COMBINED RADIOIMMUNOTHERAPY WITH RADIOTHERAPY

放射免疫治疗与放射治疗相结合

• 批准号: 2843985
• 负责人: JOHN L HUMM
• 金额: $ 12.88万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至 2003-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2843985
• 关键词: apoptosis; athymic mouse; autoradiography; colorectal neoplasms; combination cancer therapy; histopathology; immunocytochemistry; immunoglobulin G; molecular weight; monoclonal antibody; neoplasm /cancer immunotherapy; neoplasm /cancer radiation therapy; neoplastic cell; neoplastic growth; nonhuman therapy evaluation; proliferating cell nuclear antigen; radiation dosage; radiobiology; radiotracer

This grant application examines the hypothesis that radiolabeled antibody heterogeneity is the principal source of failure of radioimmunotherapy (RIT). It proposes that this limitation can be overcome by the combination of RIT with external beam radiotherapy (XRT). This study will investigate the interaction between XRT with RIT, and determine the optimum combination of these two modalities for maximum tumor efficacy. The hypothesis will be tested with the murine SW1222 colorectal xenograft model system using intact A33 IgG monoclonal antibody as the targeting agent and its single chain hypervariable sFv fragment. There are four specific aims: (1) To determine the 3D microdistribution of radiolabeled A33 IgG within the SW1222 tumor xenograft system using phosphor plate autoradiography. The dependence of the distribution will be investigated with respect of the antibody/antigen molar ratio, the effect of molecular weight, by concomitant administration of the single chain hypervariable fragment sFv A33 with the parent A33 IgG, and following pre-external beam irradiation. (2) To determine how radiation tissue damage facilitates/impedes the penetration of antibody into the tumor. This will be achieved by conventional histological and immunohistochemical stains designed to ascertain the effects of radiation damage on tumor blood supply, tumor cell density, as well as antigen density and inflammatory response. These changes will be used to provide a scientific rationale for the measured radiolabeled antibody distribution from specific aim 1. In addition, this aim will attempt to quantitate changes in tumor cell response by determining the fraction of cells undergoing apoptotic cell death, (by the tunel assay), as well as changes in the fraction of cycling cells, (determined by IUdR incorporation and Ki67 and PCNA immunohistochemistry), as a surrogate of mitotic cell death. (3) To determine the therapeutic efficacy by tumor growth delay and cure after treatment with XRT and RIT alone and then in combination. Experiments will be performed in which tumors are treated with XRT followed by RIT, XRT and RIT simultaneously, and RIT prior to XRT, in order to determine the optimum combination therapy. Variations in the tumor response will be correlated with the results from aim 1 and 2. (4) To develop a radiobiological model, which determines the therapeutic effectiveness from a heterogeneous activity distribution. The model will be tested using information from the source distribution from autoradiographic data (aim 1) to predict overall tumor response measured by specific aim 3.

该赠款申请研究了这样一个假设，即放射性标记的抗体异质性是放射免疫疗法（RIT）失败的主要来源。 它提出，可以通过将RIT与外束放射疗法（XRT）组合来克服这种局限性。 这项研究将研究XRT与RIT之间的相互作用，并确定这两种方式的最佳组合以获得最大的肿瘤功效。 该假设将使用完整的A33 IgG单克隆抗体作为靶向剂及其单链高变量SFV片段，使用完整的A33 IgG单克隆抗体使用鼠SW1222结直肠移植模型系统进行测试。 有四个具体的目的：（1）使用磷光板自显影术确定SW1222肿瘤异种移植系统中放射性标记A33 IgG的3D微分布。 分布的依赖性将通过抗体/抗原摩尔比（分子量的效果）与亲本A33 IgG以及外部前束照射后，研究分子量的影响，分子量的效果，分子量的影响，分子量的影响。 （2）确定辐射组织损伤如何促进/阻碍抗体渗透到肿瘤中。 这将通过常规的组织学和免疫组织化学染色来实现，旨在确定辐射损伤对肿瘤血液供应，肿瘤细胞密度以及抗原密度和炎症反应的影响。这些变化将用于为从特定目的的测得的放射标记的抗体分布提供科学原理1。此外，此目的将通过确定经历凋亡细胞死亡的细胞的分数来定量肿瘤细胞反应的变化（通过TUNEL分析）（通过TUNEL分析）（通过TUNEL分析），以及由IUDR IMPUN和KI67 IMPRINIS INFRINCER IMPRINT和PCNA IMPRININGINING oudr IMPRINIS IMPRUN和KI67 IMPERINIS INFRINCIN和KI67 imp.66确定。有丝分裂细胞死亡。 （3）通过单独使用XRT和RIT治疗后，然后结合使用肿瘤生长延迟和治愈来确定治疗功效。将进行实验，在其中用XRT处理肿瘤，然后同时进行RIT，XRT和RIT，并在XRT之前进行RIT，以确定最佳联合治疗。肿瘤反应的变化将与AIM 1和2的结果相关。（4）开发了放射生物学模型，该模型决定了异质活性分布的治疗有效性。 该模型将使用来自放射自显影数据的源分布（AIM 1）的信息进行测试，以预测特定目标3测量的总体肿瘤反应。