Kawakami Yutaka, Fujita Tomonobu, Kudo Chie, Sakurai Toshiharu, Udagawa Masaru, Yaguchi Tomonori, Hasegawa Go, Hayashi Emiko, Ueda Yoko, Iwata Tomoko, Wang Qinfu, Okada Starlyn, Tsukamoto Nobuo, Matsuzaki Yuriko, Sumimoto Hidetoshi
Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University, School of Medicine, Tokyo, Japan.
Front Biosci. 2008 Jan 1;13:1952-8. doi: 10.2741/2814.
Human tumor antigens were identified using various immunological and genetic methods, and immune responses to the identified antigens were evaluated in cancer patients. Autologous tumor specific unique antigens derived from genetic alterations in cancer cells were isolated from patients with favorable prognosis after immunotherapy, indicating that they are attractive targets for immunotherapy. Immunogenicity of shared antigens was found to differ among patients due to antigen expression in cancer cells and patients' immunoreactivity. These observations suggest that personalization may be applied for cancer immunotherapy. We therefore developed intratumoral DC administration protocols that are able to induce immune responses to both unique and shared tumor antigens expressed in each individual cancer. By combining cryoablative tumor pretreatment and TLR stimulated DC, the anti-tumor effect of the intratumoral DC administration was significantly augmented in a murine tumor model. This improved protocol enhanced systemic induction of anti-tumor CD8+ CTL, and was able to regress relatively large remote untreated tumors. In clinical trials, systemic immune induction was observed by intratumoral DC administration following cryoablative tumor treatment, although anti-tumor effects are relatively weak, indicating that additional interventions are required for more effective immunotherapy.
利用各种免疫和基因方法鉴定人类肿瘤抗原，并在癌症患者中评估对所鉴定抗原的免疫反应。从免疫治疗后预后良好的患者中分离出源自癌细胞基因改变的自体肿瘤特异性独特抗原，这表明它们是免疫治疗的有吸引力的靶点。由于癌细胞中的抗原表达和患者的免疫反应性，发现共享抗原的免疫原性在患者之间存在差异。这些观察结果表明个性化可能适用于癌症免疫治疗。因此，我们开发了瘤内树突状细胞（DC）给药方案，该方案能够诱导针对每个个体癌症中表达的独特和共享肿瘤抗原的免疫反应。通过结合冷冻消融肿瘤预处理和 Toll 样受体（TLR）刺激的 DC，在小鼠肿瘤模型中瘤内 DC 给药的抗肿瘤作用显著增强。这种改进的方案增强了抗肿瘤 CD8 + 细胞毒性 T 淋巴细胞（CTL）的全身诱导，并能够使相对较大的远处未治疗肿瘤消退。在临床试验中，冷冻消融肿瘤治疗后通过瘤内 DC 给药观察到全身免疫诱导，尽管抗肿瘤作用相对较弱，这表明需要额外的干预措施以实现更有效的免疫治疗。
