Wei B R, Ghetie M A, Vitetta E S
Immunology Graduate Program, University of Texas Southwestern Medical Center at Dallas 75235-8576, USA.
Clin Cancer Res. 2000 Feb;6(2):631-42.
Immunoconjugates (ICs) consist of a targeting moiety and a toxic moiety and have the specificity that traditional cancer therapy lacks. At appropriate doses, ICs are safe and effective in treating various cancers in experimental animals and in humans. However, because cures are rarely achieved using single agents, regimens involving combinations of agents with different mechanisms of action must be evaluated. In this study, we explored the efficacy and toxicity of a combination of two IC therapies, radioimmunotherapy (RIT) and immunotoxin (IT) therapy, to treat advanced, disseminated human lymphoma in immunodeficient mice. We proposed to use the bystander effect of RIT to reduce large tumor burdens, followed by an IT to eliminate residual tumor cells. Our results indicate that, when used alone, both RIT and IT therapy were safe and effective, but not curative. When the two therapies were combined, efficacy and toxicity became dependent on the temporal order of administration. Thus, with the doses used in this study, when RIT was administered after IT therapy, the regimen was curative. In contrast, when RIT was administered before IT therapy, the combination was highly toxic or even lethal. Both RIT and IT therapy induced pulmonary vascular leak, but with different kinetics. When RIT was given prior to IT therapy, the pulmonary vascular leak became life-threatening but not when the two agents were administered in the reverse order.
免疫缀合物（ICs）由靶向部分和毒性部分组成，具有传统癌症治疗所缺乏的特异性。在适当剂量下，ICs在实验动物和人类中治疗各种癌症时安全有效。然而，由于单药治疗很少能实现治愈，因此必须评估涉及不同作用机制药物联合的治疗方案。在本研究中，我们探讨了两种IC治疗方法，即放射免疫疗法（RIT）和免疫毒素（IT）疗法联合治疗免疫缺陷小鼠晚期播散性人类淋巴瘤的疗效和毒性。我们建议利用RIT的旁观者效应来减轻大的肿瘤负荷，然后使用IT消除残留的肿瘤细胞。我们的结果表明，单独使用时，RIT和IT疗法均安全有效，但不能治愈。当两种疗法联合使用时，疗效和毒性取决于给药的时间顺序。因此，在本研究使用的剂量下，当IT疗法后给予RIT时，该方案具有治愈性。相反，当RIT在IT疗法之前给予时，联合治疗具有高毒性甚至致命。RIT和IT疗法均诱导肺血管渗漏，但动力学不同。当RIT在IT疗法之前给予时，肺血管渗漏会危及生命，但当两种药物以相反顺序给药时则不会。
