Bristol-Myers Squibb Company, PO Box 4000, Princeton, NJ 08543, USA.
Cancer Immunol Immunother. 2013 Sep;62(9):1533-45. doi: 10.1007/s00262-013-1451-5. Epub 2013 Jul 20.
Ipilimumab, a cytotoxic T-lymphocyte antigen-4 (CTLA-4) binding agent, has proven to be an effective monotherapy for metastatic melanoma and has shown antitumor activity in trials when administered with other therapeutic agents. We hypothesized that the combination of ipilimumab with chemotherapeutic agents, such as ixabepilone, paclitaxel, etoposide, and gemcitabine, may produce therapeutic synergy based on distinct but complementary mechanisms of action for each drug and unique cellular targets. This concept was investigated using a mouse homolog of ipilimumab in preclinical murine tumor models, including SA1N fibrosarcoma, EMT-6 mammary carcinoma, M109 lung carcinoma, and CT-26 colon carcinoma. Results of CTLA-4 blockade in combination with one of various chemotherapeutic agents demonstrate that synergy occurs in settings where either agent alone was not effective in inducing tumor regression. Furthermore, when combined with CTLA-4 blockade, ixabepilone, etoposide, and gemcitabine elicited prolonged antitumor effects in some murine models with induction of a memory immune response. Future investigations are warranted to determine which specific chemo-immunotherapy combinations, if any, will produce synergistic antitumor effects in the clinical setting.
伊匹单抗是一种细胞毒性 T 淋巴细胞相关抗原 4（CTLA-4）结合剂，已被证明是转移性黑色素瘤的有效单药治疗药物，并且在与其他治疗药物联合使用时显示出抗肿瘤活性。我们假设伊匹单抗与化疗药物（如伊沙匹隆、紫杉醇、依托泊苷和吉西他滨）联合使用可能会产生治疗协同作用，这基于每种药物不同但互补的作用机制和独特的细胞靶点。这一概念在包括 SA1N 纤维肉瘤、EMT-6 乳腺癌、M109 肺癌和 CT-26 结肠癌在内的临床前小鼠肿瘤模型中，使用小鼠同源的伊匹单抗进行了研究。结果表明，在单独使用任一药物不能有效诱导肿瘤消退的情况下，CTLA-4 阻断联合各种化疗药物可产生协同作用。此外，当与 CTLA-4 阻断联合使用时，伊沙匹隆、依托泊苷和吉西他滨在一些诱导记忆免疫反应的小鼠模型中产生了延长的抗肿瘤作用。未来的研究需要确定哪些特定的化疗免疫治疗组合（如果有的话）将在临床环境中产生协同抗肿瘤作用。
