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Date of Award

8-1998

Degree Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

Department

Medical Sciences

Supervisor

Dr. Jack Gauldie

Abstract

Many tumors express antigens that are capable of being recognized by effector cells of the immune system. However, these tumors persist in immunocompetent hosts. The mechanism by which immune effector cells are rendered unresponsive to these antigens is unknown. Previous data from our laboratory demonstrated the use of adenoviral vectors constructed to express single cytokines (IL-2 and IL-12) in mediating regression of tumors in a mouse mammary adenocarcinoma model. The ability of these molecules to enhance the immune response to effectively regress these tumors was hampered by toxicities associated with these factors. To over come this toxicity and enhance the efficacy of IL-2, double recombinant adenoviral vectors expressing the co-stimulatory molecules B7-1 or B7-2 with IL-2 were constructed to allow for the expression of both immuno-modulatory molecules from the same cell. An alternative approach to enhancing the efficacy of these factors involved the use of double recombinant adenoviral vectors expressing combinations of the chemokine lymphotactin with IL-2 and IL-12. Mammary tumor cells from transgenic mice expressing polyoma middle T (PyMT) or an oncogenic form of the proto-oncogene Neu (Neu 8142) were transplated into syngeneic FVB/N recipients to establish the subcutaneous tumor models. Intra-tumoral injection of adenoviral vectors constructed to express murine B7-1 or B7-2 and IL-2 resulted in regression of PyMT or Neu (8142) tumor bearing mice, superior to that observed for the single cytokine or co-stimulatory molecule expressing vectors. Cured mice were shown to have generated systemic immunity to a subsequent challenge with fresh tumor cells and tumor specific cytotoxic T lymphocyte activity could be detected. Intra-tumoral injection of adenoviral vectors constructed to express lymphotactin IL-2 or IL-12 demonstrated complete regression in a small number of PyMT tumor bearing mice. None of these single cytokine or chemokine expressing vectors was capable of inducing regression of Neu (8142) tumors. In contrast, administration of vectors expressing either a combination of lymphotactin and IL-2 or lymphotactin and IL-12 resulted in an increased incidence of complete regression in both tumor models. All regressed mice demonstrated systemic protection and anti-PyMT CTL. The activity of these vectors in the Neu tumor model is different and suggests some variance in the immunogenicity of the two tumor models. These results demonstrate the ability of double recombinant vectors expressing the co-stimulatory molecules (B7-1 or B7-2) or lymphotactin in combination with IL-2 or IL-12 to enhance the anti-tumor effects of either cytokine alone. These vectors demonstrated no associated toxicities, due to the reduced levels of cytokine that are needed to maximally co-operate with the co-stimulatory or chemokine molecules. Development of this type of vector system will lead to much improved clinical protocols for cancer therapy.

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