Rochlitz Christoph, Dreno Brigitte, Jantscheff Peter, Cavalli Franco, Squiban Patrick, Acres Bruce, Baudin Martine, Escudier Bernard, Heinzerling Lucie, Morant Rudolf, Herrmann Richard, Dietrich Pierre-Yves, Dummer Reinhard
Departement Innere Medizin, Abteilung für Onkologie, Kantonsspital, Petersgraben 4, CH-4031 Basel, Switzerland.
Cancer Gene Ther. 2002 Mar;9(3):289-95. doi: 10.1038/sj.cgt.7700441.
Systemic IL-2 has shown some activity in metastatic melanoma, but its use is severely limited by toxicity. TG2001 is a product in which the human IL-2 cDNA was incorporated into the genome of Vero cells, a monkey fibroblast cell line. The goal of this intratumorally applied therapy was to create an antitumor immune response stimulated by xeno-antigens and local production of IL-2 in the close vicinity of tumor-specific antigens. TG2001 was reported to have a good safety profile in two previous dose-escalating phase I studies performed in 18 patients with various solid tumors, with encouraging clinical responses in three patients. The objectives of this study were to evaluate the tolerance and incidence of tumor regression in patients with metastatic melanoma, following repeated administration of Vero-IL-2 cells.
This was on open-label, randomized phase II study comparing two doses of Vero-IL-2, 5x10(5) and 5x10(6) cells. Twenty-eight patients with metastatic melanoma were enrolled in the study, 14 in each treatment group. Patients received TG2001 by intratumoral injection on days 1, 3, and 5 every 4 weeks for four cycles, and every 8 weeks thereafter, until evidence of progressive disease (PD). Criteria for patient selection included histologically proven metastatic melanoma, with one tumor accessible for product administration, and at least another tumor site for response assessment. Evaluation included tumor measurements, humoral and T cell-mediated local and systemic immune response, humoral response to Vero cells, adverse events and standard laboratory parameters.
None of the patients achieved a confirmed objective response. Stable disease (SD) was seen in six (43%) and eight patients (57%) at the 5x10(5) and the 5x10(6) dose level, respectively. Two patients, one in each group, died during the study (i.e., within 1 month after the last injection) due to PD. Three patients exhibited antibody responses to Vero cells. T-cell immunity, serum cytokine levels and cytokine mRNA expression in tumor biopsies did not show meaningful alterations after therapy, except for a trend toward an increase in intratumoral TH2 cytokine (IL-4 and/or IL-10) levels. The study drug was well tolerated at both dose levels and side effects mainly consisted of injection site pain and erythema, and pyrexia.
The intratumoral administration of TG2001 was generally well tolerated in patients with metastatic melanoma, and transient disease stabilization was observed in 50% of patients.
全身性白细胞介素-2（IL-2）在转移性黑色素瘤中已显示出一定活性，但其应用因毒性而受到严重限制。TG2001是一种将人IL-2 cDNA整合到猴成纤维细胞系Vero细胞基因组中的产品。这种瘤内应用疗法的目标是通过异种抗原刺激产生抗肿瘤免疫反应，并在肿瘤特异性抗原附近局部产生IL-2。在先前对18例患有各种实体瘤的患者进行的两项剂量递增的I期研究中，据报道TG2001具有良好的安全性，3例患者出现了令人鼓舞的临床反应。本研究的目的是评估转移性黑色素瘤患者在重复给予Vero-IL-2细胞后的耐受性和肿瘤消退发生率。
这是一项开放标签、随机的II期研究，比较两种剂量的Vero-IL-2，即5×10⁵和5×10⁶个细胞。28例转移性黑色素瘤患者入组本研究，每个治疗组14例。患者每4周在第1、3和5天通过瘤内注射接受TG2001，共四个周期，此后每8周注射一次，直至出现疾病进展（PD）证据。患者选择标准包括组织学证实的转移性黑色素瘤，有一个肿瘤可用于产品给药，且至少有另一个肿瘤部位用于反应评估。评估包括肿瘤测量、体液和T细胞介导的局部和全身免疫反应、对Vero细胞的体液反应、不良事件和标准实验室参数。
没有患者达到确认的客观反应。在5×10⁵和5×10⁶剂量水平下，分别有6例（43%）和8例（57%）患者出现疾病稳定（SD）。两名患者，每组各一名，在研究期间（即最后一次注射后1个月内）因PD死亡。3例患者对Vero细胞产生抗体反应。除瘤内TH2细胞因子（IL-4和/或IL-10）水平有升高趋势外，治疗后肿瘤活检中的T细胞免疫、血清细胞因子水平和细胞因子mRNA表达未显示有意义的改变。研究药物在两个剂量水平下耐受性良好，副作用主要包括注射部位疼痛、红斑和发热。
TG2001瘤内给药在转移性黑色素瘤患者中总体耐受性良好，50%的患者观察到疾病短暂稳定。
