Current challenges and optimization strategies for CAR-T cell therapy for solid tumors
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摘要: 近年来，嵌合抗原受体T细胞（chimeric antigen receptor T-cell，CAR-T）疗法在血液肿瘤治疗中取得了突破性进展。然而，由于实体瘤异于血液肿瘤的特性，CAR-T在实体瘤治疗中并未取得很好的疗效。限制CAR-T疗效的关键因素主要包括实体瘤细胞本身及其特殊的肿瘤微环境（tumor microenvironment，TME）两方面，在CAR-T向肿瘤组织部位浸润、CAR-T在TME中维持抗肿瘤活性以及CAR-T对肿瘤细胞的靶向性识别杀伤等多个过程中损害CAR-T功能。为了解决这些问题，越来越多的临床前研究提出了潜在有效的解决办法，相应的临床研究也相继开展。本文将对CAR-T细胞治疗实体瘤的现存挑战及相应的优化策略进行综述，以期为CAR-T疗法的未来探索提供参考。Abstract: The sequential launch of chimeric antigen receptor T-cell (CAR-T cell) therapy products caused a breakthrough in the treatment of hematological tumors. However, owing to the differences in properties between solid tumors and hematological tumors, CAR-T cell shave not been used much in the treatment of solid tumors. Solid tumor cells themselves and their distinctive tumor microenvironment (TME) are two crucial factors limiting the efficacy of CAR-T cells by impairing their function in multiple processes, including their infiltration into the tumor site, maintenance of their anti-antitumor activity in the TME, and targeted recognition killing of tumor cells. To address these problems, an increasing number of preclinical studies have proposed potential effective solutions, and corresponding clinical studies also have been carried out. This manuscript focuses on reviewing the existing challenges and corresponding optimization strategies for CAR-T cells in solid tumor treatment, aiming to provide a reference for future exploration of its applications.
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患者女性，57岁，无吸烟史。因咳痰伴痰中带血1个月于2012年3月就诊陆军总医院，PET-CT检查提示：右肺癌，肺门、纵隔多发淋巴结转移，L2骨转移。免疫组织化学检测：肺来源可能性大。心包积液检测示：查见鳞癌（图 1），EGFR基因突变阴性。诊断为：1）右肺鳞癌Ⅳ期（pT4N3M1），肺门、纵隔多发淋巴结转移癌，骨转移癌，心包积液。2）高血压Ⅲ级高危。患者拒绝放、化疗，服用靶向药物治疗。遂于2012年3月开始口服靶向药物吉非替尼250 mg qd。2个月疗效评价：疗效稳定（SD），见图 2。2015年7月患者出现腰部疼痛，2015年9月16日复查胸部CT示：双肺部多发结节，右肺部结节明显增大。考虑其为缓慢进展，继续给予患者服用吉非替尼并加用甲磺酸阿帕替尼500 mg qd。因患者为高血压Ⅲ级，服阿帕替尼期间严密监测患者血压、定期复查尿常规。患者耐受情况好，未见明显不良反应。2个月后复查CT示：肺部，疗效评价病灶稳定（SD），见图 3。患者2016年2月5日因出现头痛、四肢抽搐，外院胸部CT提示病变进展（PD）。阿帕替尼无疾病生存期为5个月余。经激素、利尿、放疗对症治疗后，头痛及四肢抽搐缓解，改行阿帕替尼联合AZD9291治疗。2016年3月7日患者复查骨扫描未见新发骨转移癌灶，胸部CT提示肺病灶未见增大，疗效评价SD，现患者正在随访中。
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图 1 心包积液查见鳞癌细胞（HE染色×200）Figure 1. Squamous cell carcinomas were found in pericardial effusion (H & E staining ×200)小结 阿帕替尼对肺鳞癌的疗效尚不明确。针对非小细胞肺癌（NSCLC），一项Ⅱ期临床试验纳入135例非鳞非小细胞肺癌患者，随机以2：1的比例口服阿帕替尼750 mg qd和安慰剂，结果显示阿帕替尼组的中位无疾病进展生存期优于安慰剂组（4.7个月vs.1.9个月，HR 0.278，95%CI：0.170~0.455，P < 0.000 1）。阿帕替尼组的有效率为12.2%（安慰剂组为0），疾病控制率为68.9%（安慰剂组24.4%）（P=0.015 8，P < 0.000 1）。不良反应大多为高血压、蛋白尿以及手-足综合征，但一般为轻度或中度，可耐受[1]。总而言之，阿帕替尼对于晚期非鳞非小细胞肺癌效果显著。而李旭等[2]选取86例晚期NSCLC患者，随机分为2组，治疗组给予甲磺酸阿帕替尼治疗，对照组给予紫杉醇单药化疗随访记录两组患者CEA、CYFRA21-1、VEGF、MMP-9以及疗效情况。结果示阿帕替尼组CEA、CYFRA21-1分别为（14.01±1.04、4.42±0.35）ng/mL，均优于紫杉醇组（18.05±1.86、18.05±1.86）ng/mL（P < 0.05）。阿帕替尼VEGF、MMP-9分别为（285.49±35.47、1008.28±85.16）ng/mL，均优于紫杉醇组（494.82±50.16、1459.54±119.75）ng/mL（P < 0.05）。阿帕替尼组总有效率为95.35%，高于紫杉醇组76.74%（P < 0.05）。
本例为EGFR阴性的肺鳞癌患者，靶向治疗失败后口服阿帕替尼，疗效佳，无疾病生存期长达5个月余。这提示阿帕替尼治疗鳞癌效果依然显著，值得进一步研究和应用。
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