胃癌的免疫治疗

Advances in immunotherapy for gastric cancer

目的了解免疫治疗在胃癌中应用的研究进展。方法复习近年来关于免疫治疗在胃癌中应用的相关文献并加以综述。结果迄今为止,对于肿瘤的免疫疗法主要包括免疫检查点阻断、肿瘤疫苗和过继性免疫治疗。目前针对免疫检查点阻断研究较多的主要是针对程序性死亡受体-1(PD-1)和细胞毒性T淋巴细胞相关抗原4 (CTLA-4)的抗体。有一系列研究证实pembrolizumab对PD-1配体表达阳性的进展期食管胃癌有效,抗PD-1单抗nivolumab成为了首个在亚洲获得晚期胃癌治疗适应证批准的免疫检查点抑制剂,存在错配修复缺陷的患者更能从抗PD-1治疗中获益;以CTLA-4为治疗靶点的免疫检查点阻断治疗虽然也有报道,但有研究发现中晚期胃癌患者并未从CTLA-4单抗ipilimumab的治疗中获益。针对胃癌的肿瘤疫苗治疗在早期已有报道,由于在胃癌中肿瘤细胞异质性高,而早期的靶向自体抗原的肿瘤疫苗疗效不稳定,基于高通量测序的新生抗原识别和筛选程序复杂,疫苗制备的周期长,如何个体化筛选抗原,选择能有效激活T细胞识别并杀伤肿瘤细胞的抗原等问题仍需要克服。目前有研究报道过继性免疫治疗中肿瘤浸润淋巴细胞(TIL)在胃癌中的表达情况可以判断其预后,但目前TIL治疗胃癌报道以个案报道为主,仍处在探索阶段;目前在美国ClinicalTrail网站注册的针对胃癌的嵌合抗原受体T细胞(CAR-T)临床试验有13项,目前多数仍在招募患者阶段,大规模临床应用研究尚未开展,目前也并无相关疗效报道。结论肿瘤的免疫治疗受到了来自全世界的广泛关注,以抗PD-1及其配体为代表的免疫检查点抑制治疗在晚期胃癌的治疗中已经展现了巨大的治疗潜力,但目前仍有许多亟待解决的问题,如免疫治疗应用有效的患者范围较小,免疫检查点抑制剂的疗效筛选指标也尚不明确,肿瘤疫苗和过继性细胞治疗目前的临床研究数据较少且目前并没有证据证明其在胃癌治疗中的有效性,现有的治疗方案与免疫治疗的联合使用疗效仍然需要更多的临床试验去探索。

Objective To summarize advances in immunotherapy for gastric cancer. Method The relevant literatures about immunotherapy for gastric cancer in recent years were reviewed. Results Recently, the immunotherapy for the tumors mainly included the immune checkpoint blocking, tumor vaccine, and adoptive immunotherapy. There were many studies on the immune checkpoint blocking, mainly targeting the antibodies of programmed death receptor 1 (PD-1) and cytotoxic T-lymphocyte associated antigen 4 (CTLA-4). A series of studies had shown that the pembrolizumab was effective in the patients with advanced gastric cancer who expressed PD-1 ligand positive. The nivolumab had become the first immune checkpoint inhibitor approved for the treatment of advanced gastric cancer in Asia, and the patients with mismatch repair defects could benefit more from the PD-1 treatment. Although the CTLA-4 targeted immune checkpoint blocking therapy had been reported, some studies had found that the patients with advanced gastric cancer didn't benefit from the treatment of CTLA-4 monoclonal antibody ipilimumab. The tumor vaccine therapy in the gastric cancer had been reported. Due to the high heterogeneity of tumor cells in the gastric cancer, the tumor vaccine efficacy of autoantibody was not stable, based on the highthroughput sequencing of neoantigens identification and screening process was complex, the vaccine preparation needed the longer period, how to individualized screening the neoantigen, and the selection of antigens that could effectively activate the T cells to recognize and kill the tumor cells still needed to be overcame. Conclusions Tumor immunotherapy has received worldwide attention. Anti-PD-1 and its ligand as representative immune checkpoint statin therapy in treatment of advanced gastric cancer has showed great potential, but at present there are still many problems need to be solved, such as number of applicable patients of immunotherapy is small, curative effect of immune checkpoint inhibitor screening index also is not clear, tumor vaccine and adoptive cell therapy are promising but there is lack of evidence from clinical research data, combined use of existing treatments and immunotherapy on curative effect still needs more clinical trials to explore.