Stimulating the Immune System

Different gene therapy approaches have been put forward to stimulate the immune system. The basic principle underlying immunotherapy in cancer is that tumors have

Table 1 Gene Therapy Strategies

Stimulating the immune system. Transfer of suicide genes. Replacement of tumor suppressor genes. Inhibition of oncogenes. Inhibition of angiogenesis. Induction of apoptosis.

Enhancement of radiation therapy and/or chemotherapy.

antigens that are capable of provoking weak humoral or cellular reactions. By activating this immune response against tumor cells through gene transfer it is hoped that tumors can be eradicated either by the transferred gene product or activation of the patient's own immune system. In animal models, the administration of cytokines such as inter-leukin (IL)-2, IL-4, IL-6, IL-7, IL-12, tumor necrosis factor (TNF)-a, interferons and granulocyte macrophage colony-stimulating factor (GM-CSF) have resulted in tumor regression (8). The systemic administration of cytokines in human trials though has been limited by the severe toxicity of these cytokines. Gene therapy strategies offer an opportunity to overcome these limitations because of the potential for local delivery to injected tumor with reduction in systemic toxicity (9-11). Another approach to make tumor cells more immunogenic involves the cotransfer of stimulatory molecules such as B7.1 and B7.2. These molecules provide a key event in T-cell activation, and are often lacking on the surface of tumor cells. Zajac et al. used a nonreplicative vaccinia virus expressing HLA-A0201-restricted Melan-A/Mart-127_35, gp100280_288, and tyrosinase^ epitopes together with Human B7.1 and B7.2 costimulatory molecules in a phase I/II trial in metastatic melanoma patients (12). In a large majority of patients, the reagent was able to induce specific CTL responses although major clinical responses were not seen (12). The utilization of cytokine-based gene therapy strategies for the development of tumor cell vaccines through ex vivo delivery methods is another approach. Although these gene therapy strategies appear to stimulate the immune system and may ultimately produce long-term antitumor protection, problems with targeting the immune system include the heterogeneity of tumor antigen expression, which prevents a predictable response by the immune system to gene transfer.

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