Pilot study for the evaluation of T-cell-mediated tumor immunotherapy by cytokine gene transfer in patients with malignant tumors
Induction of T-cell-mediated cytotoxicity and immunity against specific tumor antigens by vaccination with devitalized autologous tumor tissue and (a) autologous or (b) allogeneic fibroblasts as a constitutive paracrine source of interleukin-2 (IL-2). benefit for solid tumors, notably malignant melanoma and renal cell carcinoma. However, objective responses occur only in a minority of patients and are usually transient, and treatment is often associated with significant toxicity. Therefore a more selective delivery of immunostimulatory cytokines may improve treatment results. Recent data indicate the presence of MHC-restricted, tumor-specific cytotoxic T cells (CTL) in patients with malignant melanoma and renal cell carcinoma that may be capable of efficient tumor rejection. These CTL recognize tumor-associated antigens, for example, mutated proto-oncogenes, genes with expression restricted to the tumor cell lineage, and genes that are normally expressed only in the fetal period. Current theory holds that these CTL may not be activated properly due to the lack of costimulatory signals in the immediate context of their target cells and are therefore unable to lyze tumor cells in vivo. Those costimulatory signals appear to be provided physiologically by accessory molecules (e.g., B7) or soluble cytokines. In accordance with this theory, animal studies have demonstrated the therapeutic efficacy of tumor vaccines that have been genetically modified to secrete T-cell stimulating cytokines as a second signal for CTL activation. Based on these studies, this clinical trial attempts to induce antitumor immunity by stimulating tumor-specific CTL with a genetically engineered vaccine. The vaccine is composed of autologous tumor cells, presumably carrying tumor-associated antigens, mixed with IL-2 secreting fibroblasts as a paracrine source of IL-2 to provide an efficient costimulatory signal for activation of CTL.