Chemo-immunotherapy of metastatic colorectal carcinoma with gemcitabine plus FOLFOX 4 followed by subcutaneous granulocyte macrophage colony-stimulating factor and interleukin-2 induces strong immunologic and antitumor activity in metastatic colon cancer patients
Chemo-immunotherapy of metastatic colorectal carcinoma with gemcitabine plus FOLFOX 4 followed by subcutaneous granulocyte macrophage colony-stimulating factor and interleukin-2 induces strong immunologic and antitumor activity in metastatic colon cancer patients
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DOI：
10.1200/jco.2005.12.147
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发表时间：
2005-12-10
影响因子：
45.3
通讯作者：
Francini, G
中科院分区：
文献类型：
--
作者：
Correale, P;Cusi, MG;Francini, G
目的 抗癌药物杀死肿瘤细胞可能得到其免疫和药理作用的支持。化疗实际上能够（A）上调肿瘤相关抗原的表达，包括癌胚抗原（CEA）或其他靶分子，例如胸苷酸合酶（TS）； (B)下调肿瘤细胞对肿瘤抗原特异性细胞毒性T淋巴细胞诱导的死亡信号的抵抗力。这为联合化疗和免疫治疗提供了基本原理。 材料和方法 我们描述了一项转化性 II 期试验的结果，该试验旨在评估结直肠癌患者中吉西他滨 + FOLFOX-4（奥沙利铂、氟尿嘧啶和亚叶酸）联合化疗的毒性、抗肿瘤活性和免疫学作用，随后皮下注射粒细胞巨噬细胞集落刺激因子和低剂量白细胞介素 2。该研究涉及 29 名患者（16 名男性和 13 名女性，平均年龄为 69 岁），其中 21 名患者接受过既往治疗，19 名患者出现肝脏受累。 结果 该治疗耐受性良好，诱导了非常高的客观缓解率 (68.9%) 和疾病控制率 (96.5%)，平均疾病进展时间为 12.5 个月。对 20 名患者的外周血单核细胞 (PBMC) 进行的免疫学研究显示，对结肠癌抗原的增殖反应增强，抑制性调节性 T 淋巴细胞 (CD4(+)CD25(T-reg)(+)) 显着减少。对 5 名获得客观缓解的 HLA-A((star))02.01(+) 患者的 PBMC 进行的细胞荧光研究显示，已知 CEA 和 TS 衍生表位特异的溶细胞 T 淋巴细胞前体的频率增加。 结论 结果表明，我们的方案在结直肠癌患者中具有很强的免疫学和抗肿瘤活性，值得在 III 期试验中进行研究。
Purpose Tumor cell killing by anticancer drugs may be supported by their immuno- and pharmacologic effects. Chemotherapy is in fact able to (A) upregulate tumor-associated antigen expression, including carcinoembryonic antigen (CEA) or other target molecules such as thymidylate synthase (TS); and (B) downregulate tumor cell resistance to the death signals induced by tumor antigen-specific cytotoxic T lymphocytes. This provides the rationale for combining chemo- and immunotherapy.Materials and Methods We describe the results of a translational phase II trial designed to evaluate the toxicity, antitumor activity and immunologic effects of gemcitabine + FOLFOX-4 (oxaliplatin, fluorouracil, and folinic acid) polychemotherapy followed by the subcutaneous administration of granulocyte macrophage colony-stimulating factor and low-dose interleukin-2 in colorectal carcinoma patients. The study involved 29 patients (16 men and 13 women with a mean age of 69 years), 21 of whom had received a previous line of treatment, and 19 had liver involvement.Results The treatment was well tolerated and induced very high objective response (68.9%) and disease control rates (96.5%), with an average time to progression of 12.5 months. An immunologic study of peripheral blood mononuclear cells (PBMC) taken from 20 patients showed an enhanced proliferative response to colon carcinoma antigen and a significant reduction in suppressive regulatory T lymphocytes (CD4(+)CD25(T-reg)(+)). A cytofluorimetric study of the PBMCs of five HLA-A((star))02.01(+) patients who achieved an objective response showed an increased frequency of cytolytic T lymphocyte precursors specific for known CEA- and TS-derived epitopes.Conclusion The results show that our regimen has strong immunologic and antitumor activity in colorectal cancer patients and deserves to be investigated in phase III trials.