COMBINED RADIOIMMUNOTHERAPY WITH RADIOTHERAPY

放射免疫治疗与放射治疗相结合

• 批准号: 6350245
• 负责人: JOHN L HUMM
• 金额: $ 15.7万
• 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/6350245
• 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.

这项拨款申请检验了放射性标记抗体异质性是放射免疫治疗（RIT）失败的主要原因的假设。它提出，这一限制可以通过RIT与外束放疗（XRT）的组合来克服。本研究将探讨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疗效。该假设将在小鼠SW1222结直肠癌异种移植模型系统中进行验证，该模型使用完整的A33 IgG单克隆抗体作为靶向剂及其单链高变sFv片段。有四个具体目的：(1)利用荧光板放射自显影技术确定SW1222肿瘤移植系统中放射标记的A33 IgG的三维微分布。通过将单链高变片段sFv A33与母体A33 IgG同时施用，并进行预外束照射，研究其分布与抗体/抗原摩尔比、分子量的影响的相关性。(2)确定放射性组织损伤如何促进/阻碍抗体向肿瘤的渗透。这将通过常规的组织学和免疫组织化学染色来实现，这些染色旨在确定辐射损伤对肿瘤血液供应、肿瘤细胞密度、抗原密度和炎症反应的影响。这些变化将用于为特异靶1测量的放射性标记抗体分布提供科学依据。此外，本研究将尝试通过确定凋亡细胞死亡的细胞比例（通过隧道试验）以及循环细胞比例的变化（通过IUdR掺入和Ki67和PCNA免疫组织化学测定）来量化肿瘤细胞反应的变化，作为有丝分裂细胞死亡的替代。(3)观察XRT和RIT单独或联合治疗后肿瘤生长延迟和治愈的疗效。我们将对肿瘤进行XRT后RIT、XRT和RIT同时治疗、RIT后XRT的实验，以确定最佳的联合治疗方案。肿瘤反应的变化将与目的1和目的2的结果相关。(4)建立放射生物学模型，从异质性活性分布中确定治疗效果。该模型将使用来自放射自显像数据（目标1）的源分布信息进行测试，以预测通过特定目标3测量的总体肿瘤反应。