Phase I clinical trial with IL-2-transfected xenogeneic cells administered in subcutaneous metastatic tumours: clinical and immunological findings.
Various studies have emphasized an immunodepression state observed at the tumour site. To reverse this defect and based upon animal studies, we initiated a phase I clinical trial of gene therapy in which various doses of xenogeneic monkey fibroblasts (Vero cells) genetically engineered to produce human IL-2 were administered intratumorally in 8 patients with metastatic solid tumours. No severe adverse effect was observed in the 8 patients analysed during this clinical trial even in the highest dose (5 yen 107 cells) group. This absence of toxicity seems to be associated with rapid elimination of Vero-IL-2 cells from the organism. Indeed, exogenous IL-2 mRNA could no longer be detected in the peripheral whole blood 48 hours after Vero-IL-2 cell administration. In addition, we did not find any expression of exogenous IL-2 mRNA in post-therapeutic lesions removed 29 days after the start of therapy. A major finding of this trial concerns the two histological responses of two treated subcutaneous nodules not associated with an apparent clinical response. The relationship between local treatment and tumour regression was supported by replacement of tumour cells by inflammatory cells in regressing lesions and marked induction of T and natural killer cell derived cytokines (IL-2, IL-4, IFNg ...) in post-therapeutic lesions analysed 28 days after the start of Vero-IL-2 administration. Gene therapy using xenogeneic cells as vehicle may therefore present certain advantages over other vectors, such as its complete absence of toxicity. Furthermore, the in vivo biological effect of immunostimulatory genes, i.e IL-2-, may be potentiated by the xenogeneic rejection reaction.
Tartour
E
E
Department of Tumor Biology, Institut Curie, Université Pierre et Marie Curie, Paris, France.
Mehtali
M
M
Sastre-Garau
X
X
Joyeux
I
I
Mathiot
C
C
Pleau
J M
JM
Squiban
P
P
Rochlitz
C
C
Courtney
M
M
Jantscheff
P
P
Herrmann
R
R
Pouillart
P
P
Fridman
W H
WH
Dorval
T
T
D000230:Adenocarcinoma / Q000276:immunology / Q000556:secondary / Q000628:therapy*; D000328:Adult; D000368:Aged; D000818:Animals; D001706:Biopsy; D002522:Chlorocebus aethiops; D016207:Cytokines / Q000097:blood; D015316:Genetic Therapy / Q000009:adverse effects / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D006801:Humans; D015552:Injections, Intralesional; D007376:Interleukin-2 / Q000009:adverse effects / Q000235:genetics* / Q000276:immunology; D008875:Middle Aged; D012333:RNA, Messenger / Q000097:blood / Q000378:metabolism; D012878:Skin Neoplasms / Q000276:immunology / Q000556:secondary / Q000628:therapy*; D014162:Transfection; D014709:Vero Cells
D016207:Cytokines; D007376:Interleukin-2; D012333:RNA, Messenger