Relaxin-FOLFOX-IL-12 triple combination therapy engages memory response and achieves long-term survival in colorectal cancer liver metastasis
Relaxin-FOLFOX-IL-12 triple combination therapy engages memory response and achieves long-term survival in colorectal cancer liver metastasis
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DOI：
10.1016/j.jconrel.2019.12.053
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发表时间：
2020-03-10
影响因子：
10.8
通讯作者：
Huang, Leaf
中科院分区：
文献类型：
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作者：
Hu, Mengying;Zhou, Xuefei;Huang, Leaf
在结直肠癌(CRC)肝转移的现有治疗中，由于肝内丰富的间质和免疫抑制环境，诱导记忆T细胞反应效率低下，导致疾病进展快，复发率高，生存期短。激发广泛的记忆T细胞反应涉及两个基本步骤：用强健和持久的抗原信号刺激原始T细胞；用生存因子维持分化的记忆T细胞。在这里，我们展示了一种合理的三联方案设计，包括松弛素(RLN)、FOLFOX(5-氟尿嘧啶、亚叶酸钙和奥沙利铂的组合)和IL-12，成功地刺激了中枢记忆T细胞，并在侵袭性实验性CRC肝转移模型中实现了长期存活。在RLN基因治疗的间质失活后，顺序给予FOLFOX和IL-12基因治疗，可完全治愈近50%的小鼠已建立的结直肠癌肝转移，并对肿瘤复发提供长期保护。这项研究可能强调唤起记忆反应作为治疗结直肠癌肝转移的根治疗法的潜力。
Induction of memory T cell response is inefficient in colorectal cancer (CRC) liver metastasis following existing therapies due to abundant stroma and immunosuppressive environment within the metastatic liver, which leads to fast disease progression, high recurrence rate, and short survival. Two fundamental steps are involved to elicit extensive memory T cell response: stimulation of naive T cells with robust and persistent antigen signals; and maintenance of differentiated memory T cells with survival factors. Here, we demonstrate a rational design of triple combination regimen, including relaxin (RLN), FOLFOX (combination of 5-fluorouracil, leucovorin, and oxaliplatin), and IL-12, successfully stimulates central memory T cells and achieves long-term survival in an aggressive experimental CRC liver metastasis model. Sequential administration of FOLFOX and IL-12 gene therapy following stromal deactivation by RLN gene therapy completely cured established CRC liver metastases in similar to 50% of mice and provided long-lasting protection against tumor recurrence. The study here may highlight the potential of evoking memory response as a curative therapy for the treatment of CRC liver metastasis.