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首页> 外文期刊>British Journal of Cancer >Dose escalation with repeated intrathecal injections of 131I-labelled MAbs for the treatment of central nervous system malignancies
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Dose escalation with repeated intrathecal injections of 131I-labelled MAbs for the treatment of central nervous system malignancies

机译：鞘内注射131I标记的单克隆抗体反复鞘内注射治疗中枢神经系统恶性肿瘤的剂量递增

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We have previously demonstrated a 33% response rate in patients with primitive neurectodermal tumours after the direct injection of 131I-monoclonal antibodies (MAbs) into the cerebrospinal fluid (CSF). Dose-limiting toxicity is myelosuppression due to the passage of the radioimmunoconjugate from the CSF to the blood compartment. This occurs at doses of 2220 MBq of 131I-MAb and above, although this is not seen in all patients studied and appears to be related to the degree of prior therapy received. Rather than attempting to improve the efficacy of this approach to the treatment of disseminated disease within the CSF compartment by dose escalation and haemopoietic rescue, we have explored the possibility of repeatedly administering the radioimmunoconjugate. Eight patients were recruited to the study, two of whom received two and six of whom received three injections of 131I-MAb. After repeated administration of 131I-MAb pharmacokinetic data revealed that, with one exception, the radioimmunoconjugate cleared from the CSF compartment with similar kinetics, while its residence time in the blood decreased with each injection. This was due to the development of an anti-mouse Ig response in the blood. Clearance of 131I-MAb from the ventricular CSF appears to be independent of the presence of an anti-mouse Ig response in this compartment. The differential clearance of the radioimmunoconjugate from the ventricular CSF and from the blood results in a marked increase in the therapeutic index that can be achieved. Up to 5920 MBq of 131I-MAb was administered as the third injection of radioimmunoconjugate and combined doses of up to 12,500 MBq were given without either haematological or neurological toxicity. These data illustrate that dose escalation and thus an increase in the dose rate delivered to tumour cells within the CSF is possible if ways are found to reduce the residence time of the radioimmunoconjugate in the blood compartment. Suggestions as to how this can best be achieved are reviewed in detail.
机译：我们先前已经证明，将131I单克隆抗体（MAb）直接注射入脑脊液（CSF）后，患有原始神经直肠真皮肿瘤的患者的响应率达到33％。剂量限制性毒性是由于放射性免疫缀合物从CSF传递到血液室而引起的骨髓抑制。这在131I-MAb的剂量为2220 MBq或以上时发生，尽管在所有研究的患者中均未见到，并且似乎与先前接受的治疗程度有关。我们没有尝试通过剂量增加和造血抢救来提高这种方法治疗脑脊液腔内弥漫性疾病的功效，而是探索了反复施用放射免疫缀合物的可能性。招募了8名患者参加研究，其中2名接受了2次注射，其中6名接受了3次131I-MAb注射。重复施用131I-MAb后，药代动力学数据显示，除一个例外，放射免疫缀合物以相似的动力学方式从CSF隔室清除，而每次注射后其在血液中的停留时间减少。这是由于血液中产生了抗小鼠Ig反应。从心室CSF清除131I-MAb似乎与该隔室中抗小鼠Ig反应的存在无关。放射免疫缀合物从心室CSF和血液中的差异清除导致可达到的治疗指数显着提高。作为第三次放射免疫缀合物的注射，给予高达5920 MBq的131I-MAb，并给予高达12,500 MBq的联合剂量，而没有血液学或神经毒性。这些数据表明，如果发现减少放射免疫缀合物在血液腔室中的停留时间的方法，则剂量的增加以及因此传递至CSF内的肿瘤细胞的剂量率的增加是可能的。详细讨论了有关如何最好地实现这一点的建议。

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