COMBINED RADIOIMMUNOTHERAPY WITH RADIOTHERAPY

放射免疫治疗与放射治疗相结合

• 批准号: 6150259
• 负责人: JOHN L HUMM
• 金额: $ 15.21万
• 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/6150259
• 关键词: apoptosis; athymic mouse; autoradiography; colorectal neoplasms; combination cancer therapy; histopathology; immunocytochemistry; immunoglobulin G; molecular weight; monoclonal antibody; neoplasm /cancer radioimmunotherapy; 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。 它提出可以通过 RIT 与外照射放射治疗 (XRT) 的结合来克服这一限制。 本研究将研究 XRT 与 RIT 之间的相互作用，并确定这两种方式的最佳组合，以实现最大的肿瘤疗效。 该假设将通过鼠 SW1222 结直肠异种移植模型系统进行测试，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。 有四个具体目标：(1) 使用磷光板放射自显影确定 SW1222 肿瘤异种移植系统内放射性标记的 A33 IgG 的 3D 微分布。 将通过同时施用单链高变片段sFv A33与亲本A33 IgG，并在预外束照射后，研究抗体/抗原摩尔比、分子量的影响的分布依赖性。 (2) 确定放射组织损伤如何促进/阻碍抗体渗透到肿瘤中。 这将通过传统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。这些变化将用于为特定目标 1 测量的放射性标记抗体分布提供科学依据。此外，该目标将尝试通过确定经历凋亡细胞死亡的细胞比例来量化肿瘤细胞反应的变化，（通过tunel测定），以及循环细胞分数的变化（通过 IUdR 掺入以及 Ki67 和 PCNA 免疫组织化学测定），作为有丝分裂细胞死亡的替代。 (3)以XRT和RIT单独治疗和联合治疗后肿瘤生长延迟和治愈来确定治疗效果。将进行实验，其中先用 XRT 治疗肿瘤，然后用 RIT 治疗，同时用 XRT 和 RIT 治疗，以及先用 RIT 治疗再用 XRT 治疗，以确定最佳联合治疗。肿瘤反应的变化将与目标1和2的结果相关。(4)开发放射生物学模型，该模型根据异质活性分布确定治疗效果。 该模型将使用放射自显影数据（目标 1）的源分布信息进行测试，以预测特定目标 3 测量的总体肿瘤反应。