We have evaluated the systemic administration of Interleukin-4 (IL-4) alone and then in combination with IL-2 to patients with cancer. Responses were only observed in patients treated with both cytokines and included patients with melanoma and renal cell cancer as well as in a single patient with breast carcinoma. Synergistic toxicity was also observed, primarily that ascribed to a vascular leak syndrome but also including a major sensation of nasal congestion and gastritis and frank gastric ulceration on occasion. Evaluation of rejecting allografts and sites of tumor associated with an immune response consistently have demonstrated the presence of IL-4 message or protein, making it perhaps the most frequent cytokine observed at such sites. The local production of IL-4 at the site of tumor vaccine has in five separate murine studies been associated with the induction of protective immunity and regression of the transfected tumor as well as, in some studies, established metastic cancer. IL-4 is a pleiotropic cytokine that activates vascular endothelial cells, monocytes, dendritic cells and lymphocytes. It induces the local endothelium to express the vascular cell adhesion molecule, VCAM. This facilitates trafficking of macrophages, eosinophils and lymphocytes to sites of inflammation. GM-CSF and IL-4 are potent costimulators of murine and human dendritic cell proliferation, enhancing effective tumor derived peptide vaccination in vivo and in vitro respectively. IL-4 promotes T-cell growth following appropriate activation by mitogen or antigen and synergizes with IL-2 in the growth of tumor infiltrating lymphocytes. Although it decreases the production of proinflammatory cytokines by macrophages, it enhances antigen presentation. We have begun a clinical gene therapy protocol and enlisted 15 patients to date.
The specific aims of this project are to: 1: Evaluate the effects of IL-4 gene therapy on dendritic cell activation and stimulation of T-helper cells. Patients with cancer will be assessed for evidence of systemic immune response at draining lymph node and distant sites following local delivery of IL-4; 2: Determine the immunologic effects and therapeutic efficacy of systemic cytokine (IL-2, IL-10 or IL- 12) delivered in conjunction with this tumor vaccine, first in murine models and then in patients with cancer. Engineered fibroblasts will be tested for their ability to enhance an immune response in combination with systemic cytokine administration and 3: Determine the most effective combination of IL-4 gene therapy with other expressed gene products as components of a tumor vaccine. The use of IL-4 in combination with IL-1, GM-CSF, hepatocyte growth factor and the herpes thymidine kinase gene will be tested in murine models.
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