TUMOR LOCALIZATION/THERAPEUTIC ACTIVITY OF NK CELLS IN ADOPTIVE IMMUNOTHERAPY

我们对这场战争成功或失败的基础知之甚少。 适应性免疫疗法（AIT），但随着对 过继转移效应细胞的抗肿瘤机制，其 可能会大大改善这种治疗方式。 因此，为了评估和改善疗效， IL-2激活的NK细胞作为效应细胞在癌症AIT中的作用， 这些细胞在过继移植后定位到肿瘤中的能力 转移将被研究，并且它们在体内的抗肿瘤作用将被研究。 将对确定的转移进行分析。 基于 在肺和肝的同系啮齿动物模型中的先前工作 转移，假设虽然一定数量的A- NK细胞可能必须定位于恶性组织中， 为了诱导其回归，数量可能会因 转移灶的位置及其组织学类型。 此外，虽然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 不能沿着保证治疗效果。据预测 A-NK细胞在AIT中的成功将取决于 足够数量的特异性针对恶性肿瘤的效应细胞 组织的抗肿瘤活性的维持， 注射效应细胞。 为了验证这一预测和相关的 假设，将检查以下内容：a）A的能力- NK细胞定位于啮齿动物实验性肺转移， 肝脏、腹膜腔和皮下组织; B） 不同器官肿瘤密度之间的关系 浸润A-NK细胞和治疗功效; c）影响 肿瘤异质性和血管化对A-NK细胞杀伤活性的影响 细胞定位于肿瘤部位; d） 肿瘤浸润性A-NK细胞和f）可能存在的 肿瘤环境中可能下调或损害 e）用于抵消A-NK细胞的抑制性免疫应答的策略， 肿瘤内抑制因子的作用，以及 通过使用长- 活的Peg-IL-2而不是短寿命的常规IL-2。 的结果 这些调查应有助于确定最佳条件 用于基于A-NK细胞的癌症AIT，并提供 在类似试验中考虑和评估的关键参数 转移性癌症患者的临床AIT。

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.