OX40 is a potent immune-stimulating target in late-stage cancer patients.
OX40 is a potent immune-stimulating target in late-stage cancer patients.
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DOI：
10.1158/0008-5472.can-12-4174
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发表时间：
2013-12-15
期刊：
影响因子：
11.2
通讯作者：
Weinberg AD
中科院分区：
文献类型：
--
作者：
Curti BD;Kovacsovics-Bankowski M;Morris N;Walker E;Chisholm L;Floyd K;Walker J;Gonzalez I;Meeuwsen T;Fox BA;Moudgil T;Miller W;Haley D;Coffey T;Fisher B;Delanty-Miller L;Rymarchyk N;Kelly T;Crocenzi T;Bernstein E;Sanborn R;Urba WJ;Weinberg AD
0X 40是一种有效的共刺激受体，其可以增强T淋巴细胞表面上的T细胞受体信号传导，导致它们被特异性识别的抗原激活。特别地，树突状细胞上存在的配体与0X 40的接合显著增加了T细胞的增殖、效应子功能和存活。临床前研究表明，OX 40激动剂可提高抗肿瘤免疫力，改善无瘤生存期。在这项研究中，我们进行了一项I期临床试验，使用小鼠单克隆抗体（mAb），激动晚期癌症患者的人OX 40信号转导。接受一个疗程抗OX 40 mAb治疗的患者显示出可接受的毒性特征，12/30例患者中至少有一处转移性病灶消退。从机制上讲，这种治疗增加了T和B细胞对报告抗原免疫的应答，导致肿瘤浸润淋巴细胞中CD 4 + FoxP 3+调节性T细胞上的OX 40优先上调，并增加了黑素瘤患者中T和B细胞的抗肿瘤反应性。我们的研究结果在临床上验证了OX 40作为癌症患者治疗的有效免疫刺激靶点，提供了一种可推广的工具来有利地影响循环T细胞、B细胞和肿瘤内调节性T细胞的抗肿瘤特性。
OX40 is a potent co-stimulatory receptor that can potentiate T cell receptor signaling on the surface of T lymphocytes, leading to their activation by a specifically recognized antigen. In particular, OX40 engagement by ligands present on dendritic cells dramatically increases the proliferation, effector function and survival of T cells. Preclinical studies have shown that OX40 agonists increase anti-tumor immunity and improve tumor-free survival. In this study, we performed a Phase I clinical trial using a mouse monoclonal antibody (mAb) that agonizes human OX40 signaling in patients with advanced cancer. Patients treated with one course of the anti-OX40 mAb showed an acceptable toxicity profile and regression of at least one metastatic lesion in 12/30 patients. Mechanistically, this treatment increased T and B cell responses to reporter antigen immunizations, led to preferential upregulation of OX40 on CD4+ FoxP3+ regulatory T cells in tumor-infiltrating lymphocytes and increased the anti-tumor reactivity of T and B cells in patients with melanoma. Our findings clinically validate OX40 as a potent immune-stimulating target for treatment in cancer patients, providing a generalizable tool to favorably influence the antitumor properties of circulating T cells, B cells and intratumoral regulatory T cells.