TUMOR LOCALIZATION/THERAPEUTIC ACTIVITY OF NK CELLS IN ADOPTIVE IMMUNOTHERAPY

人们对……成败的基础知之甚少 过继免疫疗法(AIT)，但随着对 过继转移效应细胞的抗肿瘤机制(S) 可能会大大改善这种治疗方式。 因此，以评估和提高疗效为目标 在肿瘤的AIT中，IL-2激活的NK细胞作为效应细胞， 领养后这些细胞在肿瘤中的定位能力 将对转移及其体内抗肿瘤作用进行研究 针对已确定的转移进行分析。基于 肺和肝同基因啮齿动物模型的研究进展 转移，假设当一定数量的A- NK细胞可能必须按顺序定位在恶性组织中 为了诱导它的回归，这个数字可能会根据 转移瘤的位置和组织学类型。 此外，A-NK细胞在恶性肿瘤中的定位 组织似乎是治疗效果的先决条件，它可能 不能长期保证治疗效果。据预测， A-NK细胞在AIT中的成功将取决于 足够数量的针对恶性肿瘤的效应细胞 组织，并维持其抗肿瘤活性。 注射效应细胞。来测试这一预测和与之相关的 假设，将检验以下内容：a)A- NK细胞定位于啮齿动物实验性肺部转移， 肝脏、腹膜腔和皮下组织；b) 肿瘤密度与各脏器的关系 浸润性A-NK细胞与疗效；c)影响 肿瘤异质性和血管生成对A-NK细胞功能的影响 定位于肿瘤部位的细胞；d)功能状态 肿瘤浸润性A-NK细胞和f)可能存在 肿瘤环境中可能下调或损害的因素 A-NK细胞，以及e)对抗抑制的策略 肿瘤内抑制因素的影响，以及 通过使用长效抗肿瘤药物获得肿瘤内高浓度的IL-2 活的Peg-IL-2而不是短暂的常规IL-2。结果是 这些调查应该有助于确定最佳条件 用于基于A-NK细胞的癌症AIT，并提供 在模拟试验中要考虑和评估的关键参数 转移性癌症患者的临床辅助治疗。

Very little is known about the basis for the success or failure of adoptive-immunotherapy (AIT), but with increased insight into the anti-tumor mechanism(s) of adoptively transferred effector cells, it may be possible to improve considerably this therapeutic modality. Thus, with the objective of evaluating and improving the efficacy of IL-2-activated NK cells as effector cells in AIT of cancer, the ability of these cells to localize into tumors following adoptive transfer will be investigated, and their anti-tumor effect in vivo against established metastases will be analyzed. Based on previous work in syngeneic rodent models of lung and liver metastases, it is hypothesized that while a certain number of A- NK cells must probably localize into the malignant tissue in order to induce its regression, the number might differ depending on the location of the metastases and on their histological type. Furthermore, while localization of A-NK cells in the malignant tissues appears to be a prerequisite for therapeutic effect, it might not along guarantee therapeutic efficacy. It is predicted that the success of A-NK cells in AIT will depend on both the delivery of sufficient numbers of effector cells specifically to the malignant tissue, and the maintenance of the anti-tumor activity of the injected effector cells. To test this prediction and the associated hypotheses, the following will be examined: a) the ability of A- NK cells to localize into rodent experimental metastases in lungs, livers, peritoneal cavity, and subcutaneous tissue; b) The relationship in various organs between the density of tumor- infiltrating A-NK cells and therapeutic efficacy; c) The influence of tumor heterogeneity and vascularization on the ability of A-NK cells to localize at sites of tumors; d) The functional status of tumor-infiltrating A-NK cells and f) the possible presence of factors in the tumor milieu which might downregulate or damage the A-NK cells, and e) Strategies for counteracting the inhibitory effect of intratumoral suppressor factors, and the possibility to obtain high intratumoral concentrations of IL-2 by the use of long- lived Peg-IL-2 instead of short-lived regular IL-2. The results of there investigations should help to identify the optimal conditions for A-NK cell-based AIT of cancer and provide indications of the key parameters to consider and assess in analogous trials of clinical AIT for patients with metastatic cancer.