Phase I clinical trial with IL-2-transfected xenogeneic cells administered in subcutaneous metastatic tumours: clinical and immunological findings

Abstract

Summary 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 ¥ 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.

Effects of triterpene saponins from Astragalus species on in vitro cytokine release

“…By having cytokine production that is still under the homeostatic control of the host, cytokine-gene activators might carry more beneficial safety profiles than their protein counterparts (Gillis and Williams, 1998). In fact, Tartour et al (2000), have reported that in 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 eight patients with metastatic solid tumors and no severe adverse effect was observed in the eight patients analyzed during this clinical trial even in the highest dose group. Another therapeutic approach is utilization of IL-2 inducing agents in order to stimulate the patient's body to produce IL-2.…”

Immunotherapy of metastatic melanoma by intratumoral injections of Vero cells producing human IL-2: Phase II randomized study comparing two dose levels

“…Our study confirms the favorable toxicity profile of Vero -IL -2 treatment seen in the two phase I studies reported previously. 11,12 In addition, although we did not see a single PR or CR, 14 of 28 patients ( 50% ) achieved SD lasting for up to 4 months. This observation can by no means be taken as proof of the clinical efficacy of Vero -IL -2.…”

“…36 Interestingly, in our two phase I studies, the most important clinical and immunological responses occurred at the two lower dose levels using Vero -IL -2 cells producing relatively high amounts of 14,000 U per 10 5 cells per day. 11,12 Although our results in humans cannot be quantitatively compared to those by Schmidt et al for various biological and technical reasons, it can be speculated that the ''bell -shaped dose response curve'' to IL -2 described in animals might indeed also play a role in clinical trials in humans. For that reason, we had designed our phase II study as a randomized comparison of two dose levels, but the lack of efficiency of TG2001 in our study makes any conclusion on a dose -response effect of IL -2 impossible.…”

“…11 Low toxicity and histological remission in two patients were also seen in an independent second phase I study of TG2001, mainly including patients with breast cancer. 12 As a continuation of these encouraging preclinical and phase I data, we started a multicentric randomized phase II study of Vero -IL -2 cells in 28 patients with metastatic melanoma, the results of which are described in this report.…”

Dendritic cells infected with a vaccinia virus interleukin-2 vector secrete high levels of IL-2 and can become efficient antigen presenting cells that secrete high levels of the immunostimulatory cytokine IL-12

“…Vaccinia virus (VV) was chosen because its virology and safety are well described. Similarly, IL-2 was selected because it has demonstrated powerful effects in some animal models, 5 and in human clinical trials, [6][7][8] including MM.…”