SA-4-1BBL as the immunomodulatory component of a HPV-16 E7 protein based vaccine shows robust therapeutic efficacy in a mouse cervical cancer model.
SA-4-1BBL as the immunomodulatory component of a HPV-16 E7 protein based vaccine shows robust therapeutic efficacy in a mouse cervical cancer model.
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DOI：
10.1016/j.vaccine.2010.06.073
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发表时间：
2010-08-16
期刊：
影响因子：
5.5
通讯作者：
Shirwan, Haval
中科院分区：
文献类型：
--
作者：
Sharma, Rajesh K.;Srivastava, Abhishek K.;Yolcu, Esma S.;MacLeod, Kathryn J.;Schabowsky, Rich-Henry;Madireddi, Shravan;Shirwan, Haval
宫颈癌是全球女性癌症相关死亡的主要原因。目前基于HPV(人乳头瘤病毒)晚期基因蛋白L1的预防性疫苗在治疗环境中无效。因此，迫切需要开发针对HPV相关癌症的治疗性疫苗。HPV E7癌蛋白在宫颈癌中表达，并与细胞转化和转化表型的维持有关。因此，E7蛋白是开发宫颈癌治疗性亚单位疫苗的理想靶点。然而，这种蛋白的低抗原性可能需要强大的佐剂才能达到治疗效果。我们最近创造了一种新的嵌合形式的4-1BBL共刺激分子与核心链霉亲和素(SA-4-1BBL)工程，并证明了它的安全和多效性的免疫系统的各种细胞。在此，我们测试了SA-4-1BBL作为HPV-16E7重组蛋白治疗性疫苗的免疫调节成分在表达TC-1肿瘤的E7小鼠宫颈癌模型中的应用。单次皮下接种可有效根除约70%的小鼠已建立的肿瘤。该疫苗的治疗效果与强劲的初始和记忆性CD4+和CD8+T细胞反应、Th1细胞因子反应、CD4+和CD8+T细胞向肿瘤的渗透以及增强NK细胞杀伤有关。重要的是，NK细胞在疫苗介导的治疗中扮演着重要的角色，因为它们的身体消耗影响了疫苗的效力。总而言之，这些数据表明SA-4-1BBL作为一种新型多功能免疫调节剂用于开发针对癌症和慢性感染的治疗性疫苗。
Cervical cancer is the leading cause of cancer-related deaths among women worldwide. Current prophylactic vaccines based on HPV (Human papillomavirus) late gene protein, L1 are ineffective in therapeutic settings. Therefore, there is an acute need for the development of therapeutic vaccines for HPV associated cancers. The HPV E7 oncoprotein is expressed in cervical cancer and has been associated with the cellular transformation and maintenance of the transformed phenotype. As such, E7 protein represents an ideal target for the development of therapeutic subunit vaccines against cervical cancer. However, the low antigenicity of this protein may require potent adjuvants for therapeutic efficacy. We recently generated a novel chimeric form of the 4-1BBL costimulatory molecule engineered with core streptavidin (SA-4-1BBL) and demonstrated its safe and pleiotropic effects on various cells of the immune system. We herein tested the utility of SA-4-1BBL as the immunomodulatory component of HPV-16 E7 recombinant protein based therapeutic vaccine in the E7 expressing TC-1 tumor as a model of cervical cancer in mice. A single subcutaneous vaccination was effective in eradicating established tumors in approximately 70% of mice. The therapeutic efficacy of the vaccine was associated with robust primary and memory CD4+ and CD8+ T cell responses, Th1 cytokine response, infiltration of CD4+ and CD8+ T cells into the tumor, and enhanced NK cell killing. Importantly, NK cells played an important role in vaccine mediated therapy since their physical depletion compromised vaccine efficacy. Collectively, these data demonstrate the utility of SA-4-1BBL as a new class of multifunctional immunomodulator for the development of therapeutic vaccines against cancer and chronic infections.
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DOI：
10.4049/jimmunol.0803241
发表时间：
2009-06-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Lee SW;Salek-Ardakani S;Mittler RS;Croft M
通讯作者：
Croft M
影响因子：
8
作者：
Georgopoulos, NT;Proffitt, JL;Blair, GE
通讯作者：
Blair, GE
影响因子：
4.4
作者：
Elpek, Kutlu G.;Yolcu, Esma S.;Shirwan, Haval
通讯作者：
Shirwan, Haval
影响因子：
5.5
作者：
Schabowsky RH;Elpek KG;Madireddi S;Sharma RK;Yolcu ES;Bandura-Morgan L;Miller R;MacLeod KJ;Mittler RS;Shirwan H
通讯作者：
Shirwan H
影响因子：
5.8
作者：
Cui, ZR;Huang, L
通讯作者：
Huang, L