Developing Immunotherapy Strategies for Cancer Treatment

Linardakis, Emmanouela (2003). Developing Immunotherapy Strategies for Cancer Treatment. PhD thesis The Open University.



The goal of this thesis was to develop potent tumour cell vaccines that can be used as an effective strategy for cancer treatment. Allogeneic tumour cell vaccines hold great promise for cancer treatment. Cytokine modification has been proven effective in enhancing the immunogenicity of tumour cell vaccines. This work here shows that modification of the allogeneic K1735 cells to express the immunostimulatory cytokines GM-CSF, IL-12 or IFN-ɣ, however, was not effective in augmenting the immunogenicity of the vaccine and irradiated cytokine-modified vaccines could not protect animals from autologous tumour challenge. These data are in agreement with recent literature. Similar results were obtained when K1735 cells were modified to express heat shock proteins. Analysis of the injection site of irradiated K1735 vaccine cells demonstrated that clearance of the K1735 cells from the injection site correlated well with the induction of proinflammatory cytokines and infiltration by non-specific effector cells such as NK cells.

FMG-induced fusion was next investigated as a novel and effective way of releasing tumour antigens from allogeneic vaccine cells in an immunostimulatory fashion. Expression of the Vesicular Stomatitis Virus G glycoprotein by K1735 or B16 cells lead to the formation of extensive syncytia in vitro. Vaccination of mice with irradiated 2-day fusing allogeneic K1735 or syngeneic B16 cells showed no significant therapeutic benefit relative to irradiated unfused cells. Interestingly, vaccination of mice with a hybrid K1735/B16 fusing vaccine repeatedly lead to significant protective and therapeutic immunity against a B16 challenge. Overall, VSV-G mediated syncitial death was shown to be a highly immunogenic event that promotes the induction of potent specific antitumour immunity in the context of allogeneic vaccines. The mechanism of immunogenicity of fusing hybrid vaccines was investigated.

Generation of long-term human allogeneic fusing tumour cell vaccines for translation of this work into clinical application was next investigated. A human melanoma cell line stably transduced with the gene for a hyperfusogenic form of the Gibbon ape leukemia virus FMG gene was generated. The Tet-On system of transcriptional control was employed to control gene expression and thus GALV-mediated fusion. Very high levels of fusion could be obtained following the addition of doxocycline in culture. This cell line could form the basis of human melanoma fusing vaccine.

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