乳腺癌免疫治疗的研究进展

doi:10.3877/cma.j.issn.1674-0807.2018.01.009

免疫治疗是继手术、放射治疗、化疗、内分泌治疗等之后的乳腺癌重要治疗手段。近年来，随着免疫学的不断发展，乳腺癌的免疫治疗取得了很大的进步，并日益受到临床医师的重视。笔者简述了针对乳腺癌治疗相关靶点的治疗性疫苗，如免疫检查点相关疫苗、特异性抗原疫苗、细胞疫苗、病毒载体疫苗和双特异性抗体疫苗等，同时，还介绍了近年来针对乳腺癌的预防性疫苗，这将有利于临床医师进一步了解乳腺癌免疫治疗的现状与进展。

关键词: 乳腺肿瘤, 免疫疗法, 疫苗

表1 治疗性乳腺癌疫苗的临床试验

疫苗及联合药物		乳腺癌类型	例数	临床试验	生物标志物或效应	临床疗效	参考文献
免疫检查点相关疫苗及联合用药		?	?	?	?	?	?
?	IMP321＋紫杉醇	转移性乳腺癌	30	1期/2期	APC、自然杀伤细胞与CD8^＋效应T细胞的比例呈持续性增加	PFS率：90%	[2]
?	tremelimumab＋依西美坦	转移性激素敏感型乳腺癌	26	1期	外周血中ICOS^＋T细胞/FoxP3^＋调节性T细胞的比率显著增加	ORR：42%	[3]
?	ipilimumab、冷冻消融或两者联合治疗	浸润性乳腺癌	19	1期	外周血中Th1、激活的ICOS^＋T细胞及CD4^＋T、CD8^＋T细胞升高	NR	[4]
?	pembrolizumab	PD-L1阳性晚期三阴性乳腺癌	32	1b期	NR	6个月PFS率：23.3%	[5]
?	MPDL3280A	PD-L1阳性或PD-L1阴性乳腺癌	54	1a期	CD8^＋T细胞增殖和IL-18水平增加	ORR：19%，其中2例CR，2例PR	[6]
?	atezolizumab	转移性三阴性乳腺癌	115	1期	TIL和CD8^＋T细胞水平增加	提高生存率	[7]
特异性抗原疫苗及联合用药		?	?	?	?	?	?
?	HER-2肽＋GM-CSF佐剂	Ⅲ、Ⅵ期HER-2阳性乳腺癌，卵巢癌和肺癌	64	1期	HER-2特异性DTH、T细胞、Ab	NR	[8,9,10,11,12]
?	HER-2 ICD蛋白＋GM-CSF佐剂	Ⅱ～Ⅳ期HER-2阳性乳腺癌和卵巢癌	29	1期	HER-2特异性Ab和T细胞	NR	[13]
?	HER-2肽＋GM-CSF佐剂和曲妥珠单克隆抗体	Ⅳ期HER-2阳性乳腺癌	22	1期/2期	HER-2特异性T细胞，血浆TGF-β减少	NR	[14]
?	HER-2蛋白＋AS15佐剂和拉帕替尼	Ⅳ期HER-2阳性乳腺癌	12	1期	HER-2特异性Ab和T细胞免疫应答	NR	[15]
?	HER-2肽＋GM-CSF佐剂	Ⅳ期HER-2阳性乳腺癌和卵巢癌	14	1期	HER-2特异性DTH，能分泌IFN-γ和溶解肿瘤细胞的CD8^＋T细胞	NR	[16]
?	GP2＋GM-CSF＋曲妥珠单克隆抗体	HER-2阳性乳腺癌	17	Ib期	IFN-γ分泌增加	NR	[17]
?	STn-KLH＋CY和KLH＋CY相对照	Ⅳ期乳腺癌	1 028	3期	新特异性疫苗Ab	无差异	[18]
?	MUC1	Ⅱ期乳腺癌	31	3期	NR	对OS有益	[19,20]
?	肿瘤相关糖抗原Lewis Y与神经节苷脂GD2	Ⅳ期乳腺癌	6	1期	提高特异性抗体水平	潜在临床应用价值	[21]
?	生存素肽±IFN	晚期/复发乳腺癌	14	1期	生存素特异性T细胞	SD率：14%	[21]
?	乳球蛋白cDNA	Ⅳ期乳腺癌	14	1期	乳球蛋白特异性T细胞	可能获益	[22]
乳腺癌细胞疫苗及联合用药		?	?	?	?	?	?
?	HER-2-DC (lapuleucel-T)	Ⅳ期HER-2阳性乳腺癌	18	1期	HER-2特异性T细胞增殖	SD率：16.7%	[23]
?	p53-DC	Ⅳ期乳腺癌	26	2期	p53特异性T细胞：38%，Ab：42%	SD率：42%	[24]
?	异源性分泌型GM-CSF乳腺肿瘤细胞＋低剂量CY和DOX	Ⅳ期乳腺癌	28	1期	HER-2特异DTH和Ab；最佳化疗剂量CY为200 mg/m²，DOX为35 mg/m²	NR	[25]
?	异源性分泌型GM-CSF乳腺肿瘤细胞＋低剂量CY和曲妥珠单克隆抗体	Ⅳ期HER-2阳性乳腺癌	20	1期	HER-2特异DTH和CD8^＋T细胞，Tregs和MDSCs减少	6个月CB率：55%；PFS：7个月；OS：42个月	[26]
?	CY、噻替派、卡铂联合DC-CIK	转移性三阴性乳腺癌	23	1期	NR	PR率：13%，SD率：56.6%	[27]
病毒载体疫苗及联合用药		?	?	?	?	?	?
?	PANVAC?	转移性乳腺癌	12	1期	特异性CD4^＋T细胞应答，并产生高水平的CEA特异性T细胞	SD率：33%CR率：8%	[28]
双特异性抗体及联合用药		?	?	?	?	?	?
?	连有活化T细胞的抗HER-2/CD3双特异性抗体	转移性乳腺癌	23	1期	诱导固有免疫应答	SD率：59.1%	[29]

表1 治疗性乳腺癌疫苗的临床试验

疫苗及联合药物		乳腺癌类型	例数	临床试验	生物标志物或效应	临床疗效	参考文献
免疫检查点相关疫苗及联合用药		?	?	?	?	?	?
?	IMP321＋紫杉醇	转移性乳腺癌	30	1期/2期	APC、自然杀伤细胞与CD8^＋效应T细胞的比例呈持续性增加	PFS率：90%	[2]
?	tremelimumab＋依西美坦	转移性激素敏感型乳腺癌	26	1期	外周血中ICOS^＋T细胞/FoxP3^＋调节性T细胞的比率显著增加	ORR：42%	[3]
?	ipilimumab、冷冻消融或两者联合治疗	浸润性乳腺癌	19	1期	外周血中Th1、激活的ICOS^＋T细胞及CD4^＋T、CD8^＋T细胞升高	NR	[4]
?	pembrolizumab	PD-L1阳性晚期三阴性乳腺癌	32	1b期	NR	6个月PFS率：23.3%	[5]
?	MPDL3280A	PD-L1阳性或PD-L1阴性乳腺癌	54	1a期	CD8^＋T细胞增殖和IL-18水平增加	ORR：19%，其中2例CR，2例PR	[6]
?	atezolizumab	转移性三阴性乳腺癌	115	1期	TIL和CD8^＋T细胞水平增加	提高生存率	[7]
特异性抗原疫苗及联合用药		?	?	?	?	?	?
?	HER-2肽＋GM-CSF佐剂	Ⅲ、Ⅵ期HER-2阳性乳腺癌，卵巢癌和肺癌	64	1期	HER-2特异性DTH、T细胞、Ab	NR	[8,9,10,11,12]
?	HER-2 ICD蛋白＋GM-CSF佐剂	Ⅱ～Ⅳ期HER-2阳性乳腺癌和卵巢癌	29	1期	HER-2特异性Ab和T细胞	NR	[13]
?	HER-2肽＋GM-CSF佐剂和曲妥珠单克隆抗体	Ⅳ期HER-2阳性乳腺癌	22	1期/2期	HER-2特异性T细胞，血浆TGF-β减少	NR	[14]
?	HER-2蛋白＋AS15佐剂和拉帕替尼	Ⅳ期HER-2阳性乳腺癌	12	1期	HER-2特异性Ab和T细胞免疫应答	NR	[15]
?	HER-2肽＋GM-CSF佐剂	Ⅳ期HER-2阳性乳腺癌和卵巢癌	14	1期	HER-2特异性DTH，能分泌IFN-γ和溶解肿瘤细胞的CD8^＋T细胞	NR	[16]
?	GP2＋GM-CSF＋曲妥珠单克隆抗体	HER-2阳性乳腺癌	17	Ib期	IFN-γ分泌增加	NR	[17]
?	STn-KLH＋CY和KLH＋CY相对照	Ⅳ期乳腺癌	1 028	3期	新特异性疫苗Ab	无差异	[18]
?	MUC1	Ⅱ期乳腺癌	31	3期	NR	对OS有益	[19,20]
?	肿瘤相关糖抗原Lewis Y与神经节苷脂GD2	Ⅳ期乳腺癌	6	1期	提高特异性抗体水平	潜在临床应用价值	[21]
?	生存素肽±IFN	晚期/复发乳腺癌	14	1期	生存素特异性T细胞	SD率：14%	[21]
?	乳球蛋白cDNA	Ⅳ期乳腺癌	14	1期	乳球蛋白特异性T细胞	可能获益	[22]
乳腺癌细胞疫苗及联合用药		?	?	?	?	?	?
?	HER-2-DC (lapuleucel-T)	Ⅳ期HER-2阳性乳腺癌	18	1期	HER-2特异性T细胞增殖	SD率：16.7%	[23]
?	p53-DC	Ⅳ期乳腺癌	26	2期	p53特异性T细胞：38%，Ab：42%	SD率：42%	[24]
?	异源性分泌型GM-CSF乳腺肿瘤细胞＋低剂量CY和DOX	Ⅳ期乳腺癌	28	1期	HER-2特异DTH和Ab；最佳化疗剂量CY为200 mg/m²，DOX为35 mg/m²	NR	[25]
?	异源性分泌型GM-CSF乳腺肿瘤细胞＋低剂量CY和曲妥珠单克隆抗体	Ⅳ期HER-2阳性乳腺癌	20	1期	HER-2特异DTH和CD8^＋T细胞，Tregs和MDSCs减少	6个月CB率：55%；PFS：7个月；OS：42个月	[26]
?	CY、噻替派、卡铂联合DC-CIK	转移性三阴性乳腺癌	23	1期	NR	PR率：13%，SD率：56.6%	[27]
病毒载体疫苗及联合用药		?	?	?	?	?	?
?	PANVAC?	转移性乳腺癌	12	1期	特异性CD4^＋T细胞应答，并产生高水平的CEA特异性T细胞	SD率：33%CR率：8%	[28]
双特异性抗体及联合用药		?	?	?	?	?	?
?	连有活化T细胞的抗HER-2/CD3双特异性抗体	转移性乳腺癌	23	1期	诱导固有免疫应答	SD率：59.1%	[29]

表2 关于预防乳腺癌复发疫苗的临床试验

疫苗	乳腺癌类型	样本量	临床试验	生物标志物	临床疗效	参考文献
HER-2 E75肽疫苗＋GM-CSF佐剂	辅助疗法后没有疾病征兆的早期HER-2阳性乳腺癌	试验组：108例；对照组：79例	1期/2期	HER-2特异性记忆性T细胞；Tregs和TGF-β增加	5年DFS率：87.7%	[58]
HER-2 DC内接种	DCIS	27例	1期	HER-2特异性T细胞；50%外科手术残留的DCIS中HER-2表达低下	手术后NED者占18.5%	[59]

表2 关于预防乳腺癌复发疫苗的临床试验

疫苗	乳腺癌类型	样本量	临床试验	生物标志物	临床疗效	参考文献
HER-2 E75肽疫苗＋GM-CSF佐剂	辅助疗法后没有疾病征兆的早期HER-2阳性乳腺癌	试验组：108例；对照组：79例	1期/2期	HER-2特异性记忆性T细胞；Tregs和TGF-β增加	5年DFS率：87.7%	[58]
HER-2 DC内接种	DCIS	27例	1期	HER-2特异性T细胞；50%外科手术残留的DCIS中HER-2表达低下	手术后NED者占18.5%	[59]

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