REGRESSION OF EXPERIMENTAL BURKITT'S LYMPHOMA IN ATHYMIC MICE

特异性转导淋巴细胞或肿瘤细胞的给药 细胞因子基因代表了治疗癌症的新方法。 通过提供抗肿瘤效应细胞或刺激抗肿瘤 这些实验模式导致了肿瘤部位的免疫 在一些现有肿瘤的致瘤性和消退性降低 实验模型。近年来，逆转录病毒介导的体内转移 疱疹病毒衍生的胸苷激酶(Tk)基因的比例 脑胶质瘤肿瘤细胞使其对 抗病毒药物。它还导致了其他肿瘤细胞的死亡，而不是 转导tk基因，通过不明确的旁观者效应。 尽管有这些实验结果，效应器的靶向性 淋巴细胞与抗癌细胞因子和药物敏感因子 对于特定的肿瘤部位，其临床应用有限，因为 它涉及相对复杂的程序，而这些程序并不广泛使用。我们 考虑到肿瘤细胞杀伤可能是由 用良性细胞接种荷瘤宿主，这些细胞是 如果接种到同一宿主上，通常会被摧毁。我们推论说 通过在体内刺激局部的细胞毒反应，人们可能达到 通过旁观者效应杀死肿瘤细胞。当注射时 经照射的裸鼠皮下注射人B细胞 与EB病毒(EBV)一起永生的人要么不能生长，要么不能 长成小肿瘤，很快就会通过坏死和结疤而消退。 这种回归的机制还没有完全了解，但已经被 归因于残留的宿主免疫力。在同一实验系统中， 人Burkitt淋巴瘤细胞一般发展为致死性恶性 肿瘤。在本研究中，我们检查了接种EBV- 永生化B细胞可能对实验性肿瘤有抗肿瘤作用 无瘤小鼠的伯基特淋巴瘤。同时接种EBV- 永生化B细胞和Burkitt淋巴瘤细胞 皮下部位导致肿瘤消退，坏死和 伤痕累累。同样，同时接种EBV永生化B 皮下不同部位的细胞和Burkitt淋巴瘤细胞 导致了一定比例的伯基特肿瘤的消退。 此外，大多数已建立的人类Burkitt‘s肿瘤已经消退 瘤内接种EB病毒后出现坏死和疤痕- 永生化的B细胞。EBV永生化的B细胞继续发挥作用 这种抗肿瘤作用，即使在被辐射杀死的情况下也是如此。这个 Burkitt淋巴瘤治疗的实验方法 利用裸鼠排斥EBV永生化B细胞的能力 靶向对恶性肿瘤细胞的有效抗肿瘤反应 无法引出它。最近，我们开始研究 本实验中Burkitt淋巴瘤消退的机制 系统。初步信息表明，一组小鼠细胞因子 在肿瘤部位产生的趋化因子与肿瘤有关 回归。

Administration of lymphocytes or tumor cells transduced with specific cytokine genes represent novel approaches for the treatment of cancer. By either providing antitumor effector cells or stimulating antitumor immunity at the tumor site these experimental modalities have resulted in decreased tumorigenicity and regression of existing tumors in a number of experimental models. Recently, retroviral-mediated transfer in vivo of a herpes-virus-derived thymidine kinase (tk) gene into a proportion of brain glioma tumor cells rendered them sensitive to destruction by an antiviral drug. It also led to death of other tumor cells, not transduced with the tk gene, through a poorly defined bystander effect. In spite of these experimental results, the targeting of effector lymphocytes as well as anticancer cytokines and drug sensitivity factors to particular tumor sites has had limited clinical applications because it involves relatively complex procedures not widely available. We considered the possibility that tumor cell killing might be induced by inoculation of the tumor-bearing host with benign cells which are normally destroyed if inoculated into the same host. We reasoned that by stimulating a local cytotoxic response in vivo one might achieve killing of tumor cells through a bystander effect. When injected subcutaneously into irradiated athymic (nude) mice, human B cells immortalized with Epstein-Barr virus (EBV) either fail to grow or give rise to small tumors that soon regress through necrosis and scarring. The mechanism for this regression is not fully understood but has been attributed to residual host immunity. In the same experimental system, human Burkitt's lymphoma cells generally develop into lethal malignant tumors. In the present study, we examined whether inoculation of EBV- immortalized B cells might have an antitumor effect against experimental Burkitt's lymphoma in athymic mice. Simultaneous inoculation of EBV- immortalized B cells and Burkitt's lymphoma cells in the same subcutaneous site resulted in tumors that regressed with necrosis and scarring. Similarly, simultaneous inoculation of EBV-immortalized B cells and Burkitt's lymphoma cells in separate subcutaneous sites resulted in regression of a proportion of the Burkitt's tumors. Furthermore, most of the established human Burkitt's tumors regressed with necrosis and scarring after intratumor inoculations with EBV- immortalized B cells. The EBV-immortalized B cells continued to exert this antitumor effect even when killed with irradiation. The experimental approach to Burkitt's lymphoma treatment described here exploits the ability of athymic mice to reject EBV-immortalized B cells to target an effective antitumor response to malignant cells normally incapable of eliciting it. Recently, we have began to study the mechanisms mediating Burkitt's lymphoma regression in this experimental system. Preliminary information suggests that a set of murine cytokines and chemokines produced at the tumor site are responsible for tumor regression.