Satoh Yuji, Esche Clemens, Gambotto Andrea, Shurin Galina V, Yurkovetsky Zoya R, Robbins Paul D, Watkins Simon C, Todo Satoru, Herberman Ronald B, Lotze Michael T, Shurin Michael R
Biologic Therapeutics Program, University of Pittsburgh Cancer Institute, 5725 CHP-MT, 200 Lothrop Street, Pittsburgh, PA 15213, USA.
J Exp Ther Oncol. 2002 Nov-Dec;2(6):337-49. doi: 10.1046/j.1359-4117.2002.01050.x.
Colorectal cancer is one of the most common fatal malignancies in the United States, with an incidence second only to lung cancer. The liver is the most common site of colorectal metastases and frequently the only affected organ once the primary tumor has been surgically removed. The only potentially curative treatment for metastatic colorectal cancer in the liver is surgery, although most patients are not eligible for resection. We have therefore, evaluated the therapeutic efficacy of dendritic cells (DCs) engineered to express IL-12 in a liver metastasis model. Direct administration of DCs into the portal vein significantly inhibited the growth of established MC38 colon carcinoma in the liver in C57BL/6 mice. This effect was accompanied by an intratumoral accumulation of CD4+, CD8+, and NLDC-145+ immune effector cells, and also resulted in a systemic immune response as determined by enhanced production of IFN-gamma by T lymphocytes isolated from both spleen and draining lymph nodes. Evaluation of homing of Cy3-labeled DCs following the portal vein injection confirmed their distribution in the liver and lymphoid tissue. Thus, a local delivery of DCs transduced with the IL-12 gene can not only inhibit colorectal tumor growth in vivo but also mount systemic antitumor immune responses. This approach is likely to improve the outcome of immunotherapy for metastatic colorectal cancer since high numbers of tumor-associated DCs positively correlate with a more favorable prognosis. Simultaneous local gene therapy with IL-12 will further improve clinical efficacy without placing the patient at risk for systemic toxicity.
结直肠癌是美国最常见的致命恶性肿瘤之一，发病率仅次于肺癌。肝脏是结直肠癌转移最常见的部位，并且在原发性肿瘤手术切除后，肝脏常常是唯一受影响的器官。对于肝脏转移性结直肠癌，唯一可能治愈的治疗方法是手术，尽管大多数患者不符合切除条件。因此，我们在肝转移模型中评估了经基因工程改造以表达白细胞介素-12（IL-12）的树突状细胞（DCs）的治疗效果。将DCs直接注入门静脉可显著抑制C57BL/6小鼠肝脏中已形成的MC38结肠癌的生长。这种效应伴随着肿瘤内CD4 +、CD8 +和NLDC-145 +免疫效应细胞的积聚，并且还导致了全身免疫反应，这是通过从脾脏和引流淋巴结分离的T淋巴细胞增强产生γ干扰素来确定的。门静脉注射后对Cy3标记的DCs归巢的评估证实了它们在肝脏和淋巴组织中的分布。因此，局部递送经IL-12基因转导的DCs不仅可以在体内抑制结直肠癌的生长，还可以引发全身抗肿瘤免疫反应。由于大量肿瘤相关DCs与更有利的预后呈正相关，这种方法可能会改善转移性结直肠癌免疫治疗的效果。同时使用IL-12进行局部基因治疗将进一步提高临床疗效，而不会使患者面临全身毒性风险。
