Xiang R, Lode H N, Dolman C S, Dreier T, Varki N M, Qian X, Lo K M, Lan Y, Super M, Gillies S D, Reisfeld R A
Department of Immunology, The Scripps Research Institute, La Jolla, California 92037, USA.
Cancer Res. 1997 Nov 1;57(21):4948-55.
A recombinant humanized antibody-interleukin 2 fusion protein (huKS1/4-IL-2) was used to direct IL-2 to the tumor microenvironment and elicit a T cell-mediated eradication of established pulmonary and hepatic CT26-KSA colon carcinoma metastases in syngeneic BALB/c mice. This antitumor effect was specific because a fusion protein, which was nonreactive with these tumor cells, failed to exert any such effect. The efficacy of the huKS1/4-IL-2 fusion protein in eliminating metastases was documented because mixtures of monoclonal antibody huKS1/4 with recombinant human IL-2 were ineffective and, at best, only partially reduced tumor load. Two lines of evidence indicated the eradication of metastases and the absence of minimal residual disease in animals treated with the fusion protein: first, the lack of detection of CT26-KSA cells by reverse transcription-PCR, which can detect one tumor cell in 10(6) liver cells; and second, the tripling of life span. The effector mechanism involved in this tumor eradication is dependent on T cells because the IL-2-directed therapy is ineffective in T cell-deficient SCID mice. The essential effector cells were further characterized as CD8+ T cells by in vivo depletion studies. Such T cells, isolated from tumor-bearing mice after fusion protein therapy, elicited MHC class I-restricted cytotoxicity in vitro against colon carcinoma target cells. Taken together, these data indicate that fusion protein-directed IL-2 therapy induces a T cell-dependent host immune response capable of eradicating established colon cancer metastases in an animal tumor model.
一种重组人源化抗体 - 白细胞介素2融合蛋白（huKS1/4 - IL - 2）被用于将白细胞介素2导向肿瘤微环境，并在同基因BALB/c小鼠中引发T细胞介导的对已建立的肺和肝CT26 - KSA结肠癌转移灶的清除。这种抗肿瘤作用具有特异性，因为一种与这些肿瘤细胞无反应的融合蛋白未能发挥任何此类作用。记录了huKS1/4 - IL - 2融合蛋白在消除转移灶方面的功效，因为单克隆抗体huKS1/4与重组人白细胞介素2的混合物无效，且充其量只能部分降低肿瘤负荷。有两条证据表明用融合蛋白治疗的动物中转移灶被清除且无微小残留病：第一，通过逆转录 - PCR未检测到CT26 - KSA细胞，该方法可在10(6)个肝细胞中检测到一个肿瘤细胞；第二，寿命延长了两倍。这种肿瘤清除所涉及的效应机制依赖于T细胞，因为白细胞介素2导向的治疗在T细胞缺陷的SCID小鼠中无效。通过体内清除研究进一步将关键效应细胞鉴定为CD8 + T细胞。从融合蛋白治疗后的荷瘤小鼠中分离出的此类T细胞，在体外引发了针对结肠癌靶细胞的MHC I类限制性细胞毒性。综上所述，这些数据表明融合蛋白导向的白细胞介素2治疗可诱导一种T细胞依赖性宿主免疫反应，能够在动物肿瘤模型中清除已建立的结肠癌转移灶。
