CYTOKINE GENE-THERAPY OR INFUSION AS TREATMENT FOR SOLID HUMAN CANCER

In the induction of tissue-directed immune responses, cytokines tend t o be released within the affected tissues. We used two strategies to e xpose tumor tissues to continuous high levels of cytokines: First, a v accinia interleukin (IL)2 recombinant was injected directly intratumor ally 3-weekly at 10(7) pfus/dose in six patients with the solid tumor malignant mesothelioma (MM). No virus excretion was detectable. At eac h cycle vaccinia-IL-2 mRNA (SQ [semi-quantitative] reverse transcripti on polymerase chain reaction) was maximal 24-72 h following injection reduced at 8 days and faded by 21 days. No tumor regression occurred. Second, based on the success of granulocyte macrophage colony-stimulat ing factor (GM-CSF) in gene transfer experiments, we conducted a study using continuous intratumoral GM-CSF infusion in eight patients with MM using a portable pump at doses of 10 mu/(c)g/24 h over 8 weeks. Sys temic neutrophil agglutination and local catheter-related difficulties occurred. Two patients demonstrated tumor necrosis, one of whom had a marked progressive mono-nuclear cell infiltration of the tumor associ ated with a partial response (>50% reduction in tumor area). Murine st udies using our MM model in CBA and BALB/C mice have demonstrated that B7-1 and allo-class I transfections induce strong tumor-specific cyto toxic T lymphocyte responses: GM-CSF, IL-12, and IL-2 induced mixed no nspecific plus specific responses, whereas B7-2 and class II transfect ions were not effective. We conclude that increased intratumoral cytok ine concentrations can be generated using both gene transfer and cytok ine infusion approaches; however, both have their limitations and, at this stage, have not produced dramatic antitumor effects in humans.