Connor J, Bannerji R, Saito S, Heston W, Fair W, Gilboa E
Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York 10021.
J Exp Med. 1993 Apr 1;177(4):1127-34. doi: 10.1084/jem.177.4.1127.
This study explored the use of interleukin 2 (IL-2) and interferon gamma (IFN-gamma) gene-modified tumor cells as cellular vaccines for the treatment of bladder cancer. The mouse MBT-2 tumor used is an excellent model for human bladder cancer. This carcinogen-induced tumor of bladder origin resembles human bladder cancer in its etiology and histology, and responds to treatment in a manner similar to its human counterpart. Using retroviral vectors, the human IL-2 and mouse IFN-gamma genes were introduced and expressed in MBT-2 cells. The tumor-forming capacity of the cytokine gene-modified MBT-2 cells was significantly impaired, since no tumors formed in mice injected intradermally with either IL-2- or IFN-gamma-secreting cells, using cell doses far exceeding the minimal tumorigenic dose of parental MBT-2 cells. Furthermore, mice that rejected the IL-2- or IFN-gamma-secreting tumor cells became highly resistant to a subsequent challenge with parental MBT-2 cells, but not to 38C13 cells, a B cell lymphoma of the same genetic background. To approximate the conditions as closely as possible to the conditions prevailing in the cancer patient, inactivated cytokine-secreting cells were used to treat animals bearing tumors established by orthotopic implantation of MBT-2 cells into the bladder wall of the animal. Treatment of mice carrying a significant tumor burden with IL-2-secreting MBT-2 cells had a significant inhibitory effect on tumor progression with extended survival. Moreover, in 60% of the mice the tumor regressed completely and the animals remained alive and free of detectable tumor for the duration of the observation period. Treatment of tumor-bearing animals with IL-2-secreting MBT-2 cells was superior to the use of cisplatin, a chemotherapeutic agent used in the treatment of bladder cancer. The therapeutic effect of IFN-gamma-secreting cells was minimal and treatment with unmodified MBT-2 cells had no effect on tumor growth or survival, showing that the parental MBT-2 cells were nonimmunogenic in this experimental setting. Most importantly, mice that exhibited complete tumor regression after treatment with IL-2-secreting MBT-2 cells became resistant to a subsequent challenge with a highly tumorigenic dose of parental MBT-2 cells, indicating that long-term immunological memory was established in the "cured" mice.
本研究探索了使用白细胞介素2（IL-2）和干扰素γ（IFN-γ）基因修饰的肿瘤细胞作为细胞疫苗来治疗膀胱癌。所使用的小鼠MBT-2肿瘤是人类膀胱癌的优良模型。这种由致癌物诱导的膀胱源性肿瘤在病因学和组织学上与人类膀胱癌相似，并且对治疗的反应方式与其人类对应物相似。利用逆转录病毒载体，将人类IL-2和小鼠IFN-γ基因导入MBT-2细胞并使其表达。细胞因子基因修饰的MBT-2细胞的成瘤能力显著受损，因为给小鼠皮内注射分泌IL-2或IFN-γ的细胞（细胞剂量远远超过亲本MBT-2细胞的最小致瘤剂量）后，小鼠未形成肿瘤。此外，排斥分泌IL-2或IFN-γ肿瘤细胞的小鼠对随后亲本MBT-2细胞的攻击具有高度抗性，但对相同遗传背景的B细胞淋巴瘤38C13细胞不具有抗性。为了尽可能接近癌症患者的实际情况，使用灭活的分泌细胞因子的细胞来治疗通过将MBT-2细胞原位植入动物膀胱壁而建立肿瘤的动物。用分泌IL-2的MBT-2细胞治疗携带显著肿瘤负荷的小鼠对肿瘤进展具有显著的抑制作用，并延长了生存期。此外，60%的小鼠肿瘤完全消退，并且在观察期内动物存活且未检测到肿瘤。用分泌IL-2的MBT-2细胞治疗荷瘤动物优于使用顺铂（一种用于治疗膀胱癌的化疗药物）。分泌IFN-γ的细胞的治疗效果极小，用未修饰的MBT-2细胞治疗对肿瘤生长或存活没有影响，表明在该实验环境中亲本MBT-2细胞无免疫原性。最重要的是，用分泌IL-2的MBT-2细胞治疗后肿瘤完全消退的小鼠对随后高致瘤剂量的亲本MBT-2细胞的攻击具有抗性，这表明在“治愈”的小鼠中建立了长期免疫记忆。
