Möller P, Sun Y, Dorbic T, Alijagic S, Makki A, Jurgovsky K, Schroff M, Henz B M, Wittig B, Schadendorf D
Universitätshautklinik, Virchow Klinikum, Humboldt-Universität zu Berlin, Germany.
Br J Cancer. 1998 Jun;77(11):1907-16. doi: 10.1038/bjc.1998.317.
Recently, cytokine gene transfer into tumour cells has been shown to mediate tumour regression in animal models via immunomodulation. Consequently, a number of clinical protocols have been developed to treat cancer patients with cytokine gene-modified tumour cells. Here, we report the results of a clinical phase I trial using for the first time autologous, interleukin 7 gene-modified tumour cells for vaccination of ten patients with disseminated malignant melanoma. Melanoma cells were expanded in vitro from surgically removed metastases, transduced by a ballistic gene transfer technique and were then injected after in vitro irradiation s.c. at weekly intervals. Clinically, there was no major toxicity except for mild fever, and no major clinical response towards vaccination was observed. Eight of ten patients completed the initial three s.c. vaccinations and were eligible for immunological evaluation. Post vaccination, peripheral mononuclear cells (PBMCs) were found to contain an increased number of tumour-reactive proliferative as well as cytolytic cells, as determined by a limiting dilution analysis. In three of six patients, the frequencies of anti-melanoma cytolytic precursor cells increased between 2.6- and 28-fold. Two of these patients showed a minor clinical response. Analysis of the autologous tumour cell vaccines regarding IL-7 secretion after gene transfer, HLA class I and class II cell surface expression, secretion of immunosuppressive mediators (TGF-beta1, IL-10) and various melanoma-associated tumour antigens revealed a very diverse expression profile. In conclusion, vaccination using gene-modified autologous melanoma cells induced immunological changes in a group of advanced, terminally ill patients. These changes can be interpreted as an increased anti-tumour immune response. However, immunological modulation was most pronounced in patients in good physical condition. Therefore, patients with minimal tumour load or minimal residual disease might preferentially benefit from tumour cell vaccination in further studies. In order to evaluate the effects of the cytokine gene-modified tumour cell vaccines more precisely, an antigenically better defined vaccine is needed.
最近，细胞因子基因导入肿瘤细胞已被证明可通过免疫调节在动物模型中介导肿瘤消退。因此，已经制定了一些临床方案，用细胞因子基因修饰的肿瘤细胞治疗癌症患者。在此，我们报告了一项I期临床试验的结果，该试验首次使用自体白细胞介素7基因修饰的肿瘤细胞对10例播散性恶性黑色素瘤患者进行疫苗接种。黑色素瘤细胞从手术切除的转移灶中体外扩增，通过基因枪转移技术转导，然后在体外照射后每周一次皮下注射。临床上，除了轻度发热外没有重大毒性，并且未观察到对疫苗接种的重大临床反应。10例患者中有8例完成了最初的三次皮下疫苗接种，并有资格进行免疫学评估。疫苗接种后，通过有限稀释分析确定，外周血单个核细胞（PBMC）中肿瘤反应性增殖细胞和细胞溶解细胞的数量增加。在6例患者中的3例中，抗黑色素瘤细胞溶解前体细胞的频率增加了2.6至28倍。其中2例患者显示出轻微的临床反应。对基因转移后IL-7分泌、HLA I类和II类细胞表面表达、免疫抑制介质（TGF-β1、IL-10）分泌以及各种黑色素瘤相关肿瘤抗原的自体肿瘤细胞疫苗分析显示出非常多样的表达谱。总之，使用基因修饰的自体黑色素瘤细胞进行疫苗接种在一组晚期绝症患者中诱导了免疫学变化。这些变化可解释为抗肿瘤免疫反应增强。然而，免疫调节在身体状况良好的患者中最为明显。因此，肿瘤负荷最小或残留疾病最少的患者可能在进一步研究中优先从肿瘤细胞疫苗接种中获益。为了更精确地评估细胞因子基因修饰的肿瘤细胞疫苗的效果，需要一种抗原定义更好的疫苗。
