TY - JOUR
T1 - Cytokine gene therapy or infusion as treatment for solid human cancer
T2 - Third Keystone Symposium on Cellular Immunology and the Immunotherapy of Cancer; Gene Therapy
AU - Robinson, Bruce W.S.
AU - Mukherjee, Sutapa A.
AU - Davidson, Andrew
AU - Morey, Susan
AU - Musk, Arthur W.
AU - Ramshaw, Ian
AU - Smith, David
AU - Lake, Richard
AU - Haenel, Thomas
AU - Garlepp, Michael
AU - Marley, Julia
AU - Leong, Clement
AU - Caminschi, Irina
AU - Scott, Bernadette
PY - 1998/5
Y1 - 1998/5
N2 - 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.
AB - 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.
KW - Cancer immunotherapy
KW - Cytokines
KW - Gene therapy
KW - Granulocyte-macrophage colony-stimulating factor
KW - Interleukin-2
KW - Vaccinia
UR - http://www.scopus.com/inward/record.url?scp=0031924007&partnerID=8YFLogxK
U2 - 10.1097/00002371-199805000-00007
DO - 10.1097/00002371-199805000-00007
M3 - Article
C2 - 9610913
AN - SCOPUS:0031924007
SN - 1524-9557
VL - 21
SP - 211
EP - 217
JO - Journal of Immunotherapy
JF - Journal of Immunotherapy
IS - 3
ER -