteria will not provide an easy answer to the treatment of human malignant disease