Cytokine gene therapy or infusion as treatment for solid human cancer: Third Keystone Symposium on Cellular Immunology and the Immunotherapy of Cancer; Gene Therapy

Bruce W.S. Robinson, Sutapa A. Mukherjee, Andrew Davidson, Susan Morey, Arthur W. Musk, Ian Ramshaw, David Smith, Richard Lake, Thomas Haenel, Michael Garlepp, Julia Marley, Clement Leong, Irina Caminschi, Bernadette Scott

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Abstract

In the induction of tissue-directed immune responses, cytokines tend to be released within the affected tissues. We used two strategies to expose tumor tissues to continuous high levels of cytokines: First, a vaccinia interleukin (IL)2 recombinant was injected directly intratumorally 3-weekly at 107 pfus/dose in six patients with the solid tumor malignant mesothelioma (MM). No virus excretion was detectable. At each cycle vaccinia-IL-2 mRNA (SQ [semi-quantitative] reverse transcription poly-merase 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-stimulating 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 µ/cg/24 h over 8 weeks. Systemic neutrophil agglutination and local catheter-related difficulties occurred. Two patients demonstrated tumor necrosis, one of whom had a marked progressive mononuclear cell infiltration of the tumor associated with a partial response (>50% reduction in tumor area). Murine studies using our MM model in CBA and BALB/C mice have demonstrated that B7-1 and allo-class I transfections induce strong tumor-specific cytotoxic T lymphocyte responses: GM-CSF, IL-12 and IL-2 induced mixed nonspecific plus specific responses, whereas B7-2 and class II transfections were not effective. We conclude that increased intratumoral cytokine concentrations can be generated using both gene transfer and cytokine infusion approaches: however, both have their limitations and, at this stage, have not produced dramatic antitumor effects in humans.

Original languageEnglish
Pages (from-to)211-217
Number of pages7
JournalJournal of Immunotherapy
Volume21
Issue number3
DOIs
Publication statusPublished - May 1998
Externally publishedYes

Keywords

  • Cancer immunotherapy
  • Cytokines
  • Gene therapy
  • Granulocyte-macrophage colony-stimulating factor
  • Interleukin-2
  • Vaccinia

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    Robinson, B. W. S., Mukherjee, S. A., Davidson, A., Morey, S., Musk, A. W., Ramshaw, I., Smith, D., Lake, R., Haenel, T., Garlepp, M., Marley, J., Leong, C., Caminschi, I., & Scott, B. (1998). Cytokine gene therapy or infusion as treatment for solid human cancer: Third Keystone Symposium on Cellular Immunology and the Immunotherapy of Cancer; Gene Therapy. Journal of Immunotherapy, 21(3), 211-217. https://doi.org/10.1097/00002371-199805000-00007