A murine model of B-cell lymphoma, manipulation of costimulatory and cytokine expression to generate effective immunotherapeutic cancer vaccines

grantor: University of TorontoAdvances in fundamental immunological principles have fueled excitement in the area of cancer immunotherapy. Manipulation of molecules important in the recognition and activation of various effector cells within the immune system provides a strategy by which tumour cells may become more immunogenic. The proceeding research describes the development of a murine model for B-cell lymphoma using a non immunogenic, highly tumourigenic cell line, A20. Subcutaneous injection of live A20 cells results in tumour growth in 100% of inoculated syngeneic BALB/c mice. By introducing the costimulatory molecule, B7-1, and the cytokine interleukin-12 (IL-12), a potent whole-cell vaccine was generated, allowing for systemic protection against modified as well as parental tumour cells. Although interleukin-12 was effective in a vaccination model, only the B7-1/IL-12 combination was effective in preventing tumour growth in an established tumour model. ' In vitro' and 'in vivo' experiments show that the mechanism by which IL-12 or B7-1/IL-12 mediate anti-tumour immune responses are multifactorial. CD4+ and CD8+ T cells, as well as natural killer cells contribute to the observed anti-tumour immunity. The second modality used to generate an effective immune response is the manipulation of the level of expression of the costimulatory molecule B7-2. Although, the A20 cell line expresses MHC I, MHC II, and B7-2, the immune system is not activated effectively to generate anti-tumour immunity. The proceeding studies show that the level of expression of B7-2 is critical in the activation of anti-tumour responses. By increasing the level of B7-2 above a threshold, the A20 cell line becomes an immunogenic tumour capable of eliciting effective cytotoxic T cell as well as natural killer cell responses.Ph.D