程序性死亡因子1/程序性死亡因子配体1在乳腺癌免疫治疗中的意义

doi:10.3877/cma.j.issn.1674-0807.2020.06.011

程序性死亡因子1(PD-1)和程序性死亡因子配体1(PD-L1)作为免疫检查点中的共抑制信号，参与了肿瘤细胞免疫逃逸过程。近年来，免疫治疗逐渐成为了肿瘤靶向治疗的新思路。笔者概述了PD-1/PD-L1的表达机制及其在不同类型乳腺癌免疫治疗中的研究进展，介绍了免疫相关不良反应的发生情况，以供同行参考。

关键词: 乳腺肿瘤, 免疫治疗, PD-1, PD-L1

表1 PD-1/PD-L1抑制剂用于乳腺癌治疗的临床研究概况

研究名称	NCT编号	受试者	治疗方案	结果	试验分期
TONIC^[56]	NCT02499367	67例TNBC	分为5组：多柔比星组、环磷酰胺组、顺铂组、放射治疗组(8 Gy×3)及无诱导治疗组。2周后，均接受3 mg/kg nivolumab治疗	总体ORR 20%，顺铂组23%和多柔比星组35%。多柔比星组和顺铂组检测到PD-1/PD-L1和细胞毒性T细胞途径的免疫相关基因上调	Ⅱ
KEYNOTE-012^[31]	NCT01848834	111例TNBC	每2周静脉注射pembrolizumab，10 mg/kg	ORR 18.5%，mPFS 1.9个月，mOS 10.2个月	Ⅰb
KETNOTE-086队列A^[57]	NCT02447003	170例mTNBC	每3周静脉注射pembrolizumab 200 mg，持续2年	总体ORR 5.3%，DCR 7.6%；PD-L1阳性患者ORR 5.7%，DCR 9.5%；mPFS2个月，mOS 8.9个月	Ⅱ
KETNOTE-086队列B^[58]	NCT02447003	84例PD-L1阳性mTNBC	每3周静脉注射pembrolizumab 200 mg，持续2年	ORR 21.4%，DCR 23.8%，mPFS 2.1个月，mOS 18.0个月	Ⅱ
KEYNOTE-355^[59]	NCT02819518	847例mTNBC	pembrolizumab+化疗组与安慰剂+化疗组	中位随访时间：17.5个月比15.5个月；CPS≥10患者的PFS：9.7个月比5.6个月；CPS≥1患者的PFS：7.6个月比5.6个月	Ⅲ
I-SPY 2^[60]	NCT01042379	104例TNBC和113例HR(+)/HER-2(-)乳腺癌	标准新辅助化疗(紫杉醇、多柔比星、环磷酰胺)加pembrolizumab治疗，对照组不接受pembrolizumab治疗	TNBC患者中：pembrolizumab组与对照组的pCR：60.0%比20.0%；HR(+)/HER-2(-)患者中，34%比13%	Ⅱ
MDPL3280^[61]	NCT01375842	27例TNBC	分别以15、20 mg/kg及1 200 mg固定剂量，静脉注射atezolizumab，每3周1次	ORR 24%，2例完全缓解，3例部分缓解，24周后PFS为33%	Ⅰa
Impassion130^[52]	NCT02425891	902例mTNBC	白蛋白结合型紫杉醇+atezolizumab组与白蛋白结合型紫杉醇+安慰剂组	PFS: 7.5个月比5.0个月；mOS: 21.0个月比18.7个月；PD-L1阳性患者中mOS：25.0个月比18.0个月	Ⅲ
JAVELIN^[62]	NCT01772004	174例MBC	每2周静脉注射avelumab，10 mg/kg，治疗2～50周	ORR 3.0%, TNBC组ORR 5.2%；所有病例中PD-L1阳性与阴性患者的ORR为16.7%比1.6%，TNBC组中ORR比为22.2%比2.6%	Ⅰ
GeparNuevo^[63]	NCT02685059	174例原发性TNBC	durvalumab/安慰剂+白蛋白结合型紫杉醇联用剂量密集型EC(表柔比星+环磷酰胺)方案	durvalumab组与安慰剂组的pCR 53.4%比44.2%，PD-L1阳性肿瘤存在pCR率升高趋势	Ⅱ
MEDI4736^[64]	NCT02489448	TNBC	3、10 mg/kg durvalumab+白蛋白结合型紫杉醇治疗	10 mg/kg durvalumab的给药方式是安全的，该实验第二阶段正在进行，预计招募50例患者入组	Ⅰ
ICONIC^[65]	NCT02904226	晚期实体瘤	A组：JTX-2011的3+3剂量递增设计；B组：JTX-2011的3+3剂量递增设计联用nivolumab；C组：在超过3种高表达ICOS的肿瘤中，应用JTX-2011；D组：在超过5种高表达ICOS的肿瘤中，JTX-2011与nivolumab联用	将评价ORR、反应持续时间、DCR、PFS、OS，目前未完成	Ⅰ/Ⅱ
联合放射治疗^[66]	NCT02639026	MBC	durvalumab+tremelimumab联合放射治疗，放射剂量8 Gy×3组比17 Gy×1组	受试者招募中	Ⅰ

表1 PD-1/PD-L1抑制剂用于乳腺癌治疗的临床研究概况

研究名称	NCT编号	受试者	治疗方案	结果	试验分期
TONIC^[56]	NCT02499367	67例TNBC	分为5组：多柔比星组、环磷酰胺组、顺铂组、放射治疗组(8 Gy×3)及无诱导治疗组。2周后，均接受3 mg/kg nivolumab治疗	总体ORR 20%，顺铂组23%和多柔比星组35%。多柔比星组和顺铂组检测到PD-1/PD-L1和细胞毒性T细胞途径的免疫相关基因上调	Ⅱ
KEYNOTE-012^[31]	NCT01848834	111例TNBC	每2周静脉注射pembrolizumab，10 mg/kg	ORR 18.5%，mPFS 1.9个月，mOS 10.2个月	Ⅰb
KETNOTE-086队列A^[57]	NCT02447003	170例mTNBC	每3周静脉注射pembrolizumab 200 mg，持续2年	总体ORR 5.3%，DCR 7.6%；PD-L1阳性患者ORR 5.7%，DCR 9.5%；mPFS2个月，mOS 8.9个月	Ⅱ
KETNOTE-086队列B^[58]	NCT02447003	84例PD-L1阳性mTNBC	每3周静脉注射pembrolizumab 200 mg，持续2年	ORR 21.4%，DCR 23.8%，mPFS 2.1个月，mOS 18.0个月	Ⅱ
KEYNOTE-355^[59]	NCT02819518	847例mTNBC	pembrolizumab+化疗组与安慰剂+化疗组	中位随访时间：17.5个月比15.5个月；CPS≥10患者的PFS：9.7个月比5.6个月；CPS≥1患者的PFS：7.6个月比5.6个月	Ⅲ
I-SPY 2^[60]	NCT01042379	104例TNBC和113例HR(+)/HER-2(-)乳腺癌	标准新辅助化疗(紫杉醇、多柔比星、环磷酰胺)加pembrolizumab治疗，对照组不接受pembrolizumab治疗	TNBC患者中：pembrolizumab组与对照组的pCR：60.0%比20.0%；HR(+)/HER-2(-)患者中，34%比13%	Ⅱ
MDPL3280^[61]	NCT01375842	27例TNBC	分别以15、20 mg/kg及1 200 mg固定剂量，静脉注射atezolizumab，每3周1次	ORR 24%，2例完全缓解，3例部分缓解，24周后PFS为33%	Ⅰa
Impassion130^[52]	NCT02425891	902例mTNBC	白蛋白结合型紫杉醇+atezolizumab组与白蛋白结合型紫杉醇+安慰剂组	PFS: 7.5个月比5.0个月；mOS: 21.0个月比18.7个月；PD-L1阳性患者中mOS：25.0个月比18.0个月	Ⅲ
JAVELIN^[62]	NCT01772004	174例MBC	每2周静脉注射avelumab，10 mg/kg，治疗2～50周	ORR 3.0%, TNBC组ORR 5.2%；所有病例中PD-L1阳性与阴性患者的ORR为16.7%比1.6%，TNBC组中ORR比为22.2%比2.6%	Ⅰ
GeparNuevo^[63]	NCT02685059	174例原发性TNBC	durvalumab/安慰剂+白蛋白结合型紫杉醇联用剂量密集型EC(表柔比星+环磷酰胺)方案	durvalumab组与安慰剂组的pCR 53.4%比44.2%，PD-L1阳性肿瘤存在pCR率升高趋势	Ⅱ
MEDI4736^[64]	NCT02489448	TNBC	3、10 mg/kg durvalumab+白蛋白结合型紫杉醇治疗	10 mg/kg durvalumab的给药方式是安全的，该实验第二阶段正在进行，预计招募50例患者入组	Ⅰ
ICONIC^[65]	NCT02904226	晚期实体瘤	A组：JTX-2011的3+3剂量递增设计；B组：JTX-2011的3+3剂量递增设计联用nivolumab；C组：在超过3种高表达ICOS的肿瘤中，应用JTX-2011；D组：在超过5种高表达ICOS的肿瘤中，JTX-2011与nivolumab联用	将评价ORR、反应持续时间、DCR、PFS、OS，目前未完成	Ⅰ/Ⅱ
联合放射治疗^[66]	NCT02639026	MBC	durvalumab+tremelimumab联合放射治疗，放射剂量8 Gy×3组比17 Gy×1组	受试者招募中	Ⅰ

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Significance of programmed death-1 and programmed death-ligand 1 in immunotherapy of breast cancer

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Significance of programmed death-1 and programmed death-ligand 1 in immunotherapy of breast cancer