Lode H N, Xiang R, Becker J C, Gillies S D, Reisfeld R A
Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Pharmacol Ther. 1998 Dec;80(3):277-92. doi: 10.1016/s0163-7258(98)00033-3.
Recombinant antibody-cytokine fusion proteins are immunocytokines that achieve high cytokine concentrations in the tumor microenvironment and thereby effectively stimulate cellular immune responses against malignancies. The activation and expansion of immune effector cells, such as CD8+ T lymphocytes, by interleukin-2 immunocytokines resulted in the eradication of established pulmonary and hepatic metastases of murine melanoma and colorectal carcinoma in syngeneic mouse models. These immunocytokines were equally effective in eliminating established bone marrow and liver metastases of murine neuroblastoma by activating natural killer cells. The effective eradication of metastases by immunocytokines resulted in significant prolongation in life span of mice over that of controls receiving equivalent mixtures of antibody and interleukin-2, which failed to reduce the growth of disseminated metastases. Proof of concept was established, indicating that immunocytokine-induced activation and expansion of immune effector cells in the tumor microenvironment can effectively eradicate established tumor metastases. This promising new approach to cancer immunotherapy may lead to clinical applications that improve treatment of cancer patients with minimal residual disease in an adjuvant setting.
重组抗体-细胞因子融合蛋白是免疫细胞因子，可在肿瘤微环境中实现高细胞因子浓度，从而有效刺激针对恶性肿瘤的细胞免疫反应。白细胞介素-2免疫细胞因子激活和扩增免疫效应细胞，如CD8+T淋巴细胞，导致在同基因小鼠模型中根除已建立的小鼠黑色素瘤和结直肠癌的肺和肝转移灶。这些免疫细胞因子通过激活自然杀伤细胞，在消除已建立的小鼠神经母细胞瘤的骨髓和肝转移灶方面同样有效。免疫细胞因子有效根除转移灶，导致小鼠寿命比接受等量抗体和白细胞介素-2混合物的对照组显著延长，后者未能减少播散性转移灶的生长。概念验证得以确立，表明肿瘤微环境中免疫细胞因子诱导的免疫效应细胞的激活和扩增可有效根除已建立的肿瘤转移灶。这种有前景的癌症免疫治疗新方法可能会带来临床应用，在辅助治疗中以最小的残留疾病改善癌症患者的治疗效果。
