高剂量放射免疫疗法结合同种异体肿瘤模型中的体外清除：毒性、治疗效果和肿瘤模型评估。

High-dose radioimmunotherapy combined with extracorporeal depletion in a syngeneic rat tumor model: evaluation of toxicity, therapeutic effect, and tumor model.

机构信息

Department of Oncology, Lund University, Lund, Sweden.

出版信息

Cancer. 2010 Feb 15;116(4 Suppl):1043-52. doi: 10.1002/cncr.24791.

DOI:10.1002/cncr.24791

PMID:20127949

Abstract

BACKGROUND

The aim of the current study was to investigate the possibility of increasing the maximal tolerated dose (MTD) of a tumor-selective radiolabeled antibody when radioimmunotherapy (RIT) is combined with extracorporeal depletion of radioimmunoconjugates from the circulation. Furthermore, the authors evaluated whether this increase in dose improved the therapeutic effect on solid manifest tumors in an immunocompetent animal model.

METHODS

Rats were injected with high activities/body weight of lutetium ((177)Lu)- or yttrium ((90)Y)-labeled antibody conjugates (monoclonal antibody tetraazacyclododecanetetraacetic acid-biotin) and subjected to removal of the conjugate from the circulation by extracorporeal affinity adsorption treatment 24 hours postinjection. Myelotoxicity was assessed by analysis of blood parameters for 12 weeks. The effect of increased doses in combination with extracorporeal affinity adsorption treatment was evaluated with respect to myelotoxicity and therapeutic effect in a syngeneic rat colon cancer model.

RESULTS

The MTD of (177)Lu- or (90)Y-labeled immunoconjugates could be increased 2.0x or 1.5x, respectively, when RIT was combined with extracorporeal affinity adsorption treatment. All animals treated with (177)Lu- or (90)Y-labeled antibodies showed persistent complete response of manifest tumors (approximately 10 x 15 mm) within 16 days postinjection. However, several animals showed disseminated disease 1.5 to 3 months postinjection.

CONCLUSIONS

Extracorporeal affinity adsorption treatment is a method that safely and efficiently reduces myelotoxicity associated with RIT. Extracorporeal affinity adsorption treatment allows increased administered activity without increased toxicity, with the aim of increasing the absorbed dose to the tumor. However, because tumor/normal tissue radiosensitivity ratios are more favorable in rodents, it is not possible to draw any conclusions concerning the therapeutic efficacy of increased administered activity in combination with extracorporeal affinity adsorption treatment in this study. Targeted RIT with beta-emitting radionuclides seems not to be effective in microscopic disease, because metastases developed at sites without previously known disease.

摘要

背景

本研究旨在探讨在体外清除循环中放射性免疫复合物（RIC）的情况下，增加肿瘤选择性放射性标记抗体的最大耐受剂量（MTD）的可能性。此外，作者还评估了这种剂量的增加是否可以改善免疫活性动物模型中实体显性肿瘤的治疗效果。

方法

大鼠注射高活度/体重的镥（177Lu）或钇（90Y）标记的抗体缀合物（单克隆抗体四氮杂环十二烷四乙酸-生物素），并在注射后 24 小时通过体外亲和吸附处理去除循环中的缀合物。通过分析血液参数，评估 12 周的骨髓毒性。在同种异体大鼠结肠癌模型中，评估增加剂量与体外亲和吸附处理联合应用的骨髓毒性和治疗效果。

结果

当 RIT 与体外亲和吸附处理联合应用时，177Lu 或 90Y 标记免疫缀合物的 MTD 可分别增加 2.0 倍或 1.5 倍。所有接受 177Lu 或 90Y 标记抗体治疗的动物在注射后 16 天内均表现出显性肿瘤（约 10x15mm）的持续完全缓解。然而，一些动物在注射后 1.5 至 3 个月出现播散性疾病。

结论

体外亲和吸附处理是一种安全有效地降低与 RIT 相关骨髓毒性的方法。体外亲和吸附处理允许增加给予的活性而不增加毒性，目的是增加肿瘤的吸收剂量。然而，由于啮齿动物的肿瘤/正常组织放射敏感性比值更有利，因此无法根据本研究中增加给予的活性与体外亲和吸附处理联合应用的治疗效果得出任何结论。用β发射放射性核素进行靶向 RIT 似乎对微小疾病无效，因为转移发生在先前未知疾病的部位。