利用免疫系统控制癌症

Harnessing the immune system to control cancer

随着癌症基础研究的深入,癌症的发生发展与癌细胞的免疫监视逃逸的密切关系逐渐被揭示.患者机体内多种抗肿瘤免疫细胞的存在及其抗肿瘤作用的认识,提示研究者利用免疫系统可能控制癌症.基于肿瘤免疫基础研究以及生物技术的进步,免疫治疗逐渐登上了癌症治疗的舞台.免疫治疗是一种新兴的癌症治疗手段.无论是通过激活自体免疫,还是提供过继性免疫,其疗效在近年来都不断被证实,充分证明了利用免疫系统可能有效控制甚至治愈癌症.肿瘤免疫治疗的时代已经到来.相信肿瘤基础研究的不断深入,将帮助研究者更充分有效地使用免疫系统,从而为癌症治疗提供新的有效手段,为患者带来福音.

Cancer derives from mutant oncogenic cells, which tend to thrive within immunocompromised individuals. As the basic research on cancer goes deeper, the knowledge of the existence of a variety of antitumor components is gradually revealed. Cells including NK cells, dendritic cells, B cells and T cells, and their associated immune molecules such as cytokines, ligands and antibodies, all showed particular anti-tumor effects. At the same time, immunosuppressive cells such as regular T cells, tumor associated macrophages, regulatory DCs and myeloid derived suppressive cells, and their corresponding secretory factors were revealed to suppress anti-tumor effects. These basic research findings suggest that harnessing the immune system in the right ways might control cancer. The earliest immunotherapy can be retrieved to 1891, when William Coley used bacteria to treat cancer. In 1986, IL-2 was used to treat melanoma and renal carcinoma. Yet these early immunotherapies showed little anti-cancer effect. Vaccine is another approach to pursue cancer prevention and treatment. There has been two cancer vaccines in the clinical practice, includes HPV vaccine and Provenge. They were generally safe and were able to induce anti-tumor effect, but they still showed limited therapeutic effect. Since 1997, there were about 20 tumor targeting antibodies used in the clinical practice. These antibodies have shown significant anti-tumor effect. One main mechanism is that these antibodies can mediate systemic anti-tumor response from the immune system. In recent years, antibodies targeting immune checkpoint molecules CTLA-4, PD-1 and PD-L1 showed exciting therapeutic effects. These new antibodies are used to block the immune checkpoint molecules, aiming to relieve immunosuppression and release the anti-tumor effector function of the T cells. These checkpoint inhibitors can effectively improve survival of some patients failed in traditional therapies, which further confirm that tumor can be restrained by immunotherapy approach. Except for using the body＇s own immune system to fight against cancer, adoptive immune cells are also used. The earliest adoptive immune cell therapy began in 1985, when LAK cells are used to treat melanoma yet showed little effect in the clinical trials. Since the year around 2000, multiple clinical trials using CIK cells to treat cancer were launched. CIK cells were shown to improve survival of patients with advanced renal cell carcinoma, triple negative breast cancer and advanced pancreatic cancer. Rosenberg et al. reported the application of tumor infiltrating cells（TILs） to treat melanoma since 1988. TILs were able to effectively mediate tumor shrinkage. However, the application of TILs is still limited because they are hard to isolate and expand. Since 1989, chimeric antigen receptor modified T cells were developed. After about 17 years＇ improvement, these gene modified T cells showed exciting curative effect in treating hematological malignancies in multiple clinical trials. The response rate was generally high in chronic lymphocytic leukemia（60%）, acute lymphoblastic leukemia（56%–90%） and lymphoma（about 85%）. Besides, T cell receptor modified T cells also showed promising anti-tumor results in multiple clinical trials. Among which, TCRT-NY-ESO-1 showed the most favorable safety profile and efficacy in treating melanoma, sarcoma and multiple myeloma. The development of these adoptive immune cell therapies suggest that, immune cells have great anti-tumor potential, how to fully bring out their anti-tumor effects by advanced technologies is the key to achieve satisfactory therapeutic efficacy. Generally speaking, the development of immunotherapy was filled with twists and turns. Whether through activation of autologous immunity, or the transfer of adoptive immunity, the therapeutic effect of immunotherapy has been gradually confirmed in recent years. Although we have recognized harnessing the immune system can control cancer, how to use the immune system better, and raise the safety and efficacy of immunotherapy still needs further research.