恶性肿瘤生物化疗的原理与临床应用*

2017-01-06吕青综述邹征云审校

中国肿瘤临床 2016年23期

吕青综述邹征云②审校

·综述·

恶性肿瘤生物化疗的原理与临床应用*

吕青①综述邹征云①②审校

生物化疗（chemoimmunotherapy，biochemotherapy，CB）是将生物治疗和化学治疗联合应用于恶性肿瘤治疗领域的全新肿瘤综合治疗模式。目前国内外大量临床研究已经证实，肿瘤疫苗、单克隆抗体、免疫活性细胞及细胞因子等联合化疗的生物化疗可以显著提高抗肿瘤效应，在多种晚期难治性恶性实体肿瘤治疗中取得了较好的疗效。本文就生物化疗的原理、分类、临床应用及其存在的问题等进行综述

生物化疗肿瘤过继性细胞治疗单克隆抗体生物反应调节剂肿瘤疫苗

生物化疗（chemoimmunotherapy，biochemotherapy，CB）是将生物治疗和化学治疗联合应用于恶性肿瘤治疗领域的全新肿瘤综合治疗模式。生物化疗的综合治疗模式最先应用于转移性恶性黑色素瘤的治疗，与标准的高剂量干扰素治疗方案相比可延长患者无复发生存期（relapse-free survival，RFS）［1］。国外Ⅱ、Ⅲ期临床试验证实，生物化疗在某些晚期难治性恶性实体肿瘤治疗中取得了令人鼓舞的疗效。越来越多的体内外实验证实，某些化疗药物在特定的给药时间和剂量强度范围内可以通过多种机制打破机体的免疫抑制和免疫耐受状态，触发机体免疫抗肿瘤作用，此时再给予生物治疗，即可以发挥抗肿瘤协同效应［2］。本文就生物化疗的原理、分类、临床应用及其存在的问题等进行综述。

1 生物化疗的原理

化疗引起肿瘤细胞凋亡，表达并释放更多肿瘤抗原［3］，当肿瘤抗原到达区域淋巴结，增强抗原交叉递呈，若在化疗后加以辅助免疫治疗，激活抗原递呈细胞，可增强机体免疫抗肿瘤活性。Broomfield等［4］通过动物实验证明肿瘤部分切除后，序贯化疗及免疫治疗可产生抗原依赖性记忆性免疫细胞，而肿瘤完全切除后不能产生，因此，体内若有肿瘤残留，化疗后序贯免疫治疗可进一步增强免疫抗肿瘤效应，或许可以达到长期抗肿瘤效应。

化疗还可以导致肿瘤微环境中炎症介质的释放，促进抗肿瘤免疫应答反应。某些化疗药物，如5-Fu［5］，可以上调脾细胞中NK细胞分泌TNF-α的能力，从而增强其杀伤效应；紫杉醇［6］通过上调NK细胞表面NKG2D水平激活NK细胞，同时NKG2D水平的升高有助于提高曲妥珠单抗介导的ADCC作用，行新辅助化疗的乳腺癌患者中，HER-2（+）的患者外周血中NK细胞数量增多，并且这部分患者中获得病理完全缓解（pathological complete responses，pCR）的外周血中活化的NK细胞显著升高［7］。此外，某些单克隆抗体也可以导致免疫原性细胞的死亡，与化疗药物联合运用，可以放大这一效应［8］，从而促进树突状细胞（dentritic cell，DC）的吞噬及肿瘤抗原递呈能力，并通过上调肿瘤细胞CD95及细胞间黏附分子-1（intercellular cell adhesion molecule-1，ICAM-1）等细胞表面分子的表达而促进效应细胞的识别［9］。目前研究发现，具有促进肿瘤抗原摄取、加工和呈递的化疗药物有蒽环类药物［10］、紫杉烷类药物［11］及吉西他滨［9］。5-FU［12］、达卡巴嗪［14］、甲磺酸伊马替尼［14］等也可以通过增加肿瘤细胞表面分子CD95、热休克蛋白（heat shock protein，HSP）及肿瘤坏死因子相关的凋亡诱导配体（tumor necrosis factor-related apoptosis-inducing ligand，TRAIL）的表达，利于肿瘤细胞被识别和清除。因此，化疗药物作用于肿瘤细胞后可以促进机体肿瘤抗原呈递及抗肿瘤免疫应答。

有些化疗药物不仅可以诱导肿瘤细胞凋亡，在特定给药剂量及给药方式下还可以破坏免疫抑制和免疫耐受的信号通路［15］，通过平衡两者之间的关系，达到抗肿瘤目的。如某些化疗可降低调节性T细胞（regulatory T cell，Treg）、髓源性抑制细胞（myeloidderived suppressor cells，MDSC）比例。Treg是CD4+CD25+的一类细胞群，MDSC是骨髓来源CD14-CD11b+CD33+HLADR-一群异质性细胞，是树突状细胞（dendritic cells，DCs）、巨噬细胞和（或）粒细胞的前体，具有显著抑制免疫细胞应答的能力，在机体免疫耐受中发挥着主导作用。常规剂量或大剂量的化疗药物，包括环磷酰胺（cyclophosphamide，CTX）、氟达拉滨、紫杉烷类药物、吉西他滨、顺铂和博莱霉素等，可以清除包括Treg在内的抑制机体免疫应答的淋巴细胞，同样动物实验发现标准剂量的吉西他滨或顺铂能减少小鼠外周血MDSC数量［16］，而有些化疗方案却相反，能导致小鼠外周血中MDSC和Treg细胞数量增加，但在联合DC疫苗治疗后，不仅产生了具有抗原特异性的Th1及CTL细胞，同时MDSC和Treg细胞也随之减少［17］，从而提高CD8+T细胞和NK细胞免疫活性，化疗后给予肿瘤疫苗或免疫效应细胞，将有利于体内T淋巴细胞库重建，未致敏的T淋巴细胞被诱导分化为具有抗肿瘤效应的记忆细胞及细胞毒性T淋巴细胞（cytotoxic T lymphocyte，CTL），从而导致宿主体内肿瘤的消退［18-22］。

另外，某些小剂量化疗药物本身具有免疫调节作用。临床研究证实小剂量CTX的联合肿瘤疫苗放大迟发性超敏反应（delayedtype hypersensitivity，DTH），减低Treg比例，并延长患者生存时间［23］；小剂量CTX口服1个月，还可以促进抗肿瘤效应T细胞增殖，恢复自然杀伤细胞（natural killer，NK）的细胞毒性作用［24］。

体外实验研究发现，当阿霉素作用于肿瘤细胞1 h内，肿瘤细胞内的钙网蛋白（calreticulin，CRT）快速转运至细胞表面，向DC发出“eat me”信号；作用12 h后，肿瘤细胞表面表达HSP90等监控蛋白，促使DC和肿瘤细胞黏附，DC得以活化；12～18 h后，濒临死亡的肿瘤细胞持续释放高迁移率族蛋白B1（high mobility group box1，HMGB1），结合到活化的DC细胞表面，最终诱导DC成熟。

此外，靶向于肿瘤细胞表面某些特定分子的单克隆抗体或小分子化合物，如赫赛汀、美罗华、爱必妥等，不仅能够抑阻断肿瘤细胞生长过程中的某些信号通路，还能够提高肿瘤细胞对化疗药物的敏感性，序贯化疗可以进一步增强抗肿瘤疗效。

2 生物化疗分类及临床应用

2.1 化疗联合免疫调节剂（immunomodulator）

常用联合化疗治疗晚期肿瘤的免疫调节剂有粒-巨噬细胞刺激因子（granulocyte-macrophage colonystimulating factor，GM-CSF），干扰素-α（interferon-α，IFN-α），白细胞介素-2（interleukin-2，IL-2），维甲酸，细菌制剂OK432等。列举2000年以来部分化疗联合免疫调节剂治疗恶性肿瘤的临床试验及其结果（表1）。

2.2 化疗联合肿瘤疫苗

化疗可以杀伤Treg细胞，减少其数量并抑制其功能。化疗可以触发肿瘤细胞的死亡，从而使肿瘤抗原释放，APC负载更多的抗原，更好的发挥抗肿瘤反应。通过这些机制，化疗增强了肿瘤疫苗的抗肿瘤作用。列举2000年以来化疗联合肿瘤疫苗用于临床治疗晚期恶性肿瘤的部分临床试验及其结果（表2）。

2.3 化疗序贯特异性免疫效应细胞

在美国国立癌症研究院，以Dudley ME为首的生物治疗小组应用化疗序贯免疫效应细胞治疗晚期难治性恶性黑素瘤取得了令人鼓舞的疗效，他们进行了一项难治性恶性黑素瘤的临床研究，对35例患者进行非清髓的CTX联合氟达拉滨化疗后，回输清除了Treg的自体肿瘤特异性肿瘤浸润淋巴细胞（tumor infiltrating lymphocyte，TIL），后续静滴高剂量IL-2，结果显示客观有效率（objective response rate，ORR）达51%，其中PR 42.9%，CR 8.6%［47］。

2.4 单抗隆抗体联合化疗

靶向肿瘤细胞的单克隆抗体或被放射性核素标记的单克隆抗体在多种肿瘤的治疗中取得了显著疗效。这些单抗包括治疗白血病的抗CD33单抗gemtuzumab，治疗弥漫大B细胞淋巴瘤的抗CD20单抗rituximab，针对HER-2阳性乳腺癌或胃癌的trastuzumab，治疗头颈部鳞癌、晚期结直肠癌等多种实体肿瘤的针对表皮生长因子受体（epidermal growth factor receptor，EGFR）的Cetuximab（C225），还有靶向细胞毒性T淋巴细胞相关抗原CTLA4的抗CTLA4抗体Ipilimumab等。这些靶向于肿瘤细胞表面某些特定分子的单克隆抗体或小分子化合物，不仅能够抑阻断肿瘤细胞生长过程中的某些信号通路，还能够提高肿瘤细胞对化疗药物的敏感性，序贯化疗可以进一步增强抗肿瘤疗效。常用的单克隆抗体有Herceptin（赫赛汀）、rituximab（美罗华）、cetuximab（C225，爱必妥）、抗CTLA4抗体ipilimumab等。表3展示了2000年以来单抗隆抗体联合化疗的部分临床试验及其结果。

表1 2000年以来化疗联合免疫调节剂部分临床试验总结Table 1Examples of clinical studies of the therapy combining chemotherapy with immunomodulator since 2000

表2 2000年以来化疗联合肿瘤疫苗部分临床试验总结Table 2Examples of clinical studies of the therapy combining chemotherapy with tumor vaccine since 2000

表3 2000年以来单抗隆抗体联合化疗部分临床试验总结Table 3Examples of clinical studies of the therapy combining chemotherapy with monoclonal antibodies since 2000

3 生物化疗存在的问题

大多数临床试验发现生物化疗较单纯化疗的不良反应明显增加［26，28，34］，如何减低治疗的毒性作用，同时提高抗肿瘤治疗效果，是恶性肿瘤治疗领域亟待解决的难题。无论是化疗联合生物反应调节剂治疗，还是应用化疗序贯TIL及高剂量IL-2治疗晚期难治性恶性黑素瘤，在取得较好疗效的治疗模式中，所用生物反应调节剂剂量均较高，如IL-2每次静滴剂量900万U/m2，每日3次，或60～72万U/kg，每日3次；IFN-α每次注射剂量500万U/m2；GM-CSF每次注射量为250～500 μg/m2［20，21，25，47］。生物反应调节剂用量大，其不良反应必然明显。目前有文献报道，HLA-DR或HLA-DQ1的状态与IL-2疗效相关［53］；血浆血管内皮细胞生长因子（vascular endothelial growth factor，VEGF）及纤连蛋白fibronectin水平高者提示高剂量IL-2治疗无效［54］；血浆低水平的VEGFR-3与舒尼替尼的疗效相关［55］；Eto等［56］研究发现信号传导蛋白和转录激活物（signal transducers and activators of transcription，STAT）-3 C/C基因型肾癌患者接受IFN-α疗效明显高于T/T或C/T基因型者。因此，在治疗前，检测患者药物疗效相关的生物标记，对预计可能见效的患者施行相应的生物反应调节剂治疗非常必要。此外，某些抗氧化剂，如OTZ［57］（半胱氨酸前体物质）与IL-2联合使用可以降低化疗所致的毒性反应，但并不影响抗肿瘤效应。

目前，trastuzumab批准用于HER-2有扩增的乳腺癌或贲门癌患者，如免疫组织化学（immunohistochemisty，IHC）强阳性或荧光染色体原位杂交（fluorescence chromosomal in situ hybridization，FISH）检测有扩增；rituximab为抗CD20单克隆抗体，可以与化疗联合用于肿瘤细胞表达CD20的淋巴瘤治疗；cetuximab为EGFR单克隆抗体，对于晚期结直肠癌的治疗，目前建议与化疗联合用于K-ras基因野生型患者。对于含单克隆抗体的生物化疗，因为单克隆抗体价格昂贵，况且并非每一位患者都能见效，因此，临床使用前，也需要对其疗效预测分子进行检测，以筛选出适宜人群。

4 结语

平衡化疗药物的细胞毒性作用与免疫调节作用，探索化疗药物与各种生物治疗的合理组合，尽可能扩大其肿瘤抑制效应，又可提高免疫调节作用，是生物化疗的理想状态，这需要更深入地探究生物化疗的机制。生物化疗是晚期恶性肿瘤治疗的新模式，主要依据患者体力状况、肿瘤病理类型和分子生物学行为，将生物治疗与化疗有机结合起来，以取得最佳治疗效果，并最大限度地改善患者的生存质量，提高患者的生存时间。虽然在其应用过程中还存在不少问题，限制其临床广泛开展。但是，“量体裁衣”、“个体化治疗”，以肿瘤患者自身的生物标志为依据，个体化地施行合适的抗肿瘤生物化疗方案，这是肿瘤治疗追求的最高目标。在肿瘤疫苗或抗肿瘤免疫效应细胞制备过程中，同样面临一系列问题，如何获得有效的肿瘤抗原？采用何种抗原或基因负载或转染DC？如何分离获取抗肿瘤特异的CTL并在体外进行大规模扩增？免疫活性细胞回输前该采取何种非清髓性化疗方案，从而调整宿主体内环境，以利持久的抗肿瘤免疫应答反应？随着研究的进一步深入，这些问题将逐一解决。

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（2016-06-07收稿）

（2016-08-31修回）

（编辑：杨红欣校对：郑莉）

Theories and clinical applications of biochemotherapy for malignant carcinomas

Qing LV1,Zhengyun ZOU1,2
Correspondence to:Zhengyun ZOU;E-mail:zouzhengyun@medmail.com.cn
1Comprehensive Cancer Center，Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine,Nanjing University of Medicine,Nanjing210008,China;2Comprehensive Cancer Centre,Nanjing Drum Tower Hospital,the Affiliated Hospital of Nanjing University Medical School,Nanjing 210008,China

This work is supported by the Jiangsu Province Health Department"Six Talent Peak"program(No.WSN-007),Second Level of Nanjing Municipal Health Youth Talent Project(No.NJGL-2011225),Nanjing Municipal Medical Science and Technology Development Project (No.ZKX15012)

Chemoimmunotherapy or biochemotherapy,the combination of chemotherapy with immunotherapy,is a novel comprehensive treatment model for malignant carcinoma.In recent years,many clinical trials have shown that biochemotherapy is associated with an improved response rate.Such biological agents include tumor vaccines,monoclonal antibodies,cytokines,and immunocompetent cells.In this article,we review the theories,sort the clinical applications of novel treatments,and discuss some of the problems existing in this field.

biochemotherapy,tumor,adaptive cell-transfer therapy,monoclonal antibody,immunomodulator,tumor vaccine