Visse E, Siesjö P, Widegren B, Sjögren H O
Department of Cell and Molecular Biology, University of Lund, Sweden.
Cancer Gene Ther. 1999 Jan-Feb;6(1):37-44. doi: 10.1038/sj.cgt.7700023.
Progress in the definition of the roles of various costimulators and cytokines in determining the type and height of immune responses has made it important to explore genetically altered tumor cells expressing such molecules for therapeutic immunizations. We have studied the effect of therapeutic subcutaneous (s.c.) immunizations on the growth of preexisting intracerebral brain tumor isografts in the rat. Transfectant glioma cell clones expressing either rat interferon-gamma (IFN-gamma), rat interleukin-7 (IL-7), or rat B7-1 were selected. After irradiation (80 Gy) the clones were used for immunization (administered in up to four s.c. doses in a hind leg over 14-day intervals starting 1 day after the intracranial isografting of the parental tumor). Significant growth inhibition of the intracerebral parental tumors was induced by transfectants expressing IFN-gamma and IL-7, respectively. The strongest effect was observed with IFN-gamma-expressing cells, resulting in cures in 37% of the males and in 100% of the females. Immunization with IL-7 had a similar, strong initial effect, with significantly prolonged survival in the majority of the rats but a lower final cure rate (survival for >150 days). The B7-1-expressing tumor clones induced cures in seven of eight female rats; however, no cures were seen in the male rats. It was also shown that the B7-1-expressing cells were themselves strongly immunogenic in female rats, requiring high cell numbers to result in a progressively growing tumor upon s.c. isografting; this was not the case in male rats. As a whole, the results imply that despite the unfavorable location of intracerebral tumors, therapeutic s.c. immunizations with certain types of genetically altered tumor cells can induce complete regressions with permanent survival and without gross neurological or other apparent signs of brain damage. The present results demonstrate complete regressions when immunizations are initiated shortly after intracranial isografting, when the intracerebral tumor is small.
在确定各种共刺激分子和细胞因子在决定免疫反应类型和强度方面所起作用的定义上取得的进展，使得探索表达此类分子的基因工程改造肿瘤细胞用于治疗性免疫接种变得十分重要。我们研究了治疗性皮下免疫接种对大鼠脑内预先存在的同种异体脑肿瘤生长的影响。筛选出表达大鼠γ干扰素（IFN-γ）、大鼠白细胞介素-7（IL-7）或大鼠B7-1的转染胶质瘤细胞克隆。照射（80 Gy）后，这些克隆用于免疫接种（在亲代肿瘤颅内移植后1天开始，每隔14天在后腿皮下注射多达4剂）。分别表达IFN-γ和IL-7的转染细胞诱导了脑内亲代肿瘤的显著生长抑制。在表达IFN-γ的细胞中观察到最强的效果，导致37%的雄性大鼠和100%的雌性大鼠治愈。用IL-7免疫接种有类似的强烈初始效果，大多数大鼠的存活时间显著延长，但最终治愈率较低（存活>150天）。表达B7-1的肿瘤克隆在8只雌性大鼠中有7只治愈；然而，雄性大鼠中未见治愈情况。还表明，表达B7-1的细胞本身在雌性大鼠中具有很强的免疫原性，皮下移植时需要大量细胞才能形成逐渐生长的肿瘤；雄性大鼠中并非如此。总体而言，结果表明，尽管脑肿瘤位置不利，但用某些类型的基因工程改造肿瘤细胞进行治疗性皮下免疫接种可诱导完全消退，实现永久存活，且无明显的神经损伤或其他明显的脑损伤迹象。当在颅内移植后不久、脑内肿瘤较小时开始免疫接种时，目前的结果证明了完全消退的情况。
