免疫增效抗前列腺癌DNA疫苗抑瘤活性的初步研究
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摘要
研究背景：前列腺癌是威胁人类健康的重要疾病，特别进展到雄激素非依赖期的前列腺癌目前仍然没有特别有效的治疗方法。免疫治疗很可能成为治疗前列腺癌的很有前景的一种方法。DNA疫苗作为免疫治疗的一种方式，已经在临床前和临床实验中进行了广泛的研究，DNA疫苗具有安全性好、特异性高以及易于产业化生产等方面的优势正在成为前列腺癌免疫治疗的重要发展方向。但是，DNA疫苗也存在转染效率低下，诱导的免疫反应较弱的缺点，本研究我们通过对靶抗原的选择，佐剂的应用以及递送方式的改进等方面来加强DNA疫苗诱导的免疫反应，为前列腺癌DNA疫苗的免疫增效进行探索性研究。研究目的：本研究将前列腺干细胞抗原（PSCA）和免疫佐剂IL-12共同构建到同一真核表达载体中成为新型的前列腺癌DNA疫苗pVAX1-mPSCA-IRES-mIL-12，通过电穿孔的方法递送疫苗到小鼠体内，观察DNA疫苗的抑瘤效果并对其可能的免疫学机制进行初步的探讨。
方法：
1.将PCR方法扩增的mIL-12基因其克隆到pVAX1-IRES载体中IRES序列的下游构建免疫增效载体pVAX1-IRES-mIL-12，在此基础上将RT-PCR方法从RM-1细胞系中扩增的mPSCA基因克隆到该质粒IRES的上游，构建前列腺癌DNA疫苗pVAX1-mPSCA-IRES-mIL-12。质粒体外转染293T细胞后分别通过Western Blot验证mPSCA的表达，ELISA法验证mIL-12的真核表达；电穿孔法递送质粒到小鼠体内验，分别验证mPSCA和mIL-12基因的活体内表达。本部分中还构建了pVAX1-mPSCA质粒作为新的DNA疫苗的对照，验证了其体内外的表达情况。
2.将mPSCA基因去除信号肽后构建到原核表达载体pet-42a中，IPTG诱导并纯化mPSCA蛋白，通过Western Blot和ELISA检测纯化后的mPSCA蛋白的免疫原性。
3.将所构建的DNA疫苗采用电穿孔肌肉内注射的方式免疫小鼠，观察所构建的DNA疫苗的抑瘤效果，并对其相关的免疫学机制进行初步的研究：采用ELISA检测免疫小鼠血清中的特异抗体滴度和血清中的细胞因子的水平；采用LDH法体外检测免疫小鼠细胞毒性T淋巴细胞（CTL）反应；采用ELISPOT法检测免疫小鼠脾淋巴细胞特异性IFN-γ的分泌；采用流式细胞术检测免疫小鼠的离体肿瘤组织内的肿瘤浸润淋巴细胞；对全身其他器官进行病理组织切片染色（HE）观察疫苗免疫后小鼠其他组织有无炎症反应和组织损伤。
结果：
1.酶切及测序结果证实成功构建了pVAX1-IRES-mIL-12、pVAX1-mPSCA和pVAX1-mPSCA-IRES-mIL-12质粒，并且证实了各个质粒在体外和体内均可以有效表达。
2.酶切和测序结果证实成功构建原核表达质粒pET-42a-mPSCA，诱导并纯化出大小约为40KD的融合蛋白；Western Blot和ELISA检测显示纯化后的mPSCA蛋白具有免疫原性。
3.观察不同质粒免疫后的小鼠移植瘤生长趋势，发现与对照组相比DNA疫苗组成瘤时间延长3d；疫苗组小鼠肿瘤生长受到明显抑制，肿瘤抑制率达77.96%。DNA疫苗组小鼠体内产生的特异性抗体滴度大于12800；可以检测到疫苗组小鼠血清细胞因子IL-12和IFN-γ的增加，淋巴细胞特异性的IFN-γ的分泌达2430.00±157.36SFU/106个脾淋巴细胞；疫苗组淋巴细胞与对照组相比对肿瘤细胞的杀伤效率明显增加，在效靶比为40:1、20:1和10:1时，CTL的杀伤率分别为33.19±0.24%、26.67±0.73%和20.44±0.26%。在疫苗组免疫的小鼠肿瘤组织中可以检测到CD8+T细胞的浸润。疫苗免疫后小鼠中低量表达PSCA抗原的正常组织病理切片中没有发现自身免疫性炎症反应和组织损伤的证据。
结论：本研究在靶抗原的选择、佐剂的应用、DNA递送方式等方面为DNA疫苗的免疫增效研究做出了新的尝试。所构建的新型免疫增效DNA疫苗pVAX1-mPSCA-IRES-mIL-12与其他对照组相比在小鼠体内可以诱导产生更强的特异性细胞和体液免疫反应，能够抑制前列腺癌移植瘤的生长，并且证实用该疫苗免疫小鼠是安全的，为前列腺癌DNA疫苗的免疫增效的研究提供了一些有益的借鉴。
Background：Prostate cancer is still a significant public health problem. Most patientseventually develop into androgen-independent PCa which is poorly responsive totraditional therapies. Immunotherapy aimed at boosting the patient’s immune responseto tumor antigens represents a promising treatment option for advanced and metastaticdisease. DNA vaccines are one approach of immunotherapy that has been evaluated inmultiple preclinical models and clinical trials. The safety, specificity for the targetantigen, ease of manufacturing makes DNA vaccines particularly relevant for futuredevelopment. However, DNA vaccines have shown low efficiency of cell transfectionand immunogenicity which induce weak immune responses. Therefore, there areseveral strategies in our study taken into account for improving the DNA vaccinationefficacy, such as antigen selection, use of adjuvant and delivery systems improvement.The combination of these approaches may contribute to the optimization of the DNAvaccines for prostate cancer.Objective: In order to develop a novel anti-prostate cancer DNA vaccine, weconstructed the recombinant plasmid pVAX1-mPSCA-IRES-mIL-12which couldco-express PSCA and adjuvant IL-12in the same vector. And then we preliminarilystudied the anti-tumor activity and immune mechanism for the DNA vaccines in vitroand in vivo.
Methods:
1. The gene of mIL-12was amplified by PCR and cloned into downstream ofIRES gene in plasmid pVAX1-IRES to construct the plasmid vectorpVAX1-IRES-mIL-12. On this basis, the gene of mPSCA was amplified by RT-PCRfrom mouse prostate cancer cell line RM-1and cloned into upper stream of IRES geneto construct the DNA vaccine pVAX1-mPSCA-IRES-mIL-12. Then these plasmids were transfected into293T cells. The expression of the mPSCA and mIL-12gene wasidentified by ELISA and Western Blot assay respectively. Then the plasmid wasadministrated into mice by intramuscular electroporation (EP) for examining theexpression of mPSCA and IL-12gene in vivo. In this part we also have constructed theplasmid pVAX1-mPSCA as a control and examined its expression in vivo and in vitro.
2. At same time, mPSCA gene was cloned into pET-42a prokaryotic expressionvector. The mPSCA protein was expressed and purified. Then the mPSCA wasidentified by SDS-PAGE and Western blot test, and its antigenicity was identified byELISA.
3. C57BL/6mice were immunized by intramuscular EP using different plasmids.And then the anti-tumor activity of each plasmid was compared. Firstly, we observedand recorded the tumor growth. Meanwhile, we also studied the possible mechanism ofvaccine-induced cellular and humoral immunity. ELISA was used to detect the specificantibody titers in serum of immunized mice and the serum cytokines level; LDH assaywas used to investigate the specific CTL responses of spleen lymphocytes in vitro;ELISPOT assay was used to detect specific secreted IFN-γ for immunized mice’sspleen lymphocytes. Finally, tumor infiltrating lymphocytes (TIL) in tumor tissues wasidentified by flowcytometry. Histopathology stain (H&E) assay of several tissues wasused to find the change of immunized mice’s tissues.
Result：
1.The plasmids pVAX1-IRES-mIL-12、 pVAX1-mPSCA andpVAX1-mPSCA-IRES-mIL-12was successfully constructed and confirmed by enzymedigestion and DNA sequencing． The plasmids pVAX1-IRES-mIL-12andpVAX1-mPSCA IL-12showed successful expression mIL-12and mPSCA respectivelyin vitro and in vivo, while the plasmid pVAX1-mPSCA-IRES-mIL-12couldco-express the mPSCA and mIL-12in vitro and in vivo.
2. The mPSCA prokaryotic expression vector was successfully constructed andthe fusion protein about40KD was purified．Western Blot and ELISA demonstrated theantigenicity of the purified mPSCA protein.
3. After C57BL/6mice were immunized by intramuscular EP using differentplasmids, the morphological results were record. The time of tumor forming in vaccinegroup was longer than the control groups (9.0d Vs5.8d). The new vaccine inhabitstumour growth as compared with the controls, and the tumor control rate was77.96%.The study of possible mechanism showed the high antibody titer（>12800） wasinduced in vaccine group. The antigen specific IFN-γ which released by T cells wasalso detected in vaccine immunized mice about2430.00±157.36SFU/106splenocytes.Meanwhile, cytotoxic T lymphocytes (CTLs)-mediated cytotoxicity was33.19±0.24%、26.67±0.73%and20.44±0.26%when effector-target ratio was40:1、20:1and10:1. Meanwhile, there were no histological evidences of infiltration byinflammatory cells and tissue damage in other PSCA expressing organs.
Conclusion：
In summary, we had made some new attempts in antigen selection, use ofadjuvant and delivery methods in this study. The recombinant plasmidpVAX1-mPSCA-IRES-mIL-12was correctly constructed. This DNA vaccine caninduce the higher cellular and humoral immune responses and inhibit tumor growthafter immunization compared with control groups, and there were no histologicalevidence of autoimmune tissue injury. This kind of novel DNA vaccines provides newexploration to overcome previous immunogenicity limitation in DNA vaccinetechnology.
方法：
1.将PCR方法扩增的mIL-12基因其克隆到pVAX1-IRES载体中IRES序列的下游构建免疫增效载体pVAX1-IRES-mIL-12，在此基础上将RT-PCR方法从RM-1细胞系中扩增的mPSCA基因克隆到该质粒IRES的上游，构建前列腺癌DNA疫苗pVAX1-mPSCA-IRES-mIL-12。质粒体外转染293T细胞后分别通过Western Blot验证mPSCA的表达，ELISA法验证mIL-12的真核表达；电穿孔法递送质粒到小鼠体内验，分别验证mPSCA和mIL-12基因的活体内表达。本部分中还构建了pVAX1-mPSCA质粒作为新的DNA疫苗的对照，验证了其体内外的表达情况。
2.将mPSCA基因去除信号肽后构建到原核表达载体pet-42a中，IPTG诱导并纯化mPSCA蛋白，通过Western Blot和ELISA检测纯化后的mPSCA蛋白的免疫原性。
3.将所构建的DNA疫苗采用电穿孔肌肉内注射的方式免疫小鼠，观察所构建的DNA疫苗的抑瘤效果，并对其相关的免疫学机制进行初步的研究：采用ELISA检测免疫小鼠血清中的特异抗体滴度和血清中的细胞因子的水平；采用LDH法体外检测免疫小鼠细胞毒性T淋巴细胞（CTL）反应；采用ELISPOT法检测免疫小鼠脾淋巴细胞特异性IFN-γ的分泌；采用流式细胞术检测免疫小鼠的离体肿瘤组织内的肿瘤浸润淋巴细胞；对全身其他器官进行病理组织切片染色（HE）观察疫苗免疫后小鼠其他组织有无炎症反应和组织损伤。
结果：
1.酶切及测序结果证实成功构建了pVAX1-IRES-mIL-12、pVAX1-mPSCA和pVAX1-mPSCA-IRES-mIL-12质粒，并且证实了各个质粒在体外和体内均可以有效表达。
2.酶切和测序结果证实成功构建原核表达质粒pET-42a-mPSCA，诱导并纯化出大小约为40KD的融合蛋白；Western Blot和ELISA检测显示纯化后的mPSCA蛋白具有免疫原性。
3.观察不同质粒免疫后的小鼠移植瘤生长趋势，发现与对照组相比DNA疫苗组成瘤时间延长3d；疫苗组小鼠肿瘤生长受到明显抑制，肿瘤抑制率达77.96%。DNA疫苗组小鼠体内产生的特异性抗体滴度大于12800；可以检测到疫苗组小鼠血清细胞因子IL-12和IFN-γ的增加，淋巴细胞特异性的IFN-γ的分泌达2430.00±157.36SFU/106个脾淋巴细胞；疫苗组淋巴细胞与对照组相比对肿瘤细胞的杀伤效率明显增加，在效靶比为40:1、20:1和10:1时，CTL的杀伤率分别为33.19±0.24%、26.67±0.73%和20.44±0.26%。在疫苗组免疫的小鼠肿瘤组织中可以检测到CD8+T细胞的浸润。疫苗免疫后小鼠中低量表达PSCA抗原的正常组织病理切片中没有发现自身免疫性炎症反应和组织损伤的证据。
结论：本研究在靶抗原的选择、佐剂的应用、DNA递送方式等方面为DNA疫苗的免疫增效研究做出了新的尝试。所构建的新型免疫增效DNA疫苗pVAX1-mPSCA-IRES-mIL-12与其他对照组相比在小鼠体内可以诱导产生更强的特异性细胞和体液免疫反应，能够抑制前列腺癌移植瘤的生长，并且证实用该疫苗免疫小鼠是安全的，为前列腺癌DNA疫苗的免疫增效的研究提供了一些有益的借鉴。
Background：Prostate cancer is still a significant public health problem. Most patientseventually develop into androgen-independent PCa which is poorly responsive totraditional therapies. Immunotherapy aimed at boosting the patient’s immune responseto tumor antigens represents a promising treatment option for advanced and metastaticdisease. DNA vaccines are one approach of immunotherapy that has been evaluated inmultiple preclinical models and clinical trials. The safety, specificity for the targetantigen, ease of manufacturing makes DNA vaccines particularly relevant for futuredevelopment. However, DNA vaccines have shown low efficiency of cell transfectionand immunogenicity which induce weak immune responses. Therefore, there areseveral strategies in our study taken into account for improving the DNA vaccinationefficacy, such as antigen selection, use of adjuvant and delivery systems improvement.The combination of these approaches may contribute to the optimization of the DNAvaccines for prostate cancer.Objective: In order to develop a novel anti-prostate cancer DNA vaccine, weconstructed the recombinant plasmid pVAX1-mPSCA-IRES-mIL-12which couldco-express PSCA and adjuvant IL-12in the same vector. And then we preliminarilystudied the anti-tumor activity and immune mechanism for the DNA vaccines in vitroand in vivo.
Methods:
1. The gene of mIL-12was amplified by PCR and cloned into downstream ofIRES gene in plasmid pVAX1-IRES to construct the plasmid vectorpVAX1-IRES-mIL-12. On this basis, the gene of mPSCA was amplified by RT-PCRfrom mouse prostate cancer cell line RM-1and cloned into upper stream of IRES geneto construct the DNA vaccine pVAX1-mPSCA-IRES-mIL-12. Then these plasmids were transfected into293T cells. The expression of the mPSCA and mIL-12gene wasidentified by ELISA and Western Blot assay respectively. Then the plasmid wasadministrated into mice by intramuscular electroporation (EP) for examining theexpression of mPSCA and IL-12gene in vivo. In this part we also have constructed theplasmid pVAX1-mPSCA as a control and examined its expression in vivo and in vitro.
2. At same time, mPSCA gene was cloned into pET-42a prokaryotic expressionvector. The mPSCA protein was expressed and purified. Then the mPSCA wasidentified by SDS-PAGE and Western blot test, and its antigenicity was identified byELISA.
3. C57BL/6mice were immunized by intramuscular EP using different plasmids.And then the anti-tumor activity of each plasmid was compared. Firstly, we observedand recorded the tumor growth. Meanwhile, we also studied the possible mechanism ofvaccine-induced cellular and humoral immunity. ELISA was used to detect the specificantibody titers in serum of immunized mice and the serum cytokines level; LDH assaywas used to investigate the specific CTL responses of spleen lymphocytes in vitro;ELISPOT assay was used to detect specific secreted IFN-γ for immunized mice’sspleen lymphocytes. Finally, tumor infiltrating lymphocytes (TIL) in tumor tissues wasidentified by flowcytometry. Histopathology stain (H&E) assay of several tissues wasused to find the change of immunized mice’s tissues.
Result：
1.The plasmids pVAX1-IRES-mIL-12、 pVAX1-mPSCA andpVAX1-mPSCA-IRES-mIL-12was successfully constructed and confirmed by enzymedigestion and DNA sequencing． The plasmids pVAX1-IRES-mIL-12andpVAX1-mPSCA IL-12showed successful expression mIL-12and mPSCA respectivelyin vitro and in vivo, while the plasmid pVAX1-mPSCA-IRES-mIL-12couldco-express the mPSCA and mIL-12in vitro and in vivo.
2. The mPSCA prokaryotic expression vector was successfully constructed andthe fusion protein about40KD was purified．Western Blot and ELISA demonstrated theantigenicity of the purified mPSCA protein.
3. After C57BL/6mice were immunized by intramuscular EP using differentplasmids, the morphological results were record. The time of tumor forming in vaccinegroup was longer than the control groups (9.0d Vs5.8d). The new vaccine inhabitstumour growth as compared with the controls, and the tumor control rate was77.96%.The study of possible mechanism showed the high antibody titer（>12800） wasinduced in vaccine group. The antigen specific IFN-γ which released by T cells wasalso detected in vaccine immunized mice about2430.00±157.36SFU/106splenocytes.Meanwhile, cytotoxic T lymphocytes (CTLs)-mediated cytotoxicity was33.19±0.24%、26.67±0.73%and20.44±0.26%when effector-target ratio was40:1、20:1and10:1. Meanwhile, there were no histological evidences of infiltration byinflammatory cells and tissue damage in other PSCA expressing organs.
Conclusion：
In summary, we had made some new attempts in antigen selection, use ofadjuvant and delivery methods in this study. The recombinant plasmidpVAX1-mPSCA-IRES-mIL-12was correctly constructed. This DNA vaccine caninduce the higher cellular and humoral immune responses and inhibit tumor growthafter immunization compared with control groups, and there were no histologicalevidence of autoimmune tissue injury. This kind of novel DNA vaccines provides newexploration to overcome previous immunogenicity limitation in DNA vaccinetechnology.
引文
[1]顾方六.我国良性前列腺增生和前列腺癌发病调查.北京医科大学学报.2000.(01):36-39.
[2] Schurko B, Oh WK. Docetaxel chemotherapy remains the standard of care incastration-resistant prostate cancer. Nat Clin Pract Oncol.2008.5(9):506-7.
[3] Sonpavde G, Agarwal N, Choueiri TK, Kantoff PW. Recent advances inimmunotherapy for the treatment of prostate cancer. Expert Opin Biol Ther.2011.11(8):997-1009.
[4] Buonerba C, Ferro M, Di LG. Sipuleucel-T for prostate cancer: theimmunotherapy era has commenced. Expert Rev Anticancer Ther.2011.11(1):25-8.
[5] Bolhassani A, Safaiyan S, Rafati S. Improvement of different vaccine deliverysystems for cancer therapy. Mol Cancer.2011.10:3.
[6] Kantoff PW, Schuetz TJ, Blumenstein BA, et al. Overall survival analysis of aphase II randomized controlled trial of a Poxviral-based PSA-targetedimmunotherapy in metastatic castration-resistant prostate cancer. J Clin Oncol.2010.28(7):1099-105.
[7] Liu MA. DNA vaccines: an historical perspective and view to the future.Immunol Rev.2011.239(1):62-84.
[8] Signori E, Iurescia S, Massi E, et al. DNA vaccination strategies foranti-tumour effective gene therapy protocols. Cancer Immunol Immunother.2010.59(10):1583-91.
[9] Alam S, McNeel DG. DNA vaccines for the treatment of prostate cancer.Expert Rev Vaccines.2010.9(7):731-45.
[10] Sardesai NY, Weiner DB. Electroporation delivery of DNA vaccines: prospectsfor success. Curr Opin Immunol.2011.23(3):421-9.
[11] Khan AS, Draghia-Akli R, Shypailo RJ, Ellis KI, Mersmann H, Fiorotto ML. Acomparison of the growth responses following intramuscular GHRH plasmidadministration versus daily growth hormone injections in young pigs. Mol Ther.2010.18(2):327-33
[12] Daud AI, DeConti RC, Andrews S, et al. Phase I trial of interleukin-12plasmidelectroporation in patients with metastatic melanoma. J Clin Oncol.2008.26(36):5896-903.
[13] Wang Z, Troilo PJ, Wang X, et al. Detection of integration of plasmid DNA intohost genomic DNA following intramuscular injection and electroporation. GeneTher.2004.11(8):711-21.
[14] Hallaj-Nezhadi S, Lotfipour F, Dass C. Nanoparticle-mediated interleukin-12cancer gene therapy. J Pharm Pharm Sci.2010.13(3):472-85.
[15] Cemazar M, Jarm T, Sersa G. Cancer electrogene therapy with interleukin-12.Curr Gene Ther.2010.10(4):300-11.
[16] Biragyn A, Tani K, Grimm MC, Weeks S, Kwak LW. Genetic fusion ofchemokines to a self tumor antigen induces protective, T-cell dependentantitumor immunity. Nat Biotechnol.1999.17(3):253-8.
[17] Biragyn A, Surenhu M, Yang D, et al. Mediators of innate immunity that targetimmature, but not mature, dendritic cells induce antitumor immunity whengenetically fused with nonimmunogenic tumor antigens. J Immunol.2001.167(11):6644-53.
[1] Del VM, Bajetta E, Canova S, et al. Interleukin-12: biological properties andclinical application. Clin Cancer Res.2007.13(16):4677-85.
[2] Metzger DW. Interleukin-12as an adjuvant for induction of protective antibodyresponses. Cytokine.2010.52(1-2):102-7.
[3] Siddiqui F, Ehrhart EJ, Charles B, et al. Anti-angiogenic effects ofinterleukin-12delivered by a novel hyperthermia induced gene construct. Int JHyperthermia.2006.22(7):587-606.
[4] Leonard JP, Sherman ML, Fisher GL, et al. Effects of single-doseinterleukin-12exposure on interleukin-12-associated toxicity andinterferon-gamma production. Blood.1997.90(7):2541-8.
[5] Hallaj-Nezhadi S, Lotfipour F, Dass C. Nanoparticle-mediated interleukin-12cancer gene therapy. J Pharm Pharm Sci.2010.13(3):472-85.
[6] Cemazar M, Jarm T, Sersa G. Cancer electrogene therapy with interleukin-12.Curr Gene Ther.2010.10(4):300-11.
[7] Daud AI, DeConti RC, Andrews S, et al. Phase I trial of interleukin-12plasmidelectroporation in patients with metastatic melanoma. J Clin Oncol.2008.26(36):5896-903.
[8] Gherardi MM, Ramirez JC, Esteban M. Towards a new generation of vaccines:the cytokine IL-12as an adjuvant to enhance cellular immune responses topathogens during prime-booster vaccination regimens. Histol Histopathol.2001.16(2):655-67.
[9] Kim JJ, Yang JS, Dang K, Manson KH, Weiner DB. Engineering enhancementof immune responses to DNA-based vaccines in a prostate cancer model inrhesus macaques through the use of cytokine gene adjuvants. Clin Cancer Res.2001.7(3Suppl):882s-889s.
[10] Song K, Chang Y, Prud'homme GJ. IL-12plasmid-enhanced DNA vaccinationagainst carcinoembryonic antigen (CEA) studied in immune-gene knockoutmice. Gene Ther.2000.7(18):1527-35.
[11] Hirao LA, Wu L, Khan AS, et al. Combined effects of IL-12andelectroporation enhances the potency of DNA vaccination in macaques.Vaccine.2008.26(25):3112-20.
[12]阎瑾琦,刘荷中,王浩,张亮.双顺反子真核表达载体pVAX1-IRES的构建与鉴定.军事医学科学院院刊.2008.32(2):113-115.
[13] Pelletier J. Internal initiation of translation of eukaryotic mRNA directed by asequence derived from poliovirus RNA. Nature.1988.334(6180):320-5.
[1] Hall SJ, Klotz L, Pantuck AJ, et al. Integrated safety data from4randomized,double-blind, controlled trials of autologous cellular immunotherapy withsipuleucel-T in patients with prostate cancer. J Urol.2011.186(3):877-81.
[2] Reiter RE, Gu Z, Watabe T, et al. Prostate stem cell antigen: a cell surfacemarker overexpressed in prostatecancer. Proc Natl Acad Sci U S A.1998.95(4):1735-40.
[3] Sakamoto H, Yoshimura K, Saeki N, et al. Genetic variation in PSCA isassociated with susceptibility to diffuse-typegastric cancer. Nat Genet.2008.40(6):730-40.
[4] Feng HC, Tsao SW, Ngan HY, et al. Overexpression of prostate stem cellantigen is associated with gestationaltrophoblastic neoplasia. Histopathology.2008.52(2):167-74.
[5] Elsamman EM, Fukumori T, Tanimoto S, et al. The expression of prostate stemcell antigen in human clear cell renal cellcarcinoma: a quantitative reversetranscriptase-polymerase chain reactionanalysis. BJU Int.2006.98(3):668-73.
[6] Cheng L, Reiter RE, Jin Y, et al. Immunocytochemical analysis of prostate stemcell antigen as adjunct marker for detection of urothelial transitional cellcarcinoma in voided urine specimens. J Urol.2003.169(6):2094-100.
[7] Raff AB, Gray A, Kast WM. Prostate stem cell antigen: a prospectivetherapeutic and diagnostic target. Cancer Lett.2009.277(2):126-32.
[8] Saeki N, Gu J, Yoshida T, Wu X. Prostate stem cell antigen: a Jekyll and Hydemolecule. Clin Cancer Res.2010.16(14):3533-8.
[9] Fuessel S, Meye A, Schmitz M, et al. Vaccination of hormone-refractoryprostate cancer patients with peptidecocktail-loaded dendritic cells: results of aphase I clinical trial. Prostate.2006.66(8):811-21.
[10] Schmid HP. Re: Vaccination of hormone-refractory prostate cancer patientswith peptidecocktail-loaded dendritic cells: results of a phase1clinical trial.Eur Urol.2007.51(3):853-4.
[11] Waeckerle-Men Y, Uetz-von AE, Fopp M, et al. Dendritic cell-basedmulti-epitope immunotherapy of hormone-refractory prostate carcinoma.Cancer Immunol Immunother.2006.55(12):1524-33.
[12] Gu Z, Yamashiro J, Kono E, Reiter RE. Anti-prostate stem cell antigenmonoclonal antibody1G8induces cell death in vitro and inhibits tumor growthin vivo via a Fc-independent mechanism. Cancer Res.2005.65(20):9495-500.
[13] Antonarakis ES, Carducci MA, Eisenberger MA, et al. Phase I rapiddose-escalation study of AGS-1C4D4, a human anti-PSCA (prostate stem cellantigen) monoclonal antibody, in patients with castration-resistant prostatecancer: a PCCTC trial. Cancer Chemother Pharmacol.2012.69(3):763-71.
[14] Zhang X, Yu C, Zhao J, et al. Vaccination with a DNA vaccine based on humanPSCA and HSP70adjuvant enhances the antigen-specific CD8+T-cell responseand inhibits the PSCA+tumors growth in mice. J Gene Med.2007.9(8):715-26.
[15] Garcia-Hernandez ML, Gray A, Hubby B, Klinger OJ, Kast WM. Prostate stemcell antigen vaccination induces a long-term protective immune responseagainst prostate cancer in the absence of autoimmunity. Cancer Res.2008.68(3):861-9.
[16] Ahmad S, Casey G, Sweeney P, Tangney M, O'Sullivan GC. Prostate stem cellantigen DNA vaccination breaks tolerance to self-antigen and inhibits prostatecancer growth. Mol Ther.2009.17(6):1101-8.
[17] Krupa M, Canamero M, Gomez CE, Najera JL, Gil J, Esteban M.Immunization with recombinant DNA and modified vaccinia virus Ankara(MVA) vectors delivering PSCA and STEAP1antigens inhibits prostate cancerprogression. Vaccine.2011.29(7):1504-13.
[18] Ahmad S, Casey G, Cronin M, et al. Induction of effective antitumor responseafter mucosal bacterial vector mediated DNA vaccination with endogenousprostate cancer specific antigen. J Urol.2011.186(2):687-93.
[19] Gherardi MM, Ramirez JC, Esteban M. Towards a new generation of vaccines:the cytokine IL-12as an adjuvant to enhance cellular immune responses topathogens during prime-booster vaccination regimens. Histol Histopathol.2001.16(2):655-67.
[20] Nasu Y, Bangma CH, Hull GW, et al. Adenovirus-mediated interleukin-12genetherapy for prostate cancer: suppression of orthotopic tumor growth andpre-established lung metastases in an orthotopic model. Gene Ther.1999.6(3):338-49.
[21] Wang H, Yang G, Timme TL, et al. IL-12gene-modified bone marrow celltherapy suppresses the development of experimental metastatic prostate cancer.Cancer Gene Ther.2007.14(10):819-27.
[22] Varghese S, Rabkin SD, Liu R, Nielsen PG, Ipe T, Martuza RL. Enhancedtherapeutic efficacy of IL-12, but not GM-CSF, expressing oncolytic herpessimplex virus for transgenic mouse derived prostate cancers. Cancer Gene Ther.2006.13(3):253-65.
[23] Saika T, Satoh T, Kusaka N, et al. Route of administration influences theantitumor effects of bone marrow-derived dendritic cells engineered to produceinterleukin-12in a metastatic mouse prostate cancer model. Cancer Gene Ther.2004.11(5):317-24.
[24] Timme TL, Satoh T, Tahir SA, et al. Therapeutic targets for metastatic prostatecancer. Curr Drug Targets.2003.4(3):251-61.
[25] Fujita T, Timme TL, Tabata K, et al. Cooperative effects of adenoviralvector-mediated interleukin12gene therapy with radiotherapy in a preclinicalmodel of metastatic prostate cancer. Gene Ther.2007.14(3):227-36.
[26] Gabaglia CR, DeLaney A, Gee J, et al. Treatment combining RU486andAd5IL-12vector attenuates the growth of experimentally formed prostatetumors and induces changes in the sentinel lymph nodes of mice. J Transl Med.2010.8:98.
[27] Kim JJ, Yang JS, Dang K, Manson KH, Weiner DB. Engineering enhancementof immune responses to DNA-based vaccines in a prostate cancer model inrhesus macaques through the use of cytokine gene adjuvants. Clin Cancer Res.2001.7(3Suppl):882s-889s.
[28]韩刚,于继云,高江平.以PSCA为靶点的前列腺癌免疫治疗的研究进展.军医进修学院学报.2009.(02):225-226.
[29]任杰,高江平,阎瑾琦,江乐,于继云.人前列腺干细胞抗原的原核表达、纯化及鉴定.解放军医学杂志.2010.(08):986-988.
[1] Garcia-Hernandez ML, Gray A, Hubby B, Klinger OJ, Kast WM. Prostate stemcell antigen vaccination induces a long-term protective immune responseagainst prostate cancer in the absence of autoimmunity. Cancer Res.2008.68(3):861-9.
[2] Signori E, Iurescia S, Massi E, et al. DNA vaccination strategies foranti-tumour effective gene therapy protocols. Cancer Immunol Immunother.2010.59(10):1583-91.
[3] Schurko B, Oh WK. Docetaxel chemotherapy remains the standard of care incastration-resistant prostate cancer. Nat Clin Pract Oncol.2008.5(9):506-7.
[4] Joniau S, Abrahamsson PA, Bellmunt J, et al. Current vaccination strategies forprostate cancer. Eur Urol.2012.61(2):290-306.
[5] Wolff JA, Malone RW, Williams P, et al. Direct gene transfer into mousemuscle in vivo. Science (80-).1990.247(4949Pt1):1465-8.
[6] Liu MA. DNA vaccines: an historical perspective and view to the future.Immunol Rev.2011.239(1):62-84.
[7] Alam S, McNeel DG. DNA vaccines for the treatment of prostate cancer.Expert Rev Vaccines.2010.9(7):731-45.
[8] Ahmad S, Casey G, Sweeney P, Tangney M, O'Sullivan GC. Prostate stem cellantigen DNA vaccination breaks tolerance to self-antigen and inhibits prostatecancer growth. Mol Ther.2009.17(6):1101-8.
[9] Grossmann ME, Wood M, Celis E. Expression, specificity and immunotherapypotential of prostate-associated genes in murine cell lines. World J Urol.2001.19(5):365-70.
[10] Grant JF, Iwasawa T, Sinn HW, et al. Induction of protective immunity to RM-1prostate cancer cells with ALVAC-IL-2/IL-12/TNF-alpha combination therapy.Int J Cancer.2006.119(11):2632-41.
[11] Zolochevska O, Xia X, Williams BJ, Ramsay A, Li S, Figueiredo ML.Sonoporation delivery of interleukin-27gene therapy efficiently reducesprostate tumor cell growth in vivo. Hum Gene Ther.2011.22(12):1537-50.
[12] Gingrich JR, Barrios RJ, Foster BA, Greenberg NM. Pathologic progression ofautochthonous prostate cancer in the TRAMP model. Prostate Cancer ProstaticDis.1999.2(2):70-75.
[13] Mogensen SC, Virelizier JL. The interferon-macrophage alliance. Interferon.1987.8:55-84.
[14] Turner MS, Cohen PA, Finn OJ. Lack of effective MUC1tumorantigen-specific immunity in MUC1-transgenic mice results from a Th/Tregulatory cell imbalance that can be corrected by adoptive transfer ofwild-type Th cells. J Immunol.2007.178(5):2787-93.
[15] Hodge JW, Grosenbach DW, Aarts WM, Poole DJ, Schlom J. Vaccine therapyof established tumors in the absence of autoimmunity. Clin Cancer Res.2003.9(5):1837-49.
[1] Guru Sonpavde, Neeraj Agarwal, Toni K Choueiri, et al. Recent advances inimmunotherapy for the treatment of prostate cancer [J]. Expert Opin. Biol. Ther,2011,11(8):997-1009.
[2] Hall SJ, Klotz L, Pantuck AJ, etal. Integrated Safety Data From4Randomized,Double-Blind, Controlled Trials of Autologous Cellular Immunotherapy WithSipuleucel-T in Patients With Prostate Cancer [J]. J Urol,2011,186(3):877-81.
[3] Carlo Buonerba, Matteo Ferro, Giuseppe Di Lorenzo. Sipuleucel-T for prostatecancer: the immunotherapy era has commenced [J]. Expert Rev. Anticancer Ther,2011,11(1),25–28.
[4] Azam Bolhassani, Shima Safaiyan, Sima Rafati. Improvement of different vaccinedelivery systems for cancer therapy [J]. Molecular Cancer,2011,10(3):2-20.
[5] Margaret A. Liu. DNA vaccines: an historical perspective and view to the future [J].Immunological Reviews,2011,239(1):62–84.
[6] Emanuela Signori, Sandra Iurescia, Emanuela Massi, et al. DNA vaccinationstrategies for anti-tumour eVective gene therapy protocols [J]. Cancer ImmunolImmunother,2010,59(10):1583–1591.
[7] Sheeba Alam, Douglas G McNeel. DNA vaccines for the treatment of prostatecancer. Expert Rev [J]. Vaccines,2010,9(7):731–745.
[8] Kantoff PW, Schuetz TJ, Blumenstein BA, et al. Overall survival analysis of aPhase II randomized controlled trial of a poxviral-based PSA-targeted immunotherapyin metastatic castration-resistant prostate cancer [J]. J. Clin. Oncol,2010,28(7):1099–1105.
[9] Gulley JL, Arlen PM, Madan RA, et al. Immunologic and prognostic factorsassociated with overall survival employing a poxviral-based PSA vaccine in metastaticcastrate-resistant prostate cancer [J]. Cancer Immunol Immunother,2010,59(5):663-74.
[10] Kim JJ, Trivedi NN, Wilson DM, et al. Molecular and immunological analysis ofgenetic prostate specific antigen (PSA) vaccine [J]. Oncogene,1998,17(24):3125–3135.
[11] Pavlenko M, Roos AK, Lundqvist A, et al. A PhaseⅠtrial of DNA vaccinationwith a plasmid expressing prostate-specific antigen in patients with hormone-refractoryprostate cancer [J]. Br. J. Cancer,2004,91(4):688–694.
[12]Roos AK, Moreno S, Leder C, et al. Enhancement of cellular immune response toa prostate cancer DNA vaccine by intradermal electroporation [J]. Mol. Ther,2006,13(2):320–327.
[13] Sarfraz Ahmad, Garrett Casey, Paul Sweeney et al. Optimised electroporationmediated DNA vaccination for treatment of prostate cancer [J]. Genetic Vaccines andTherapy,2010,8(1):2-13.
[14] Miller AM, Ozenci V, Kiessling R, et al. Immune monitoring in a Phase1trial of aPSA DNA vaccine in patients with hormone-refractory prostate cancer [J]. J.Immunother,2005,28(4):389–395.
[15] Johnson LE, Frye TP, Arnot AR et al. Safety and immunological efficacy of aprostate cancer plasmid DNA vaccine encoding prostatic acid phosphatase (PAP)[J].Vaccine,2006,24(3):293–303.
[16] Johnson LE, Frye TP, Chinnasamy N, et al. Plasmid DNA vaccine encodingprostatic acid phosphatase is effective in eliciting autologous antigen-specific CD8+Tcells [J]. Cancer Immunol. Immunother,2007,56(6):885–895.
[17] McNeel DG, Dunphy EJ, Davies JG, et al. Safety and immunological efficacy of aDNA vaccine encoding prostatic acid phosphatase in patients with stage D0prostatecancer [J]. J. Clin. Oncol,2009,27(25):4047–4054.
[18] Becker JT, Olson BM, Johnson LE, et al. DNA vaccine encoding prostatic acidphosphatase (PAP) elicits long-term T-cell responses in patients with recurrent prostatecancer [J]. J. Immunother,2010,33(6):639-647.
[19] Guru Sonpavde, Neeraj Agarwal, Toni K Choueiri. Recent advances inimmunotherapy for the treatment of prostate cancer [J]. Expert Opin. Biol. Ther,2011,11(8):997-1009.
[20] Mincheff M, Zoubak S, Makogonenko Y. Immune responses against PSMA aftergene-based vaccination for immunotherapy-A: results from immunizations in animals[J]. Cancer Gene Ther,2006,13(4):436–444.
[21] Mincheff M, Tchakarov S, Zoubak S, et al. Naked DNA and adenoviralimmunizations for immunotherapy of prostate cancer: a Phase I/II clinical trial [J]. Eur.Urol,2000,38(2):208–217.
[22] Gisella E. Vittes et al. DNA fusion gene vaccines induce cytotoxic T-cell attack onnaturally processed peptides of human prostate-specific membrane antigen [J]. Eur. J.Immunol,2011,41(8):2447–2456.
[23] Youlin Kuang, Hengcheng Zhu, Xiaodong Weng, et al. Antitumor ImmuneResponse Induced by DNA Vaccine Encoding Human Prostate-specific MembraneAntigen and Mouse4-1BBL. Urology [J].2010;76(2):510.e1-6.
[24] Alves PM, Faure O, Graff-Dubois S, et al. STEAP, a prostate tumor antigen, is atarget of human CD8+T cells [J]. Cancer Immunol. Immunother,2006,55(12):1515–1523.
[25] Garcia-Hernandez Mde L, Gray A, Hubby B, Kast WM. In vivo effects ofvaccination with six-transmembrane epithelial antigen of the prostate: a candidateantigen for treating prostate cancer [J]. Cancer Res,2007,67(3):1344–1351.
[26] Fuessel S, Meye A, Schmitz M, et al. Vaccination of hormone-refractory prostatecancer patients with peptide cocktail loaded dendritic cells: results of a phase I clinicaltrial [J]. Prostate,2006,66(8):811-821.
[27] Zhang X, Yu C, Zhao J,etal. Vaccination with a DNA vaccine based on humanPSCA and HSP70adjuvant enhances the antigen-specific CD8+T-cell response andinhibits the PSCA+tumors growth in mice [J]. J Gene Med,2007,9(8):715-726.
[28] Garcia-Hernandez Mde L, Gray A, Hubby B, Kast WM, et al. Prostate stem cellantigen vaccination induces a long-term protective immune response against prostatecancer in the absence of autoimmunity [J]. Cancer Res,2008,68(3):861–869.
[29] Sarfraz Ahmad, Garrett Casey, Paul Sweeney, et al. Prostate stem cell antigenDNA vaccination breaks tolerance to self-antigen and inhibits prostate cancer growth[J]. Molecular Therapy,2009,17(6):1101–1108.
[30] Qin H, Zhou C, Wang D, Ma W, et al. Specific antitumor immune responseinduced by a novel DNA vaccine composed of multiple CTL and T helper cell epitopesof prostate cancer associated antigens [J]. Immunol Lett.2005,99(1):85-93.
[31] Magdalena Krupa, Marta Canamero, Carmen E. Gomez, et al. Immunization withrecombinant DNA and modified vaccinia virus Ankara (MVA) vectors deliveringPSCA and STEAP1antigens inhibits prostate cancer progression [J]. Vaccine,2011,29(7):1504-1513.
[32] Ferraro B, Cisper NJ, Talbott KT et al. Co-delivery of PSA and PSMA DNAvaccines with electroporation induces potent immune responses [J]. Hum Vaccin,2011,7: Suppl:120-127.
[1] Reiter RE, Gu Z, Watabe T, et al. Prostate stem cell antigen: a cell surface markeroverexpressed in prostate cancer. Proc Natl Acad Sci USA [J].1998,95(4):1735–40.
[2] Sakamoto H, Yoshimura K, Saeki N, et al. Genetic variation in PSCA is associatedwith susceptibility to diffuse-type gastric cancer [J]. Nat Genet,2008,40(6):730–40.
[3] Feng HC, Tsao SW, Ngan HY, et al. Overexpression of prostate stem cell antigen isassociated with gestational trophoblastic neoplasia [J]. Histopathology,2008,52(2):167–74.
[4] Ono H, Hiraoka N, Lee YS et al. Prostate Stem Cell Antigen, a PresumableOrgan-Dependent Tumor Suppressor Gene, is Down-Regulated in GallbladderCarcinogenesis [J]. GENES, CHROMOSOMES&CANCER,2012,51(1):30–41.
[5] Raff AB, Gray A, Kast WM. Prostate Stem Cell Antigen: A Prospective Therapeuticand Diagnostic Target [J]. Cancer Lett,2009,277(2):126-32.
[6] Moore ML, Teitell MA, Kim Y, et al. Deletion of PSCA increases metastasis ofTRAMP-induced prostate tumors without altering primary tumor formation [J].Prostate,2008,68(2):139–151.
[7] Saeki N, Gu J, Yoshida T, Wu X. Prostate stem cell antigen: a Jekyll and Hydemolecule?[J]. Clin Cancer Res,2010,16(14):3533-8.
[8] Han KR, Seligson DB, Liu X, et al. Prostate stem cell antigen expression isassociated with gleason score, seminal vesicle invasion and capsular invasion inprostate cancer[J]. J Urol,2004,171(3):1117–21.
[9] Lam JS, Yamashiro J, Shintaku IP, et al. Prostate stem cell antigen is overexpressedin prostate cancer metastases[J]. Clin Cancer Res,2005,11(7):2591–6.
[10]Reiter RE, Sato I, Thomas G, et al. Coamplification of prostate stem cell antigen(PSCA) and MYC in locally advanced prostate cancer [J]. Genes ChromosomesCancer,2000,27(1):95–103.
[11]Zhigang Z, Wenlu S. Prostate stem cell antigen (PSCA) mRNA expression inprostatic intraepithelial neoplasia: implications for the development of prostatecancer [J]. Prostate,2007,67(11):1143–51。
[12]Hara N, Kasahara T, Kawasaki T, et al. Reverse transcription-polymerase chainreaction detection of prostate-specific antigen, prostate-specific membrane antigen,and prostate stem cell antigen in one milliliter of peripheral blood: value for thestaging of prostate cancer [J]. Clin Cancer Res,2002,8(6):1794–9.
[13]Zhigang Z, Wenlu S. Flutamide reduced prostate cancer development and prostatestem cell antigen mRNA expression in high grade prostatic intraepithelial neoplasia[J]. Int J Cancer,2008,122(4):864–70.
[14]Cheng L, Reiter RE, Jin Y, et al. Immunocytochemical analysis of prostate stem cellantigen as adjunct marker for detection of urothelial transitional cell carcinoma invoided urine specimens [J]. J Urol,2003,169(6):2094–100.
[15]Elsamman E, Fukumori T, Kasai T, et al. Prostate stem cell antigen predicts tumourrecurrence in superficial transitional cell carcinoma of the urinary bladder [J]. BJUInt,2006,97(6):1202–7.
[16] Argani P, Rosty C, Reiter RE, Wilentz RE, et al. Discovery of new markers ofcancer through serial analysis of gene expression: prostate stem cell antigen isoverexpressed in pancreatic adenocarcinoma [J]. Cancer Res,2001,61(11):4320–4324.
[17]Foss CA, Fox JJ, Feldmann G, et al. Radiolabeled anti-claudin4and anti-prostatestem cell antigen: initial imaging in experimental models of pancreatic cancer [J].Mol Imaging,2007,6(2):131–9.
[18]Elsamman E, Fukumori T, Tanimoto S, Nakanishi R, Takahashi M, Toida K,Kanayama HO. The expression of prostate stem cell antigen in human clear cellrenal cell carcinoma: a quantitative reverse transcriptase-polymerase chain reactionanalysis [J]. BJU Int,2006,98:668–673.
[19]Qiao L, Feng Y. Genetic variations of prostate stem cell antigen (PSCA) contributeto the risk of gastric cancer for Eastern Asians: A meta-analysis based on16792individuals [J]. Gene,2012,493:83–91.
[20]Thomas-Kaskel AK, Zeiser R, Jochim R, et al. Vaccination of advanced prostatecancer patients with PSCA and PSA peptide-loaded dendritic cells induces DTHresponses that correlate with superior overall survival [J]. Int J Cancer,2006,119:2428–34.
[21]Waeckerle-Men Y, Uetz-von Allmen E, Fopp M, et al. Dendritic cell-basedmulti-epitope immunotherapy of hormone-refractory prostate carcinoma [J]. CancerImmunol Immunother,2006,55:1524–33.
[22]Hall SJ, Klotz L, Pantuck AJ, etal. Integrated Safety Data From4Randomized,Double-Blind, Controlled Trials of Autologous Cellular Immunotherapy WithSipuleucel-T in Patients With Prostate Cancer [J]. J Urol,2011,186(3):877-81.
[23]Gu Z, Yamashiro J, Kono E, et al. Anti-prostate stem cell antigen monoclonalantibody1G8induces cell death in vitro and inhibits tumor growth in vivo via aFc-independent mechanism [J]. Cancer Res,2005,65(20):9495–500.
[24]Antonarakis ES, Carducci MA, Eisenberger MA, et al. PhaseⅠrapiddose-escalation study of AGS-1C4D4, a human anti-PSCA (prostate stem cellantigen) monoclonal antibody, in patients with castration-resistant prostate cancer: aPCCTC trial [J]. Cancer Chemother Pharmacol, Oct22.[Epub ahead of print]
[25]Wente MN, Jain A, Kono E, et al. Prostate stem cell antigen is a putative target forimmunotherapy in pancreatic cancer [J]. Pancreas,2005,31(2):119–25.
[26]Zhang X, Yu C, Zhao J,etal. Vaccination with a DNA vaccine based on humanPSCA and HSP70adjuvant enhances the antigen-specific CD8+T-cell response andinhibits the PSCA+tumors growth in mice [J]. J Gene Med,2007,9(8):715-726.
[27]Garcia-Hernandez Mde L, Gray A, Hubby B, Kast WM, et al. Prostate stem cellantigen vaccination induces a long-term protective immune response againstprostate cancer in the absence of autoimmunity [J]. Cancer Res,2008,68(3):861–869.
[28]Sarfraz Ahmad, Garrett Casey, Paul Sweeney, et al. Prostate stem cell antigen DNAvaccination breaks tolerance to self-antigen and inhibits prostate cancer growth [J].Molecular Therapy,2009,17(6):1101–1108.
[29]Magdalena Krupa, Marta Canamero, Carmen E. Gomez, et al. Immunization withrecombinant DNA and modified vaccinia virus Ankara (MVA) vectors deliveringPSCA and STEAP1antigens inhibits prostate cancer progression [J]. Vaccine,2011,29(7):1504-1513.
[30]Ahmad S, Casey G, Cronin M, et al. Induction of effective antitumor response aftermucosal bacterial vector mediated DNA vaccination with endogenous prostatecancer specific antigen [J]. J Urol,2011,186(2):687-93.
[2] Schurko B, Oh WK. Docetaxel chemotherapy remains the standard of care incastration-resistant prostate cancer. Nat Clin Pract Oncol.2008.5(9):506-7.
[3] Sonpavde G, Agarwal N, Choueiri TK, Kantoff PW. Recent advances inimmunotherapy for the treatment of prostate cancer. Expert Opin Biol Ther.2011.11(8):997-1009.
[4] Buonerba C, Ferro M, Di LG. Sipuleucel-T for prostate cancer: theimmunotherapy era has commenced. Expert Rev Anticancer Ther.2011.11(1):25-8.
[5] Bolhassani A, Safaiyan S, Rafati S. Improvement of different vaccine deliverysystems for cancer therapy. Mol Cancer.2011.10:3.
[6] Kantoff PW, Schuetz TJ, Blumenstein BA, et al. Overall survival analysis of aphase II randomized controlled trial of a Poxviral-based PSA-targetedimmunotherapy in metastatic castration-resistant prostate cancer. J Clin Oncol.2010.28(7):1099-105.
[7] Liu MA. DNA vaccines: an historical perspective and view to the future.Immunol Rev.2011.239(1):62-84.
[8] Signori E, Iurescia S, Massi E, et al. DNA vaccination strategies foranti-tumour effective gene therapy protocols. Cancer Immunol Immunother.2010.59(10):1583-91.
[9] Alam S, McNeel DG. DNA vaccines for the treatment of prostate cancer.Expert Rev Vaccines.2010.9(7):731-45.
[10] Sardesai NY, Weiner DB. Electroporation delivery of DNA vaccines: prospectsfor success. Curr Opin Immunol.2011.23(3):421-9.
[11] Khan AS, Draghia-Akli R, Shypailo RJ, Ellis KI, Mersmann H, Fiorotto ML. Acomparison of the growth responses following intramuscular GHRH plasmidadministration versus daily growth hormone injections in young pigs. Mol Ther.2010.18(2):327-33
[12] Daud AI, DeConti RC, Andrews S, et al. Phase I trial of interleukin-12plasmidelectroporation in patients with metastatic melanoma. J Clin Oncol.2008.26(36):5896-903.
[13] Wang Z, Troilo PJ, Wang X, et al. Detection of integration of plasmid DNA intohost genomic DNA following intramuscular injection and electroporation. GeneTher.2004.11(8):711-21.
[14] Hallaj-Nezhadi S, Lotfipour F, Dass C. Nanoparticle-mediated interleukin-12cancer gene therapy. J Pharm Pharm Sci.2010.13(3):472-85.
[15] Cemazar M, Jarm T, Sersa G. Cancer electrogene therapy with interleukin-12.Curr Gene Ther.2010.10(4):300-11.
[16] Biragyn A, Tani K, Grimm MC, Weeks S, Kwak LW. Genetic fusion ofchemokines to a self tumor antigen induces protective, T-cell dependentantitumor immunity. Nat Biotechnol.1999.17(3):253-8.
[17] Biragyn A, Surenhu M, Yang D, et al. Mediators of innate immunity that targetimmature, but not mature, dendritic cells induce antitumor immunity whengenetically fused with nonimmunogenic tumor antigens. J Immunol.2001.167(11):6644-53.
[1] Del VM, Bajetta E, Canova S, et al. Interleukin-12: biological properties andclinical application. Clin Cancer Res.2007.13(16):4677-85.
[2] Metzger DW. Interleukin-12as an adjuvant for induction of protective antibodyresponses. Cytokine.2010.52(1-2):102-7.
[3] Siddiqui F, Ehrhart EJ, Charles B, et al. Anti-angiogenic effects ofinterleukin-12delivered by a novel hyperthermia induced gene construct. Int JHyperthermia.2006.22(7):587-606.
[4] Leonard JP, Sherman ML, Fisher GL, et al. Effects of single-doseinterleukin-12exposure on interleukin-12-associated toxicity andinterferon-gamma production. Blood.1997.90(7):2541-8.
[5] Hallaj-Nezhadi S, Lotfipour F, Dass C. Nanoparticle-mediated interleukin-12cancer gene therapy. J Pharm Pharm Sci.2010.13(3):472-85.
[6] Cemazar M, Jarm T, Sersa G. Cancer electrogene therapy with interleukin-12.Curr Gene Ther.2010.10(4):300-11.
[7] Daud AI, DeConti RC, Andrews S, et al. Phase I trial of interleukin-12plasmidelectroporation in patients with metastatic melanoma. J Clin Oncol.2008.26(36):5896-903.
[8] Gherardi MM, Ramirez JC, Esteban M. Towards a new generation of vaccines:the cytokine IL-12as an adjuvant to enhance cellular immune responses topathogens during prime-booster vaccination regimens. Histol Histopathol.2001.16(2):655-67.
[9] Kim JJ, Yang JS, Dang K, Manson KH, Weiner DB. Engineering enhancementof immune responses to DNA-based vaccines in a prostate cancer model inrhesus macaques through the use of cytokine gene adjuvants. Clin Cancer Res.2001.7(3Suppl):882s-889s.
[10] Song K, Chang Y, Prud'homme GJ. IL-12plasmid-enhanced DNA vaccinationagainst carcinoembryonic antigen (CEA) studied in immune-gene knockoutmice. Gene Ther.2000.7(18):1527-35.
[11] Hirao LA, Wu L, Khan AS, et al. Combined effects of IL-12andelectroporation enhances the potency of DNA vaccination in macaques.Vaccine.2008.26(25):3112-20.
[12]阎瑾琦,刘荷中,王浩,张亮.双顺反子真核表达载体pVAX1-IRES的构建与鉴定.军事医学科学院院刊.2008.32(2):113-115.
[13] Pelletier J. Internal initiation of translation of eukaryotic mRNA directed by asequence derived from poliovirus RNA. Nature.1988.334(6180):320-5.
[1] Hall SJ, Klotz L, Pantuck AJ, et al. Integrated safety data from4randomized,double-blind, controlled trials of autologous cellular immunotherapy withsipuleucel-T in patients with prostate cancer. J Urol.2011.186(3):877-81.
[2] Reiter RE, Gu Z, Watabe T, et al. Prostate stem cell antigen: a cell surfacemarker overexpressed in prostatecancer. Proc Natl Acad Sci U S A.1998.95(4):1735-40.
[3] Sakamoto H, Yoshimura K, Saeki N, et al. Genetic variation in PSCA isassociated with susceptibility to diffuse-typegastric cancer. Nat Genet.2008.40(6):730-40.
[4] Feng HC, Tsao SW, Ngan HY, et al. Overexpression of prostate stem cellantigen is associated with gestationaltrophoblastic neoplasia. Histopathology.2008.52(2):167-74.
[5] Elsamman EM, Fukumori T, Tanimoto S, et al. The expression of prostate stemcell antigen in human clear cell renal cellcarcinoma: a quantitative reversetranscriptase-polymerase chain reactionanalysis. BJU Int.2006.98(3):668-73.
[6] Cheng L, Reiter RE, Jin Y, et al. Immunocytochemical analysis of prostate stemcell antigen as adjunct marker for detection of urothelial transitional cellcarcinoma in voided urine specimens. J Urol.2003.169(6):2094-100.
[7] Raff AB, Gray A, Kast WM. Prostate stem cell antigen: a prospectivetherapeutic and diagnostic target. Cancer Lett.2009.277(2):126-32.
[8] Saeki N, Gu J, Yoshida T, Wu X. Prostate stem cell antigen: a Jekyll and Hydemolecule. Clin Cancer Res.2010.16(14):3533-8.
[9] Fuessel S, Meye A, Schmitz M, et al. Vaccination of hormone-refractoryprostate cancer patients with peptidecocktail-loaded dendritic cells: results of aphase I clinical trial. Prostate.2006.66(8):811-21.
[10] Schmid HP. Re: Vaccination of hormone-refractory prostate cancer patientswith peptidecocktail-loaded dendritic cells: results of a phase1clinical trial.Eur Urol.2007.51(3):853-4.
[11] Waeckerle-Men Y, Uetz-von AE, Fopp M, et al. Dendritic cell-basedmulti-epitope immunotherapy of hormone-refractory prostate carcinoma.Cancer Immunol Immunother.2006.55(12):1524-33.
[12] Gu Z, Yamashiro J, Kono E, Reiter RE. Anti-prostate stem cell antigenmonoclonal antibody1G8induces cell death in vitro and inhibits tumor growthin vivo via a Fc-independent mechanism. Cancer Res.2005.65(20):9495-500.
[13] Antonarakis ES, Carducci MA, Eisenberger MA, et al. Phase I rapiddose-escalation study of AGS-1C4D4, a human anti-PSCA (prostate stem cellantigen) monoclonal antibody, in patients with castration-resistant prostatecancer: a PCCTC trial. Cancer Chemother Pharmacol.2012.69(3):763-71.
[14] Zhang X, Yu C, Zhao J, et al. Vaccination with a DNA vaccine based on humanPSCA and HSP70adjuvant enhances the antigen-specific CD8+T-cell responseand inhibits the PSCA+tumors growth in mice. J Gene Med.2007.9(8):715-26.
[15] Garcia-Hernandez ML, Gray A, Hubby B, Klinger OJ, Kast WM. Prostate stemcell antigen vaccination induces a long-term protective immune responseagainst prostate cancer in the absence of autoimmunity. Cancer Res.2008.68(3):861-9.
[16] Ahmad S, Casey G, Sweeney P, Tangney M, O'Sullivan GC. Prostate stem cellantigen DNA vaccination breaks tolerance to self-antigen and inhibits prostatecancer growth. Mol Ther.2009.17(6):1101-8.
[17] Krupa M, Canamero M, Gomez CE, Najera JL, Gil J, Esteban M.Immunization with recombinant DNA and modified vaccinia virus Ankara(MVA) vectors delivering PSCA and STEAP1antigens inhibits prostate cancerprogression. Vaccine.2011.29(7):1504-13.
[18] Ahmad S, Casey G, Cronin M, et al. Induction of effective antitumor responseafter mucosal bacterial vector mediated DNA vaccination with endogenousprostate cancer specific antigen. J Urol.2011.186(2):687-93.
[19] Gherardi MM, Ramirez JC, Esteban M. Towards a new generation of vaccines:the cytokine IL-12as an adjuvant to enhance cellular immune responses topathogens during prime-booster vaccination regimens. Histol Histopathol.2001.16(2):655-67.
[20] Nasu Y, Bangma CH, Hull GW, et al. Adenovirus-mediated interleukin-12genetherapy for prostate cancer: suppression of orthotopic tumor growth andpre-established lung metastases in an orthotopic model. Gene Ther.1999.6(3):338-49.
[21] Wang H, Yang G, Timme TL, et al. IL-12gene-modified bone marrow celltherapy suppresses the development of experimental metastatic prostate cancer.Cancer Gene Ther.2007.14(10):819-27.
[22] Varghese S, Rabkin SD, Liu R, Nielsen PG, Ipe T, Martuza RL. Enhancedtherapeutic efficacy of IL-12, but not GM-CSF, expressing oncolytic herpessimplex virus for transgenic mouse derived prostate cancers. Cancer Gene Ther.2006.13(3):253-65.
[23] Saika T, Satoh T, Kusaka N, et al. Route of administration influences theantitumor effects of bone marrow-derived dendritic cells engineered to produceinterleukin-12in a metastatic mouse prostate cancer model. Cancer Gene Ther.2004.11(5):317-24.
[24] Timme TL, Satoh T, Tahir SA, et al. Therapeutic targets for metastatic prostatecancer. Curr Drug Targets.2003.4(3):251-61.
[25] Fujita T, Timme TL, Tabata K, et al. Cooperative effects of adenoviralvector-mediated interleukin12gene therapy with radiotherapy in a preclinicalmodel of metastatic prostate cancer. Gene Ther.2007.14(3):227-36.
[26] Gabaglia CR, DeLaney A, Gee J, et al. Treatment combining RU486andAd5IL-12vector attenuates the growth of experimentally formed prostatetumors and induces changes in the sentinel lymph nodes of mice. J Transl Med.2010.8:98.
[27] Kim JJ, Yang JS, Dang K, Manson KH, Weiner DB. Engineering enhancementof immune responses to DNA-based vaccines in a prostate cancer model inrhesus macaques through the use of cytokine gene adjuvants. Clin Cancer Res.2001.7(3Suppl):882s-889s.
[28]韩刚,于继云,高江平.以PSCA为靶点的前列腺癌免疫治疗的研究进展.军医进修学院学报.2009.(02):225-226.
[29]任杰,高江平,阎瑾琦,江乐,于继云.人前列腺干细胞抗原的原核表达、纯化及鉴定.解放军医学杂志.2010.(08):986-988.
[1] Garcia-Hernandez ML, Gray A, Hubby B, Klinger OJ, Kast WM. Prostate stemcell antigen vaccination induces a long-term protective immune responseagainst prostate cancer in the absence of autoimmunity. Cancer Res.2008.68(3):861-9.
[2] Signori E, Iurescia S, Massi E, et al. DNA vaccination strategies foranti-tumour effective gene therapy protocols. Cancer Immunol Immunother.2010.59(10):1583-91.
[3] Schurko B, Oh WK. Docetaxel chemotherapy remains the standard of care incastration-resistant prostate cancer. Nat Clin Pract Oncol.2008.5(9):506-7.
[4] Joniau S, Abrahamsson PA, Bellmunt J, et al. Current vaccination strategies forprostate cancer. Eur Urol.2012.61(2):290-306.
[5] Wolff JA, Malone RW, Williams P, et al. Direct gene transfer into mousemuscle in vivo. Science (80-).1990.247(4949Pt1):1465-8.
[6] Liu MA. DNA vaccines: an historical perspective and view to the future.Immunol Rev.2011.239(1):62-84.
[7] Alam S, McNeel DG. DNA vaccines for the treatment of prostate cancer.Expert Rev Vaccines.2010.9(7):731-45.
[8] Ahmad S, Casey G, Sweeney P, Tangney M, O'Sullivan GC. Prostate stem cellantigen DNA vaccination breaks tolerance to self-antigen and inhibits prostatecancer growth. Mol Ther.2009.17(6):1101-8.
[9] Grossmann ME, Wood M, Celis E. Expression, specificity and immunotherapypotential of prostate-associated genes in murine cell lines. World J Urol.2001.19(5):365-70.
[10] Grant JF, Iwasawa T, Sinn HW, et al. Induction of protective immunity to RM-1prostate cancer cells with ALVAC-IL-2/IL-12/TNF-alpha combination therapy.Int J Cancer.2006.119(11):2632-41.
[11] Zolochevska O, Xia X, Williams BJ, Ramsay A, Li S, Figueiredo ML.Sonoporation delivery of interleukin-27gene therapy efficiently reducesprostate tumor cell growth in vivo. Hum Gene Ther.2011.22(12):1537-50.
[12] Gingrich JR, Barrios RJ, Foster BA, Greenberg NM. Pathologic progression ofautochthonous prostate cancer in the TRAMP model. Prostate Cancer ProstaticDis.1999.2(2):70-75.
[13] Mogensen SC, Virelizier JL. The interferon-macrophage alliance. Interferon.1987.8:55-84.
[14] Turner MS, Cohen PA, Finn OJ. Lack of effective MUC1tumorantigen-specific immunity in MUC1-transgenic mice results from a Th/Tregulatory cell imbalance that can be corrected by adoptive transfer ofwild-type Th cells. J Immunol.2007.178(5):2787-93.
[15] Hodge JW, Grosenbach DW, Aarts WM, Poole DJ, Schlom J. Vaccine therapyof established tumors in the absence of autoimmunity. Clin Cancer Res.2003.9(5):1837-49.
[1] Guru Sonpavde, Neeraj Agarwal, Toni K Choueiri, et al. Recent advances inimmunotherapy for the treatment of prostate cancer [J]. Expert Opin. Biol. Ther,2011,11(8):997-1009.
[2] Hall SJ, Klotz L, Pantuck AJ, etal. Integrated Safety Data From4Randomized,Double-Blind, Controlled Trials of Autologous Cellular Immunotherapy WithSipuleucel-T in Patients With Prostate Cancer [J]. J Urol,2011,186(3):877-81.
[3] Carlo Buonerba, Matteo Ferro, Giuseppe Di Lorenzo. Sipuleucel-T for prostatecancer: the immunotherapy era has commenced [J]. Expert Rev. Anticancer Ther,2011,11(1),25–28.
[4] Azam Bolhassani, Shima Safaiyan, Sima Rafati. Improvement of different vaccinedelivery systems for cancer therapy [J]. Molecular Cancer,2011,10(3):2-20.
[5] Margaret A. Liu. DNA vaccines: an historical perspective and view to the future [J].Immunological Reviews,2011,239(1):62–84.
[6] Emanuela Signori, Sandra Iurescia, Emanuela Massi, et al. DNA vaccinationstrategies for anti-tumour eVective gene therapy protocols [J]. Cancer ImmunolImmunother,2010,59(10):1583–1591.
[7] Sheeba Alam, Douglas G McNeel. DNA vaccines for the treatment of prostatecancer. Expert Rev [J]. Vaccines,2010,9(7):731–745.
[8] Kantoff PW, Schuetz TJ, Blumenstein BA, et al. Overall survival analysis of aPhase II randomized controlled trial of a poxviral-based PSA-targeted immunotherapyin metastatic castration-resistant prostate cancer [J]. J. Clin. Oncol,2010,28(7):1099–1105.
[9] Gulley JL, Arlen PM, Madan RA, et al. Immunologic and prognostic factorsassociated with overall survival employing a poxviral-based PSA vaccine in metastaticcastrate-resistant prostate cancer [J]. Cancer Immunol Immunother,2010,59(5):663-74.
[10] Kim JJ, Trivedi NN, Wilson DM, et al. Molecular and immunological analysis ofgenetic prostate specific antigen (PSA) vaccine [J]. Oncogene,1998,17(24):3125–3135.
[11] Pavlenko M, Roos AK, Lundqvist A, et al. A PhaseⅠtrial of DNA vaccinationwith a plasmid expressing prostate-specific antigen in patients with hormone-refractoryprostate cancer [J]. Br. J. Cancer,2004,91(4):688–694.
[12]Roos AK, Moreno S, Leder C, et al. Enhancement of cellular immune response toa prostate cancer DNA vaccine by intradermal electroporation [J]. Mol. Ther,2006,13(2):320–327.
[13] Sarfraz Ahmad, Garrett Casey, Paul Sweeney et al. Optimised electroporationmediated DNA vaccination for treatment of prostate cancer [J]. Genetic Vaccines andTherapy,2010,8(1):2-13.
[14] Miller AM, Ozenci V, Kiessling R, et al. Immune monitoring in a Phase1trial of aPSA DNA vaccine in patients with hormone-refractory prostate cancer [J]. J.Immunother,2005,28(4):389–395.
[15] Johnson LE, Frye TP, Arnot AR et al. Safety and immunological efficacy of aprostate cancer plasmid DNA vaccine encoding prostatic acid phosphatase (PAP)[J].Vaccine,2006,24(3):293–303.
[16] Johnson LE, Frye TP, Chinnasamy N, et al. Plasmid DNA vaccine encodingprostatic acid phosphatase is effective in eliciting autologous antigen-specific CD8+Tcells [J]. Cancer Immunol. Immunother,2007,56(6):885–895.
[17] McNeel DG, Dunphy EJ, Davies JG, et al. Safety and immunological efficacy of aDNA vaccine encoding prostatic acid phosphatase in patients with stage D0prostatecancer [J]. J. Clin. Oncol,2009,27(25):4047–4054.
[18] Becker JT, Olson BM, Johnson LE, et al. DNA vaccine encoding prostatic acidphosphatase (PAP) elicits long-term T-cell responses in patients with recurrent prostatecancer [J]. J. Immunother,2010,33(6):639-647.
[19] Guru Sonpavde, Neeraj Agarwal, Toni K Choueiri. Recent advances inimmunotherapy for the treatment of prostate cancer [J]. Expert Opin. Biol. Ther,2011,11(8):997-1009.
[20] Mincheff M, Zoubak S, Makogonenko Y. Immune responses against PSMA aftergene-based vaccination for immunotherapy-A: results from immunizations in animals[J]. Cancer Gene Ther,2006,13(4):436–444.
[21] Mincheff M, Tchakarov S, Zoubak S, et al. Naked DNA and adenoviralimmunizations for immunotherapy of prostate cancer: a Phase I/II clinical trial [J]. Eur.Urol,2000,38(2):208–217.
[22] Gisella E. Vittes et al. DNA fusion gene vaccines induce cytotoxic T-cell attack onnaturally processed peptides of human prostate-specific membrane antigen [J]. Eur. J.Immunol,2011,41(8):2447–2456.
[23] Youlin Kuang, Hengcheng Zhu, Xiaodong Weng, et al. Antitumor ImmuneResponse Induced by DNA Vaccine Encoding Human Prostate-specific MembraneAntigen and Mouse4-1BBL. Urology [J].2010;76(2):510.e1-6.
[24] Alves PM, Faure O, Graff-Dubois S, et al. STEAP, a prostate tumor antigen, is atarget of human CD8+T cells [J]. Cancer Immunol. Immunother,2006,55(12):1515–1523.
[25] Garcia-Hernandez Mde L, Gray A, Hubby B, Kast WM. In vivo effects ofvaccination with six-transmembrane epithelial antigen of the prostate: a candidateantigen for treating prostate cancer [J]. Cancer Res,2007,67(3):1344–1351.
[26] Fuessel S, Meye A, Schmitz M, et al. Vaccination of hormone-refractory prostatecancer patients with peptide cocktail loaded dendritic cells: results of a phase I clinicaltrial [J]. Prostate,2006,66(8):811-821.
[27] Zhang X, Yu C, Zhao J,etal. Vaccination with a DNA vaccine based on humanPSCA and HSP70adjuvant enhances the antigen-specific CD8+T-cell response andinhibits the PSCA+tumors growth in mice [J]. J Gene Med,2007,9(8):715-726.
[28] Garcia-Hernandez Mde L, Gray A, Hubby B, Kast WM, et al. Prostate stem cellantigen vaccination induces a long-term protective immune response against prostatecancer in the absence of autoimmunity [J]. Cancer Res,2008,68(3):861–869.
[29] Sarfraz Ahmad, Garrett Casey, Paul Sweeney, et al. Prostate stem cell antigenDNA vaccination breaks tolerance to self-antigen and inhibits prostate cancer growth[J]. Molecular Therapy,2009,17(6):1101–1108.
[30] Qin H, Zhou C, Wang D, Ma W, et al. Specific antitumor immune responseinduced by a novel DNA vaccine composed of multiple CTL and T helper cell epitopesof prostate cancer associated antigens [J]. Immunol Lett.2005,99(1):85-93.
[31] Magdalena Krupa, Marta Canamero, Carmen E. Gomez, et al. Immunization withrecombinant DNA and modified vaccinia virus Ankara (MVA) vectors deliveringPSCA and STEAP1antigens inhibits prostate cancer progression [J]. Vaccine,2011,29(7):1504-1513.
[32] Ferraro B, Cisper NJ, Talbott KT et al. Co-delivery of PSA and PSMA DNAvaccines with electroporation induces potent immune responses [J]. Hum Vaccin,2011,7: Suppl:120-127.
[1] Reiter RE, Gu Z, Watabe T, et al. Prostate stem cell antigen: a cell surface markeroverexpressed in prostate cancer. Proc Natl Acad Sci USA [J].1998,95(4):1735–40.
[2] Sakamoto H, Yoshimura K, Saeki N, et al. Genetic variation in PSCA is associatedwith susceptibility to diffuse-type gastric cancer [J]. Nat Genet,2008,40(6):730–40.
[3] Feng HC, Tsao SW, Ngan HY, et al. Overexpression of prostate stem cell antigen isassociated with gestational trophoblastic neoplasia [J]. Histopathology,2008,52(2):167–74.
[4] Ono H, Hiraoka N, Lee YS et al. Prostate Stem Cell Antigen, a PresumableOrgan-Dependent Tumor Suppressor Gene, is Down-Regulated in GallbladderCarcinogenesis [J]. GENES, CHROMOSOMES&CANCER,2012,51(1):30–41.
[5] Raff AB, Gray A, Kast WM. Prostate Stem Cell Antigen: A Prospective Therapeuticand Diagnostic Target [J]. Cancer Lett,2009,277(2):126-32.
[6] Moore ML, Teitell MA, Kim Y, et al. Deletion of PSCA increases metastasis ofTRAMP-induced prostate tumors without altering primary tumor formation [J].Prostate,2008,68(2):139–151.
[7] Saeki N, Gu J, Yoshida T, Wu X. Prostate stem cell antigen: a Jekyll and Hydemolecule?[J]. Clin Cancer Res,2010,16(14):3533-8.
[8] Han KR, Seligson DB, Liu X, et al. Prostate stem cell antigen expression isassociated with gleason score, seminal vesicle invasion and capsular invasion inprostate cancer[J]. J Urol,2004,171(3):1117–21.
[9] Lam JS, Yamashiro J, Shintaku IP, et al. Prostate stem cell antigen is overexpressedin prostate cancer metastases[J]. Clin Cancer Res,2005,11(7):2591–6.
[10]Reiter RE, Sato I, Thomas G, et al. Coamplification of prostate stem cell antigen(PSCA) and MYC in locally advanced prostate cancer [J]. Genes ChromosomesCancer,2000,27(1):95–103.
[11]Zhigang Z, Wenlu S. Prostate stem cell antigen (PSCA) mRNA expression inprostatic intraepithelial neoplasia: implications for the development of prostatecancer [J]. Prostate,2007,67(11):1143–51。
[12]Hara N, Kasahara T, Kawasaki T, et al. Reverse transcription-polymerase chainreaction detection of prostate-specific antigen, prostate-specific membrane antigen,and prostate stem cell antigen in one milliliter of peripheral blood: value for thestaging of prostate cancer [J]. Clin Cancer Res,2002,8(6):1794–9.
[13]Zhigang Z, Wenlu S. Flutamide reduced prostate cancer development and prostatestem cell antigen mRNA expression in high grade prostatic intraepithelial neoplasia[J]. Int J Cancer,2008,122(4):864–70.
[14]Cheng L, Reiter RE, Jin Y, et al. Immunocytochemical analysis of prostate stem cellantigen as adjunct marker for detection of urothelial transitional cell carcinoma invoided urine specimens [J]. J Urol,2003,169(6):2094–100.
[15]Elsamman E, Fukumori T, Kasai T, et al. Prostate stem cell antigen predicts tumourrecurrence in superficial transitional cell carcinoma of the urinary bladder [J]. BJUInt,2006,97(6):1202–7.
[16] Argani P, Rosty C, Reiter RE, Wilentz RE, et al. Discovery of new markers ofcancer through serial analysis of gene expression: prostate stem cell antigen isoverexpressed in pancreatic adenocarcinoma [J]. Cancer Res,2001,61(11):4320–4324.
[17]Foss CA, Fox JJ, Feldmann G, et al. Radiolabeled anti-claudin4and anti-prostatestem cell antigen: initial imaging in experimental models of pancreatic cancer [J].Mol Imaging,2007,6(2):131–9.
[18]Elsamman E, Fukumori T, Tanimoto S, Nakanishi R, Takahashi M, Toida K,Kanayama HO. The expression of prostate stem cell antigen in human clear cellrenal cell carcinoma: a quantitative reverse transcriptase-polymerase chain reactionanalysis [J]. BJU Int,2006,98:668–673.
[19]Qiao L, Feng Y. Genetic variations of prostate stem cell antigen (PSCA) contributeto the risk of gastric cancer for Eastern Asians: A meta-analysis based on16792individuals [J]. Gene,2012,493:83–91.
[20]Thomas-Kaskel AK, Zeiser R, Jochim R, et al. Vaccination of advanced prostatecancer patients with PSCA and PSA peptide-loaded dendritic cells induces DTHresponses that correlate with superior overall survival [J]. Int J Cancer,2006,119:2428–34.
[21]Waeckerle-Men Y, Uetz-von Allmen E, Fopp M, et al. Dendritic cell-basedmulti-epitope immunotherapy of hormone-refractory prostate carcinoma [J]. CancerImmunol Immunother,2006,55:1524–33.
[22]Hall SJ, Klotz L, Pantuck AJ, etal. Integrated Safety Data From4Randomized,Double-Blind, Controlled Trials of Autologous Cellular Immunotherapy WithSipuleucel-T in Patients With Prostate Cancer [J]. J Urol,2011,186(3):877-81.
[23]Gu Z, Yamashiro J, Kono E, et al. Anti-prostate stem cell antigen monoclonalantibody1G8induces cell death in vitro and inhibits tumor growth in vivo via aFc-independent mechanism [J]. Cancer Res,2005,65(20):9495–500.
[24]Antonarakis ES, Carducci MA, Eisenberger MA, et al. PhaseⅠrapiddose-escalation study of AGS-1C4D4, a human anti-PSCA (prostate stem cellantigen) monoclonal antibody, in patients with castration-resistant prostate cancer: aPCCTC trial [J]. Cancer Chemother Pharmacol, Oct22.[Epub ahead of print]
[25]Wente MN, Jain A, Kono E, et al. Prostate stem cell antigen is a putative target forimmunotherapy in pancreatic cancer [J]. Pancreas,2005,31(2):119–25.
[26]Zhang X, Yu C, Zhao J,etal. Vaccination with a DNA vaccine based on humanPSCA and HSP70adjuvant enhances the antigen-specific CD8+T-cell response andinhibits the PSCA+tumors growth in mice [J]. J Gene Med,2007,9(8):715-726.
[27]Garcia-Hernandez Mde L, Gray A, Hubby B, Kast WM, et al. Prostate stem cellantigen vaccination induces a long-term protective immune response againstprostate cancer in the absence of autoimmunity [J]. Cancer Res,2008,68(3):861–869.
[28]Sarfraz Ahmad, Garrett Casey, Paul Sweeney, et al. Prostate stem cell antigen DNAvaccination breaks tolerance to self-antigen and inhibits prostate cancer growth [J].Molecular Therapy,2009,17(6):1101–1108.
[29]Magdalena Krupa, Marta Canamero, Carmen E. Gomez, et al. Immunization withrecombinant DNA and modified vaccinia virus Ankara (MVA) vectors deliveringPSCA and STEAP1antigens inhibits prostate cancer progression [J]. Vaccine,2011,29(7):1504-1513.
[30]Ahmad S, Casey G, Cronin M, et al. Induction of effective antitumor response aftermucosal bacterial vector mediated DNA vaccination with endogenous prostatecancer specific antigen [J]. J Urol,2011,186(2):687-93.