DeNardo S J, Mirick G R, Kroger L A, O'Grady L F, Erickson K L, Yuan A, Lamborn K R, Hellstrom I, Hellstrom K E, DeNardo G L
University of California, Davis Medical Center, Sacramento.
Cancer. 1994 Feb 1;73(3 Suppl):1023-32. doi: 10.1002/1097-0142(19940201)73:3+<1023::aid-cncr2820731341>3.0.co;2-u.
There has been little success in using radioimmunotherapy in patients with adenocarcinoma, partly because of the low tumor uptake of the administered monoclonal antibody (MoAb). The authors recently reported therapeutic response in advanced cancer patients who received 131I chimeric-L6 MoAb. The L6 MoAb identifies abundant, nonshed antigen that is expressed in many human carcinomas, including carcinomas of the lung, breast, colon, and ovary. In vitro both mouse L6 (L6) and chimeric L6 (ChL6) mediate complement-dependent tumor cytolysis with human serum, and antibody-dependent tumor cell cytolysis with normal human peripheral blood mononuclear cells. The authors have used L6 or ChL6 for radioimmunotherapy to exploit their biologic activity to create a "therapeutic window" of increased vascular permeability, allowing more 131I MoAb to reach the tumor. A reactive target is present in the vascular endothelium but can be covered by unlabeled L6 or ChL6.
Nine patients with metastatic breast cancer were treated on a therapy protocol and received imaging and therapy doses of 131I ChL6 on two sequential days at 4 week intervals. During each treatment cycle, serum cytokines, complement, albumin, and 131I ChL6 blood clearance were monitored, peripheral blood mononuclear cell activation was assessed, and tumor uptake and response were documented.
After L6 or ChL6 was infused, patients demonstrated immediate serum-complement activation, manifested by rapidly decreasing levels of serum complements 3 and 4. Tumor uptake of the second 131I MoAb (therapeutic) injection, given after the second daily injections of 200 mg MoAb, was usually higher than the tumor uptake of the first 131I MoAb (imaging) dose given after a single 200 mg infusion of MoAb. Although serum complement frequently decreased after the first 50-100 mg dose of L6 or ChL6, elevation of soluble interleukin-2 receptor (IL-2R) in serum was seen only in patients who received 150 mg or more of L6 or ChL6. In the nine treated patients, with only one exception, the higher grade of therapeutic tumor response was seen in patients with a greater increase in IL-2R levels.
The clinical importance of understanding these mechanisms is emphasized by the occurrence of measurable tumor regressions in five of the first nine advanced metastatic breast cancer patients treated in this manner. Absence of pulmonary edema and delayed release of dose-dependent IL-2R suggest that targeting of the pulmonary endothelium by L6 or ChL6 is not the major cause of the observed biologic effects. This unique response of a solid tumor to radioimmunoconjugate therapy may be secondary to both the increased delivery of the radioimmunoconjugate to tumor cells caused by enhanced vascular permeability, and to synergistic effects of radiation and activated effector cell mechanisms.
在腺癌患者中使用放射免疫疗法的成效甚微，部分原因是所给予的单克隆抗体（MoAb）在肿瘤中的摄取率较低。作者最近报道了接受¹³¹I嵌合L6 MoAb治疗的晚期癌症患者的治疗反应。L6 MoAb可识别在许多人类癌症中表达的丰富的、不脱落的抗原，包括肺癌、乳腺癌、结肠癌和卵巢癌。在体外，小鼠L6（L6）和嵌合L6（ChL6）均可与人血清介导补体依赖性肿瘤细胞溶解，并与正常人外周血单核细胞介导抗体依赖性肿瘤细胞溶解。作者使用L6或ChL6进行放射免疫治疗，以利用其生物活性创造一个血管通透性增加的“治疗窗口”，使更多的¹³¹I MoAb能够到达肿瘤部位。血管内皮中存在一个反应性靶点，但可被未标记的L6或ChL6覆盖。
9例转移性乳腺癌患者按照治疗方案接受治疗，每隔4周连续两天接受¹³¹I ChL6的成像剂量和治疗剂量。在每个治疗周期中，监测血清细胞因子、补体、白蛋白和¹³¹I ChL6的血液清除率，评估外周血单核细胞活化情况，并记录肿瘤摄取和反应。
输注L6或ChL6后，患者立即出现血清补体激活，表现为血清补体3和4水平迅速下降。在每日注射200 mg MoAb后给予的第二次¹³¹I MoAb（治疗性）注射的肿瘤摄取通常高于在单次输注200 mg MoAb后给予的第一次¹³¹I MoAb（成像）剂量的肿瘤摄取。尽管在首次给予50 - 100 mg剂量的L6或ChL6后血清补体经常下降，但仅在接受150 mg或更多L6或ChL6的患者中观察到血清可溶性白细胞介素-2受体（IL-2R）升高。在9例接受治疗的患者中，除1例例外，IL-2R水平升高幅度较大的患者出现了更高等级的治疗性肿瘤反应。
以这种方式治疗的前9例晚期转移性乳腺癌患者中有5例出现了可测量的肿瘤消退，这强调了理解这些机制的临床重要性。未出现肺水肿以及剂量依赖性IL-2R的延迟释放表明，L6或ChL6对肺内皮的靶向作用不是观察到的生物学效应的主要原因。实体瘤对放射免疫偶联物治疗的这种独特反应可能继发于血管通透性增强导致的放射免疫偶联物向肿瘤细胞的递送增加，以及辐射和活化效应细胞机制的协同作用。
