Immunotherapy of Malignancy by In Vivo Gene Transfer into Tumors

Abstract
The goal of immunotherapy is to stimulate the immune system by modification of tumor cells or expansion of lymphocytes which respond specifically to tumor antigens. In this study, we will apply techniques of direct gene transfer to enhance immune response against tumors in vivo. Patients with advanced cancer who have failed all effective therapy will be treated by injection of a DNA/liposome complex directly within the tumor. DNA encoding an HLA-B7 histocompatibility antigen and the neomycin-resistant gene in a eukaryotic expression vector will be used, and a safe and effective dose to introduce this recombinant gene in HLA-B7 patients will be established. HLA-B7 expression will be confirmed in vivo, and the immune response stimulated by the expression of this antigen will be characterized. We will also determine whether this treatment facilitates tumor regression alone or in combination with other treatment modalities. This gene transfer approach will be analyzed for its efficacy as an anti-cancer treatment. Finally, these studies will allow the development of other approaches, using different recombinant genes or in combination with cytokines or adoptive T cell therapy, to augment tumor immunity. This method to treat malignancy may provide the basis to establish the safety on this general approach, which could be extended to treat a variety of other human diseases. Many types of cancer cannot be cured by traditional medical treatments, including drugs, surgery, or radiation. In this study, an experimental treatment will be offered that may help to fight this disease. We will attempt to induce tumor regression by the introduction of genetic material that directs the synthesis of a protein which stimulates the immune system. The genetic material, DNA, will be introduced directly into the tumor by mixing it with fat bodies, or liposomes, and this mixture will be injected into the tumor. The DNA will be taken into cells and cause them to produce a protein that stimulates tissue rejection. This protein, called HLA-B7, causes cells which contain it to be recognized as foreign by the immune system. The goal of the treatment is to stimulate the immune system to attack and kill the tumor. In this study, we will determine a safe and effective dose to administer the DNA/liposome complex. Increasing amounts of this complex will be used in different patient populations. If no side effects are observed, repeated treatments will be instituted. The expression and nature of the immune response will also be characterized. This treatment may provide a therapeutic effect in cancer and could be applied to the treatment of other diseases.