Center for Cancer Research, National Institutes of Health, Experimental Transplantation and Immunology Branch, and Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Clin Cancer Res. 2011 Jun 1;17(11):3697-705. doi: 10.1158/1078-0432.CCR-11-0493. Epub 2011 Apr 26.
The success of immunotoxin therapy of cancer is limited by host production of neutralizing antibodies, which are directed toward the Pseudomonas exotoxin A (PE) component. In this proof-of-principle study using a well-established murine model, we hypothesized that a newly developed immune depletion regimen consisting of pentostatin plus cyclophosphamide would abrogate anti-immunotoxin reactivity.
BALB/c hosts were injected weekly with recombinant immunotoxin (RIT) SS1P, which is an antimesothelin Fv antibody fragment genetically fused to a 38 kDa portion of PE, and has been evaluated in clinical trials. Experimental cohorts received induction chemotherapy consisting of pentostatin (P) plus cyclophosphamide (C) prior to initial RIT exposure; some cohorts received further maintenance PC therapy of varying intensity just prior to each weekly RIT challenge. Cohorts were monitored for T, B, myeloid cell depletion, and for total anti-SS1P antibody (Ab) formation.
Controls uniformly developed anti-SS1P Ab after the third RIT exposure. Induction PC therapy reduced the frequency of hosts with anti-SS1P Ab. Abrogation of antibody generation was improved by maintenance PC therapy: nearly 100% of recipients of intensive PC maintenance were free of anti-SS1P Ab after 9 weekly RIT doses. The most effective PC regimen yielded the greatest degree of host B-cell depletion, moderate T-cell depletion, and minimal myeloid cell depletion.
Induction and maintenance PC chemotherapy safely prevented anti-immunotoxin antibody formation with uniform efficacy. These data suggest that immunotoxin therapy might be used in combination with pentostatin plus cyclophosphamide chemotherapy to improve the targeted therapy of cancer.
免疫毒素疗法治疗癌症的成功受到宿主产生中和抗体的限制，这些抗体针对绿脓杆菌外毒素 A（PE）成分。在这项使用成熟的小鼠模型进行的原理验证研究中，我们假设由喷司他丁加环磷酰胺组成的新开发的免疫耗竭方案将消除抗免疫毒素反应。
BALB/c 宿主每周注射重组免疫毒素（RIT）SS1P，这是一种抗间皮素 Fv 抗体片段，通过基因融合到 38 kDa 的 PE 部分，已在临床试验中进行了评估。实验组接受喷司他丁（P）加环磷酰胺（C）诱导化疗，然后再进行初始 RIT 暴露；一些实验组在每周 RIT 挑战前接受不同强度的维持 PC 治疗。监测各组 T、B、髓样细胞耗竭情况和总抗 SS1P 抗体（Ab）形成情况。
对照组在第三次 RIT 暴露后均产生抗 SS1P Ab。诱导性 PC 治疗降低了具有抗 SS1P Ab 的宿主频率。维持性 PC 治疗改善了抗体生成的消除：在接受 9 次每周 RIT 剂量后，接受强化 PC 维持治疗的接受者中，几乎 100%的人没有抗 SS1P Ab。最有效的 PC 方案导致宿主 B 细胞耗竭程度最大、T 细胞耗竭程度中等、髓样细胞耗竭程度最小。
诱导和维持性 PC 化疗安全地防止了抗免疫毒素抗体的形成，具有一致的疗效。这些数据表明，免疫毒素疗法可能与喷司他丁加环磷酰胺化疗联合使用，以改善癌症的靶向治疗。
