A New Strategy for Targeted Chemoimmunotherapy of Cancer

描述(由申请人提供)：在完成手术切除时 原发癌症往往是有可能的，药物治疗 转移癌的成功率要低得多，主要是因为对正常组织的损害 组织限制了可安全给药的细胞毒药物的量 病人。然而，这些抗癌药物中的大多数的疗效可以是 如果肿瘤中活性药物的量和它的 与正常组织相比，远处转移可以选择性地增加。 这项提议描述了一种实现这一目标的新战略。 我们最近证明了某些IL-2亚群在体外被激活 淋巴细胞在注入荷瘤动物体内后，显著地 擅长发现和选择性地渗透恶性组织。在这 建议我们将通过使用肿瘤搜索来利用这种能力 T细胞(CD8+)来源的淋巴细胞(TSL)作为靶向的“制导导弹” 选择性地将前药物激活剂输送到癌症转移中。这个 前药激活剂，附着在TSL上，可以转化为全身给药， 无毒前药转化为活性药物，在转移中有选择性。因为非常 少数活化的淋巴细胞分布在正常组织中，数量有限 活性药物会在骨髓和肠道等重要器官中产生。这个 用TSL代替肿瘤特异性抗体作为肿瘤特异性抗体的载体 前药物激活剂，一种被称为ADEPT的方法，提供了几个优势： 肿瘤特异性抗原的表达及其高量表达 不需要特定的抗体，TSL的主动迁移可以 与被动的相比，确保更深的穿透即使是低血管的肿瘤 抗体的扩散。 在这项建议中，我们建议通过以下方式为TSL提供前药物激活酶 不同的方法和分析肿瘤的归巢能力 携带酶的TSL以及非肿瘤相关酶的命运。vbl.使用 其中一种方法，我们现在已经证明了TSL能够带来 酶选择性地进入肿瘤，而大量酶可以 在肿瘤组织中持续至少60小时。这些发现有力地证明了 支持这一战略的可行性。将使用同基因肿瘤模型 为了验证前药物在肿瘤组织中选择性激活的假设 通过TSL转运到肿瘤的酶将导致更好的肿瘤 减少和更少(如果有)毒副作用比治疗 活性药物的最大耐受量。

DESCRIPTION (provided by applicant): While complete surgical resection of primary cancer is often possible, the pharmacological treatment of metastasizing cancer is much less successful, mainly because damage to normal tissues limits the amount of cytotoxic drugs that can be safely administered to patients. The efficacy of most of these anti-cancer drugs can, however, be improved substantially if the amount of active drug in the tumor and its distant metastases can be selectively increased compared to the normal tissues. This proposal describes a novel strategy for achieving this goal. We have recently demonstrated that certain subsets of in vitro IL-2 activated lymphocytes, after their infusion into tumor-bearing animals, are remarkably talented in finding and selectively infiltrating malignant tissues. In this proposal we will take advantage of this ability by using tumor-seeking lymphocytes (TSLs) of T cell (CD8+) origin as "guided missiles" for targeted delivery of prodrug-activators selectively into cancer metastases. The prodrug-activator, attached to the TSLs, can convert systemically administered, non-toxic prodrug into active drug selectively in the metastases. Since very few activated lymphocytes distribute into normal tissues, limited amounts of active drug will be generated in vital organs such as bone marrow and gut. The use of TSLs instead of tumor specific antibodies as carriers of prodrug-activators, an approach known as ADEPT, offers several advantages: expression of tumor specific antigens and production of high amounts of specific antibodies are not needed, and the active migration of the TSLs can ensure a deeper penetration of even hypovascularized tumors compared to passive diffusion of antibodies. In this proposal, we suggest to provide TSLs with prodrug-activating enzymes by different methods and to analyze the tumor-homing capability of the enzyme-carrying TSLs as well as the fate of non-tumor-associated enzymes. Using one of these methods, we have now shown that TSLs are capable of bringing enzyme selectively into tumors and that significant amounts of the enzyme can persist in the tumor tissue for at least 60 hours. These findings strongly supports the feasibility of this strategy. Syngeneic tumor models will be used to test the hypothesis that activation of prodrugs selectively in tumor tissue by enzymes transported to the tumors by TSLs will lead to a better tumor reduction and fewer (if any) toxic side effects than treatment with the maximally tolerated dose of the active drug.