A New Strategy for Targeted Chemoimmunotherapy of Cancer

描述（由申请人提供）：当完全手术切除 原发性癌症通常是可能的， 转移性癌症的成功率要低得多，主要是因为对正常细胞的破坏。 组织限制了可以安全施用的细胞毒性药物的量 患者然而，这些抗癌药物中的大多数的功效可以是 如果肿瘤中的活性药物的量及其 与正常组织相比，远处转移可以选择性地增加。 该提案描述了实现这一目标的新战略。 我们最近证实，某些体外IL-2活化亚群， 淋巴细胞输注到荷瘤动物体内后， 在寻找和选择性浸润恶性组织方面很有天赋。在这 建议我们将利用这种能力，通过使用肿瘤寻找 T细胞（CD 8+）来源的淋巴细胞（TSL）作为靶向免疫的“制导导弹”， 将前药活化剂选择性地递送到癌症转移中。的 与TSL连接的前药-活化剂，可以将全身给药， 无毒的前体药物转化为活性药物。因为非常 少数活化的淋巴细胞分布到正常组织中， 活性药物将在重要器官如骨髓和肠中产生。的 使用TSL代替肿瘤特异性抗体作为 前药激活剂，一种被称为ADEPT的方法，提供了几个优点： 表达肿瘤特异性抗原和产生大量的 不需要特异性抗体，TSL的主动迁移可以 与被动相比， 抗体的扩散。 在该提案中，我们建议通过以下方式为TSL提供前药活化酶： 不同的方法，并分析肿瘤归巢的能力， 携带酶的TSL以及非肿瘤相关酶的命运。使用 其中一种方法，我们现在已经表明，TSL能够带来 酶选择性地进入肿瘤，并且大量的酶可以 在肿瘤组织中持续存在至少60小时。这些发现强烈 支持这一战略的可行性。将使用同源肿瘤模型 为了检验前药在肿瘤组织中选择性活化的假设， 通过TSL运输到肿瘤的酶将导致更好的肿瘤 减少和更少（如果有的话）的毒副作用比治疗与 活性药物的最大耐受剂量。

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.