Welt S, Divgi C R, Kemeny N, Finn R D, Scott A M, Graham M, Germain J S, Richards E C, Larson S M, Oettgen H F
Memorial Sloan-Kettering Cancer Center, New York, NY 10021.
J Clin Oncol. 1994 Aug;12(8):1561-71. doi: 10.1200/JCO.1994.12.8.1561.
A phase I/II study was designed to determine the maximum-tolerated dose (MTD) of iodine 131-labeled monoclonal antibody (mAb) A33 (131I-mAb A33) administered intravenously, its limiting organ toxicity, and its radioisotope retention in tumors, and to develop preliminary evidence of antitumor activity.
Patients (N = 23) with colorectal cancer who had failed to respond to conventional chemotherapy but had not received prior radiotherapy were treated with escalating doses of 131I-mAb A33. Three or more patients were entered at each dose level, starting at 30 mCi/m2, with increments of 15 mCi/m2 to a maximal dose of 90 mCi/m2. Radiolabeling was performed to maintain a specific activity of 30 mCi/m2/4 mg mAb A33 (projected maximum, 15 mCi/mg). Patients were under strict isolation precautions until whole-body radiation levels decreased to less than 5 mrem/h at 1 m. Serial radioimmunoscintigrams were performed in some cases for up to 3 weeks after 131I-mAb A33 administration.
All 20 patients with radiologic evidence of disease showed localization of radioisotope to sites of disease. Two patients with elevated carcinoembryonic antigen (CEA) levels and negative radiologic tests did not have positive antibody scans. One patient with a small-bowel cancer also had a negative antibody scan. The major toxicity was hematologic and was more pronounced in patients with compromised bone marrow due to prior chemotherapy. Of five patients who received 78 to 84 mCi/m2 131I-mAb A33, one had grade 3 and one grade 4 toxicity; of six patients treated with 86 to 94 mCi/m2 131I-mAb A33, two had grade 4 and one grade 1 toxicity. The MTD was determined to be 75 mCi/m2 in these heavily pretreated patients. Although the isotope showed variable uptake in the normal bowel, gastrointestinal symptoms were mild (n = 8) or absent. No major responses were observed; however, three patients had evidence of mixed responses, and CEA levels decreased in two patients without clinical or radiologic measurable disease. Immunoreactivity of radiolabeled mAb A33 decreased at the highest dose levels in preparations in which specific activity exceeded 18 mCi/mg.
The A33 antigen appears to be a promising target for radioimmunotherapy of colon cancer. The modest antitumor activity of 131I-mAb A33 in heavily pretreated patients is encouraging because of its lack of toxicity in the bowel, the only antigen-positive normal tissue.
设计一项I/II期研究，以确定静脉注射碘131标记的单克隆抗体（mAb）A33（131I-mAb A33）的最大耐受剂量（MTD）、其限制器官毒性及其在肿瘤中的放射性同位素滞留情况，并提供抗肿瘤活性的初步证据。
23例对传统化疗无反应但未接受过放疗的结直肠癌患者接受递增剂量的131I-mAb A33治疗。每个剂量水平纳入3例或更多患者，起始剂量为30 mCi/m2，每次递增15 mCi/m2，最大剂量为90 mCi/m2。进行放射性标记以维持30 mCi/m2/4 mg mAb A33的比活度（预计最大值为15 mCi/mg）。患者采取严格的隔离预防措施，直至全身辐射水平在距离1米处降至低于5 mrem/h。在部分病例中，于131I-mAb A33给药后长达3周内进行系列放射免疫闪烁扫描。
所有20例有疾病影像学证据的患者均显示放射性同位素在疾病部位的定位。2例癌胚抗原（CEA）水平升高但影像学检查阴性的患者抗体扫描未呈阳性。1例小肠癌患者抗体扫描也为阴性。主要毒性为血液学毒性，在因先前化疗导致骨髓功能受损的患者中更为明显。在接受78至84 mCi/m2 131I-mAb A33治疗的5例患者中，1例出现3级毒性，1例出现4级毒性；在接受86至94 mCi/m2 131I-mAb A33治疗的6例患者中，2例出现4级毒性，1例出现1级毒性。在这些经过大量预处理的患者中，MTD确定为75 mCi/m2。尽管同位素在正常肠道中的摄取情况各异，但胃肠道症状轻微（n = 8）或无症状。未观察到主要缓解；然而，3例患者有混合反应的证据，2例无临床或影像学可测量疾病的患者CEA水平下降。在比活度超过18 mCi/mg的制剂中，放射性标记的mAb A33在最高剂量水平时免疫反应性降低。
A33抗原似乎是结肠癌放射免疫治疗的一个有前景的靶点。131I-mAb A33在经过大量预处理的患者中适度的抗肿瘤活性令人鼓舞，因为它在肠道（唯一抗原阳性的正常组织）中无毒性。
