Basile Lena A, Gallaher Timothy K, Shibata Darryl, Miller Joseph D, Douer Dan
Neumedicines Inc., 2275 East Foothill Blvd., Pasadena, California, USA.
J Transl Med. 2008 May 19;6:26. doi: 10.1186/1479-5876-6-26.
Interleukin-12 (IL-12) is a cytokine well known for its role in immunity. A lesser known function of IL-12 is its role in hematopoiesis. The promising data obtained in the preclinical models of antitumor immunotherapy raised hope that IL-12 could be a powerful therapeutic agent against cancer. However, excessive clinical toxicity, largely due to repeat dose regimens, and modest clinical response observed in the clinical trials have pointed to the necessity to design protocols that minimize toxicity without affecting the anti-tumor effect of IL-12. We have focused on the lesser known role of IL-12 in hematopoiesis and hypothesized that an important clinical role for IL-12 in cancer may be as an adjuvant hematological cancer therapy. In this putative clinical function, IL-12 is utilized for the prevention of cancer therapy-related cytopenias, while providing concomitant anti-tumor responses over and above responses observed with the primary therapy alone. This putative clinical function of IL-12 focuses on the dual role of IL-12 in hematopoiesis and immunity.
We assessed the ability of IL-12 to facilitate hematopoietic recovery from radiation (625 rad) and chemotherapy (cyclophosphamide) in two tumor-bearing murine models, namely the EL4 lymphoma and the Lewis lung cancer models. Antitumor effects and changes in bone marrow cellularity were also assessed.
We show herein that carefully designed protocols, in mice, utilizing IL-12 as an adjuvant to radiation or chemotherapy yield facile and consistent, multilineage hematopoietic recovery from cancer therapy-induced cytopenias, as compared to vehicle and the clinically-utilized cytokine granulocyte colony-stimulating factor (G-CSF) (positive control), while still providing concomitant antitumor responses over and above the effects of the primary therapy alone. Moreover, our protocol design utilizes single, low doses of IL-12 that did not yield any apparent toxicity.
Our results portend that despite its past failure, IL-12 appears to have significant clinical potential as a hematological adjuvant cancer therapy.
白细胞介素-12（IL-12）是一种因其在免疫中的作用而广为人知的细胞因子。IL-12鲜为人知的功能是其在造血过程中的作用。在抗肿瘤免疫治疗的临床前模型中获得的有前景的数据让人希望IL-12可能成为对抗癌症的有力治疗剂。然而，主要由于重复给药方案导致的过度临床毒性以及在临床试验中观察到的适度临床反应表明，有必要设计出在不影响IL-12抗肿瘤作用的情况下将毒性降至最低的方案。我们专注于IL-12在造血过程中鲜为人知的作用，并假设IL-12在癌症中的一个重要临床作用可能是作为血液系统癌症的辅助治疗。在这种假定的临床功能中，IL-12用于预防癌症治疗相关的血细胞减少，同时在单独的主要治疗所观察到的反应之上提供伴随的抗肿瘤反应。IL-12的这种假定临床功能聚焦于IL-12在造血和免疫中的双重作用。
我们在两种荷瘤小鼠模型，即EL4淋巴瘤模型和Lewis肺癌模型中，评估了IL-12促进从辐射（625拉德）和化疗（环磷酰胺）导致的造血恢复的能力。还评估了抗肿瘤作用和骨髓细胞数量的变化。
我们在此表明，在小鼠中，精心设计的方案利用IL-12作为辐射或化疗的辅助剂，与载体和临床使用的细胞因子粒细胞集落刺激因子（G-CSF）（阳性对照）相比，能从癌症治疗诱导的血细胞减少中轻松且一致地实现多谱系造血恢复，同时仍在单独的主要治疗效果之上提供伴随的抗肿瘤反应。此外，我们的方案设计使用单次低剂量的IL-12，未产生任何明显毒性。
我们的结果预示，尽管IL-12过去失败了，但它作为血液系统辅助癌症治疗似乎具有显著的临床潜力。
