Uno Tomoyasu, Takeda Kazuyoshi, Kojima Yuko, Yoshizawa Hirohisa, Akiba Hisaya, Mittler Robert S, Gejyo Fumitake, Okumura Ko, Yagita Hideo, Smyth Mark J
Department of Immunology, Juntendo University School of Medicine, Hongo 2-1-1, Bunkyo-ku, Tokyo 113-8421, Japan.
Nat Med. 2006 Jun;12(6):693-8. doi: 10.1038/nm1405. Epub 2006 May 7.
Tumor-cell apoptosis is the basis of many cancer therapies, and tumor-specific T cells are the principal effectors of successful antitumor immunotherapies. Here we show that induction of tumor-cell apoptosis by an agonistic monoclonal antibody to DR5, the apoptosis-inducing receptor for TNF-related apoptosis-inducing ligand (TRAIL), combined with T-cell activation by agonistic monoclonal antibodies to the costimulatory molecules CD40 and CD137, potently and rapidly stimulated tumor-specific effector CD8+ T cells capable of eradicating preestablished tumors. Primary fibrosarcomas initiated with the carcinogen 3-methylcholanthrene (MCA), multiorgan metastases and a primary tumor containing as many as 90% tumor cells resistant to DR5-specific monoclonal antibody were rejected without apparent toxicity or induction of autoimmunity. This combination therapy of three monoclonal antibodies (trimAb) rapidly induced tumor-specific CD8+ T cells producing interferon (IFN)-gamma in the tumor-draining lymph node, consistent with a crucial requirement for CD8+ T cells and IFN-gamma in the tumor rejection process. These results in mice indicate that a rational monoclonal antibody-based therapy that both causes tumor-cell apoptosis through DR5 and activates T cells may be an effective strategy for cancer immunotherapy in humans.
肿瘤细胞凋亡是许多癌症治疗的基础，而肿瘤特异性T细胞是成功的抗肿瘤免疫疗法的主要效应细胞。在此我们表明，通过针对DR5（肿瘤坏死因子相关凋亡诱导配体（TRAIL）的凋亡诱导受体）的激动性单克隆抗体诱导肿瘤细胞凋亡，同时通过针对共刺激分子CD40和CD137的激动性单克隆抗体激活T细胞，能够有效且快速地刺激肿瘤特异性效应CD8⁺ T细胞，这些细胞能够根除预先形成的肿瘤。由致癌物3 - 甲基胆蒽（MCA）引发的原发性纤维肉瘤、多器官转移瘤以及含有多达90%对DR5特异性单克隆抗体耐药的肿瘤细胞的原发性肿瘤均被排斥，且无明显毒性或自身免疫诱导现象。这种三种单克隆抗体联合疗法（三联抗体）在肿瘤引流淋巴结中迅速诱导产生干扰素（IFN）-γ的肿瘤特异性CD8⁺ T细胞，这与肿瘤排斥过程中CD8⁺ T细胞和IFN - γ的关键需求一致。小鼠实验的这些结果表明，一种基于单克隆抗体的合理疗法，既能通过DR5诱导肿瘤细胞凋亡又能激活T细胞，可能是人类癌症免疫治疗的有效策略。
