Developing a novel therapeutic vaccine combining IL-10 inhibitor for late stage cancers with targeted Clostridial spore oncolysis of the tumour microenvironment

Background: Cancer is a class of diseases characterised by uncontrolled proliferation of cells. Cancer represents as a major public health problem accounting for approximately 8.8 million deaths each year worldwide. Current treatments include surgical removal of tumour mass, chemotherapy, radiotherapy, or a combination of these therapies. Often these options result in side effects that can be quite detrimental to the patients. Therefore, new treatments are urgently needed. Cancer therapeutic vaccines are aiming at killing tumour cells without affecting normal cells. Vaccine induced cytotoxic T lymphocyte (CTL) responses are pivotal for the killing tumour cells. Interleukin 10 (IL-10) is a cytokine with multiple biological functions. Blocking IL-10 signalling with an anti-IL-10 receptor antibody at the time of immunisation drastically increases vaccine induced immune responses and prevents tumour growth in animal models. However, it is not clear whether there are unwanted side effects with such a blockade, and no clinical grade IL-10 inhibitor for human is available. Advanced cancers show a significant increase in angiogenesis resulting in the formation of abnormal blood vessels, which restrict blood supply and result in reduced oxygen levels within the cancer. Therefore, some areas of the late stage tumour are hypoxic and necrotic. Also, the solid tumour microenvironment (TME) is immunosuppressive. Our laboratory has developed an anaerobic Clostridium ghonii strain. When these clostridial spores are administered and regerminated in hypoxic and necrotic cancer central region, they cause significant oncolysis, leading to tumour regression in animal models. The oncolytic activity may also destroy the TME. Hypothesis and Aims: The hypothesis of the project is (1) Blocking IL-10 at the time of immunisation should increase vaccine induced T cell responses without eliciting unwanted side effects; (2) Humanised and active IL-10 inhibitors could be designed by using computerised programs; (3) Clostridial spores induce ...