Cytokine gene therapy or infusion as treatment for solid human cancer.
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 10(7) 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 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-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 micro/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.
Robinson
B W
BW
University Department of Medicine, Sir Charles Gairdner Hospital, Queen Elizabeth II Medical Centre, Perth, Australia.
Mukherjee
S A
SA
Davidson
A
A
Morey
S
S
Musk
A W
AW
Ramshaw
I
I
Smith
D
D
Lake
R
R
Haenel
T
T
Garlepp
M
M
Marley
J
J
Leong
C
C
Caminschi
I
I
Scott
B
B
D016207:Cytokines / Q000008:administration & dosage* / Q000235:genetics* / Q000627:therapeutic use; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000009:adverse effects / Q000235:genetics / Q000627:therapeutic use; D006801:Humans; D007376:Interleukin-2 / Q000009:adverse effects / Q000235:genetics / Q000627:therapeutic use; D008654:Mesothelioma / Q000628:therapy*; D012333:RNA, Messenger / Q000032:analysis; D011994:Recombinant Proteins; D014616:Vaccinia virus / Q000235:genetics
D016207:Cytokines; D007376:Interleukin-2; D012333:RNA, Messenger; D011994:Recombinant Proteins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor