Clary B M, Coveney E C, Blazer D G, Philip R, Lyerly H K
Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA.
Surgery. 1996 Aug;120(2):174-81. doi: 10.1016/s0039-6060(96)80285-6.
Vaccination of tumor-bearing animals with tumor cells genetically engineered to secrete cytokines including interleukin-2 (IL-2) and interferon-gamma (IFN-gamma) has been shown to induce effective tumor-specific immune responses capable of inhibiting local and metastatic disease. Previous unsuccessful attempts to enhance this immune response by means of the secretion of multiple cytokines possessing different immunologic mechanisms of action may have been due to the inherent inefficiency of the gene transfer systems used. We postulated that tumor cells genetically engineered by means of a novel gene transfer method resulting in high level secretion of both cytokines would be more effective than tumor cells secreting a single cytokine in inhibiting the growth of existing tumors.
Nonimmunogenic, murine pancreatic cancer cells (Panc02) were engineered to secrete IL-2, IFN-gamma, IL-2 and IFN-gamma, or neomycin phosphotransferase. Mice were inoculated with 5 x 10(5) parental Panc02 tumor cells subcutaneously. Beginning 3 days later, animals then received a series of four weekly vaccinations with irradiated Panc02/Neo, Panc02/IL2, Panc02/IFN, or Panc02/IL-2/IFN.
Treatment with Panc02/Neo, Panc02/IL-2, or Panc02/IFN resulted in 0%, 40%, and 30% tumor-free survival, respectively. In contrast, 80% of animals vaccinated with Panc02/IL2/IFN were free of tumor at 100 days. All animals free of disease were resistant to subsequent tumor challenges.
These data show that vaccination with tumor cells that secrete high levels of multiple cytokines was more effective in treating established pancreatic tumors and represents an improvement over existing single cytokine strategies.
给荷瘤动物接种经基因工程改造以分泌包括白细胞介素-2（IL-2）和干扰素-γ（IFN-γ）在内的细胞因子的肿瘤细胞，已显示可诱导有效的肿瘤特异性免疫反应，能够抑制局部和转移性疾病。先前通过分泌具有不同免疫作用机制的多种细胞因子来增强这种免疫反应的尝试未成功，可能是由于所用基因转移系统固有的低效性。我们推测，通过一种新型基因转移方法进行基因工程改造的肿瘤细胞，若能高水平分泌两种细胞因子，在抑制现有肿瘤生长方面将比分泌单一细胞因子的肿瘤细胞更有效。
对无免疫原性的小鼠胰腺癌细胞（Panc02）进行改造，使其分泌IL-2、IFN-γ、IL-2和IFN-γ，或新霉素磷酸转移酶。小鼠皮下接种5×10⁵个亲本Panc02肿瘤细胞。3天后开始，动物随后接受一系列四周一次的疫苗接种，分别用经辐射的Panc02/Neo、Panc02/IL2、Panc02/IFN或Panc02/IL-2/IFN。
用Panc02/Neo、Panc02/IL-2或Panc02/IFN治疗的动物无瘤生存率分别为0%、40%和30%。相比之下，接种Panc02/IL2/IFN的动物在100天时80%无肿瘤。所有无病动物对随后的肿瘤攻击均有抵抗力。
这些数据表明，接种能高水平分泌多种细胞因子的肿瘤细胞在治疗已形成的胰腺肿瘤方面更有效，代表了对现有单一细胞因子策略的改进。
