基因重组溶瘤腺病毒治疗中晚期胰腺癌的实验及临床研究
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摘要
胰腺癌是我国常见肿瘤,发病率和死亡率有逐年提高的趋势,由于胰腺癌解剖位置隐蔽,起病隐匿,早期多无明显临床症状,确诊时往往已逾中晚期,仅不足15%的患者有机会接受根治性手术,且对放化疗均不敏感,治疗效果及预后均不理想,总体生存率极低,5年生存率仅约5%。针对中晚期胰腺癌的治疗仍是临床胰腺专科的重点和难点。目前的治疗主要为各种体内外放疗、以吉西他滨为主的化疗。但效果均不十分理想。溶瘤病毒是经过遗传学改造而具有选择性复制能力的病毒,在正常细胞内不能增殖,而在肿瘤细胞内能利用抑癌基因的失活或缺陷选择性复制,最终导致肿瘤细胞的溶解和死亡,该机理决定了它有成为理想的肿瘤治疗药物的可能。溶瘤病毒通过多种机制杀灭肿瘤,包括直接溶解、细胞融合、释放毒性蛋白以及诱导抗肿瘤免疫反应。使用和研究较多的溶瘤病毒包括腺病毒、单纯疱疹病毒和呼肠孤病毒。H101是删除了E1-B基因因而能在肿瘤细胞中选择性复制的腺病毒。2005年,溶瘤腺病毒H101在国内获得治疗头颈部肿瘤的上市批准,从而使中国成为世界上首个批准将溶瘤病毒正式用于肿瘤临床治疗的国家。然而,尽管在体外实验和动物实验中取得了令人振奋的结果,在临床研究中,大多数溶瘤病毒的疗效却不理想。原因是多方面的,包括肿瘤、微环境、病毒和宿主免疫反应及其之间的交互作用。
本研究对基因重组人溶瘤腺病毒H101在胰腺癌瘤内注射联合吉西他滨化疗的应用进行了研究,以期进一步了解该溶瘤病毒对晚期胰腺癌局部治疗的安全性与疗效,摸索晚期胰腺癌超声内镜下治疗的新方法。我们首先利用细针原位注射技术成功构建了裸鼠胰腺原位种植瘤动物模型,并经解剖学和组织学验证。在此基础上首先研究了溶瘤病毒与经典的实体肿瘤注射药物——无水乙醇二者经瘤内注射联合化疗治疗胰腺肿瘤的疗效、安全性,发现尽管抑制肿瘤的效果略低于无水乙醇,但溶瘤病毒对抑制胰腺肿瘤也是有效的,且其在安全性上有一定优势;研究发现,二者治疗后在瘤体内外发生的免疫反应不尽相同,溶瘤病毒组有更多的淋巴细胞浸润,考虑到模型动物系无免疫力的裸鼠,这个差别很可能对减少肿瘤的免疫逃逸有很大影响,而在后面的临床试验中也部分证明了这一点。同时,本研究对溶瘤病毒瘤体内注射后病毒在体内的分布做了初步研究,发现溶瘤病毒具有高度的选择性,除注射局部的个别组织外,在胸腹腔内其余主要脏器均没有明显分布,这一结果对溶瘤病毒瘤内注射的安全性作了一个有力的补充。基于上述结论,在第三部分我们进一步研究了溶瘤病毒治疗胰腺癌的方式方法,发现瘤体内注射单针注射与多点注射的疗效类似,而瘤体注射联合静脉化疗对肿瘤的抑制优于病毒静脉给药联合化疗。这说明在溶瘤病毒治疗胰腺癌的策略上,经超声内镜瘤内注射是必要的
在获取了动物实验的结果后,我们进行了经超声内镜溶瘤病毒瘤内注射联合化疗治疗中晚期胰腺癌的临床研究。目的是通过观察超声内镜引导下瘤体内注射重组溶瘤病毒(H101)联合吉西他滨化疗治疗中晚期胰腺癌的疗效及安全性,了解溶瘤病毒联合化疗对中晚期胰腺癌的临床意义。方法选择符合入组标准的中晚期胰腺癌患者共41例,随机分为2组,病毒治疗组于超声内镜引导下行H101瘤体内注射,并于第3、10、17日行吉西他滨静脉化疗(1000mg/m2),至少2周期。对照组仅行同方案的吉西他滨化疗。分别观测术后1周、1月的血液学、生化及肿瘤指标;记录不良反应及并发症;术前后分别计算肿瘤体积及目标病灶长径总和,评定疗效;评价患者疼痛及Karnofsky评分变化;生存期随访。结果病毒治疗组及对照组患者均完成2周期治疗。治疗组不良反应主要为发热与腹泻。26.3%(5/19)的患者获得PR,31.6%(6/19)的患者为PD,42.1%(8/19)的患者为SD,无CR患者。治疗总有效率为26.3%。化疗组相应的值为PR4.5%(1/22)、PD45.5%(10/22)、SD50.0%(11/22)、无CR,总有效率4.5%。总有效率差异具有显著性意义,P=0.049。治疗后CA199下降率两组存在明显差别(P=0.032),病毒组显著优于化疗组;CEA下降率两组没有显著性差异(P=0.513)。病毒组术后的平均疼痛评分明显低于术前(3.1±1.7 vs 3.9±1.6, P=0.004),Karnofsky评分明显提高(68.4±12.1 vs 61.1±9.9, P=0.003)。两组间在疼痛改善率、黄疸加重、Karnofsky评分改善方面均有显著性差异(P=0.000、0.017、0.003)。病毒组生存期为2.5月至10月不等,中位生存期9个月,9例患者仍存活。化疗组生存期3至10月,中位生存期6个月,两组生存率有明显差异(P=0.004)。结论超声内镜引导下瘤体内注射重组溶瘤病毒联合吉西他滨化疗治疗中晚期胰腺癌的方法是安全的、有效的,能有效改善患者生存质量、降低疼痛评分,降低CA199水平,延长生存期,该部分研究的结果再次表明了溶瘤病毒经超声内镜行瘤内注射治疗胰腺肿瘤的可行性、可耐受性及安全性,以及该法联合吉西他滨化疗治疗中晚期胰腺癌的有效性。
本研究以动物实验和临床研究两方面结果表明溶瘤病毒联合吉西他滨化疗治疗胰腺癌是有效的、安全的;同无水乙醇的瘤内注射相比在改善疼痛和其余临床症状方面是有一定优势的。随着更新型溶瘤病毒的出现,该治疗很可能在未来胰腺癌的治疗中发挥更重要的作用。
Background Pancreatic carcinoma is one of the main cancer in China. It is difficult to detect in early stage for its anatomic properties.Most cases are in advanced stages and lost the opportunity of exairesis when they are defined diagnosed.Only less than 15% of the carcinomas could be resected by surgery.Because of the high resistance to chemo and radiation therapy, the overall survival rate for pancreatic cancer is extremely low. The prognosis of patients with pancreatic cancer is extremely poor,with overall 5-year survival rate of approximately 5%.Till now, treatment of pancreatic carcinoma remains a major challenge. The main therapy for locally advanced cancers involves kinds of radiotherapy in vivo and in vitro, and the chemotherapy(mainly base on Gemcitabine).But the efficiency are limited. Replication-de?cient oncolytic viruses are engineered to replicate only in tumor cells, which makes it an promissing therapeutic agent for cancer treatment. Those viruses kill tumor cells by a variety of mechanisms including direct cell lysis, cell–cell fusion, toxic proteins, and induction of antitumor immune responses. Commonly used oncolytic viruses include adenovirus, herpes simplex virus, and reovirus. H101 is an E1B-gene-deleted replication-selective adenovirus that preferentially replicates in malignant cells. In 2005, an adenovirus with E1B-55K gene deletion (H101) was approved in China as the world’s first oncolytic virus for head and neck cancer in combination with chemotherapy. Although encouraging results have been demonstrated in vitro and in animal models, most oncolytic viruses have failed to impress in the clinical setting. The explanation is multifactorial, determined by the complex interactions between the tumor and its microenvironment, the virus, and the host immune response.
To evaluate the efficacy and safety of intratumoral injection of E1B gene-deleted adenovirus (H101) combined with intravenous gemcitabine in treating pancreatic carcinomas and to research new treatment approach,we constructed an orthotopic animal model of pancreatic carcinoma through cancer cell injection, which was validated by anatomy and histology. Then, we proceeded a comparative study of the efficiency and reliability between ethanol and oncolytic virus on treating pancreatic cancer based on this model. We found that this kind of virus is effective on inhibiting the pancreatic cancer, in spite of its lower effectiveness than ethanol. The immune response induced by these two agent at exterior and interior of the tumor were different. More lymphocytes infiltration were observed in oncolytic virus group. This difference may affect the immune escape of the cancer tremendously. This conjecture were proved partly by the follow clinical trial. Meanwhile, we studied the distribution of this virus after intratumoral injection. The H101 was absent in all the other organs besides the pancreas, which means that the selectivity of the H101 was tremendous. Based on these results, we studied the modality of the oncolytic virus treatment on pancreatic cancer in PART III. We found that the therapeutic effect of single track injection was similar to multipoint injection. What’s more, intratumoral injection of oncolytic adenovirus combined with intravenous gemcitabine showed a more significant effect than intravenous virus and gemcitabine. These results may suggest the necessity of EUS-guided intratumoral injection in the therapy strategy of pancreatic cancer.
Based on the results above, to evaluate the efficacy and tolerability of EUS-guided intratumoral injection of E1B gene-deleted adenovirus (H101) combined with intravenous gemcitabine in treating unresectable pancreatic carcinomas, we carried the study of PART IV. Methods Forty-one patients with advanced adenocarcinoma of the pancreas enrolled in this study,who were allocated to two group randomly. Each one in virus group underwent two sessions of H101 intratumoral injection in combination with gemcitabine (i.v., 1000mg/m2, d3,10,17) at least. The control group undergone the chemotherapy of gemcitabine. The clinical indices, adverse effects and complications at one and four weeks after treatment were recorded respectively. The tumor size and the summation of the long diameter were calculated for efficacy assessment. The pain score and KPS were estimated before and one month after injection. Results All patients completed two cycles of treatment. Major adverse effects associated with H101 injection were fever and diarrhea. In virus group, among all the nineteen patients, 5 (26.3%) had partial response, 6 (31.6%) had progressive disease, 8 (42.1%) had stable disease, and none had complete response. The total effective power was 26.3%. While that were PR4.5%(1/22)、PD45.5%(10/22)、SD50.0%(11/22)、CR0 in control group. The total effective power was 4.5% in control group which was significantly different to that in virus group. The CA199 level of virus group was decreased deeper than control group(P=0.032). While CEA was similar(P=0.513). The pain score in virus group were decreased after 2 sessions with a significant statistical difference (3.1±1.7 vs 3.9±1.6, P=0.004). Meanwhile KPS had significant increase (68.4±12.1 vs 61.1±9.9, P=0.003). There were significant different between two groups on improvement rate of pain, aggratation of jaundice and improvement of KPS(P=0.000、0.017、0.003). The survival time and median survival time of virus group were 2.5 to 10 months and 9 months, respectively. Nine patients are still alive. While there were 3 to 10 months and 6 months in control group. The survival rate were significantly different(P=0.004). Conclusion EUS-guided E1B gene-deleted adenovirus intratumral injection in unresectable pancreatic carcinomas is efficient, feasible and well tolerable in combination with intravenous gemcitabine, which can improve the living quality and cut down the pain score of patients.
Our study showed the efficiency and reliability of intratumoral injection of oncolytic adenovirus combined with intravenous gemcitabine in treating unresectable pancreatic carcinomas based on the results from animal experiment and clinic trail. The oncolytic virus was predominant in pain release and other symptom reduction. The virus may play a more important role in pancreatic cancer therapy in future.
本研究对基因重组人溶瘤腺病毒H101在胰腺癌瘤内注射联合吉西他滨化疗的应用进行了研究,以期进一步了解该溶瘤病毒对晚期胰腺癌局部治疗的安全性与疗效,摸索晚期胰腺癌超声内镜下治疗的新方法。我们首先利用细针原位注射技术成功构建了裸鼠胰腺原位种植瘤动物模型,并经解剖学和组织学验证。在此基础上首先研究了溶瘤病毒与经典的实体肿瘤注射药物——无水乙醇二者经瘤内注射联合化疗治疗胰腺肿瘤的疗效、安全性,发现尽管抑制肿瘤的效果略低于无水乙醇,但溶瘤病毒对抑制胰腺肿瘤也是有效的,且其在安全性上有一定优势;研究发现,二者治疗后在瘤体内外发生的免疫反应不尽相同,溶瘤病毒组有更多的淋巴细胞浸润,考虑到模型动物系无免疫力的裸鼠,这个差别很可能对减少肿瘤的免疫逃逸有很大影响,而在后面的临床试验中也部分证明了这一点。同时,本研究对溶瘤病毒瘤体内注射后病毒在体内的分布做了初步研究,发现溶瘤病毒具有高度的选择性,除注射局部的个别组织外,在胸腹腔内其余主要脏器均没有明显分布,这一结果对溶瘤病毒瘤内注射的安全性作了一个有力的补充。基于上述结论,在第三部分我们进一步研究了溶瘤病毒治疗胰腺癌的方式方法,发现瘤体内注射单针注射与多点注射的疗效类似,而瘤体注射联合静脉化疗对肿瘤的抑制优于病毒静脉给药联合化疗。这说明在溶瘤病毒治疗胰腺癌的策略上,经超声内镜瘤内注射是必要的
在获取了动物实验的结果后,我们进行了经超声内镜溶瘤病毒瘤内注射联合化疗治疗中晚期胰腺癌的临床研究。目的是通过观察超声内镜引导下瘤体内注射重组溶瘤病毒(H101)联合吉西他滨化疗治疗中晚期胰腺癌的疗效及安全性,了解溶瘤病毒联合化疗对中晚期胰腺癌的临床意义。方法选择符合入组标准的中晚期胰腺癌患者共41例,随机分为2组,病毒治疗组于超声内镜引导下行H101瘤体内注射,并于第3、10、17日行吉西他滨静脉化疗(1000mg/m2),至少2周期。对照组仅行同方案的吉西他滨化疗。分别观测术后1周、1月的血液学、生化及肿瘤指标;记录不良反应及并发症;术前后分别计算肿瘤体积及目标病灶长径总和,评定疗效;评价患者疼痛及Karnofsky评分变化;生存期随访。结果病毒治疗组及对照组患者均完成2周期治疗。治疗组不良反应主要为发热与腹泻。26.3%(5/19)的患者获得PR,31.6%(6/19)的患者为PD,42.1%(8/19)的患者为SD,无CR患者。治疗总有效率为26.3%。化疗组相应的值为PR4.5%(1/22)、PD45.5%(10/22)、SD50.0%(11/22)、无CR,总有效率4.5%。总有效率差异具有显著性意义,P=0.049。治疗后CA199下降率两组存在明显差别(P=0.032),病毒组显著优于化疗组;CEA下降率两组没有显著性差异(P=0.513)。病毒组术后的平均疼痛评分明显低于术前(3.1±1.7 vs 3.9±1.6, P=0.004),Karnofsky评分明显提高(68.4±12.1 vs 61.1±9.9, P=0.003)。两组间在疼痛改善率、黄疸加重、Karnofsky评分改善方面均有显著性差异(P=0.000、0.017、0.003)。病毒组生存期为2.5月至10月不等,中位生存期9个月,9例患者仍存活。化疗组生存期3至10月,中位生存期6个月,两组生存率有明显差异(P=0.004)。结论超声内镜引导下瘤体内注射重组溶瘤病毒联合吉西他滨化疗治疗中晚期胰腺癌的方法是安全的、有效的,能有效改善患者生存质量、降低疼痛评分,降低CA199水平,延长生存期,该部分研究的结果再次表明了溶瘤病毒经超声内镜行瘤内注射治疗胰腺肿瘤的可行性、可耐受性及安全性,以及该法联合吉西他滨化疗治疗中晚期胰腺癌的有效性。
本研究以动物实验和临床研究两方面结果表明溶瘤病毒联合吉西他滨化疗治疗胰腺癌是有效的、安全的;同无水乙醇的瘤内注射相比在改善疼痛和其余临床症状方面是有一定优势的。随着更新型溶瘤病毒的出现,该治疗很可能在未来胰腺癌的治疗中发挥更重要的作用。
Background Pancreatic carcinoma is one of the main cancer in China. It is difficult to detect in early stage for its anatomic properties.Most cases are in advanced stages and lost the opportunity of exairesis when they are defined diagnosed.Only less than 15% of the carcinomas could be resected by surgery.Because of the high resistance to chemo and radiation therapy, the overall survival rate for pancreatic cancer is extremely low. The prognosis of patients with pancreatic cancer is extremely poor,with overall 5-year survival rate of approximately 5%.Till now, treatment of pancreatic carcinoma remains a major challenge. The main therapy for locally advanced cancers involves kinds of radiotherapy in vivo and in vitro, and the chemotherapy(mainly base on Gemcitabine).But the efficiency are limited. Replication-de?cient oncolytic viruses are engineered to replicate only in tumor cells, which makes it an promissing therapeutic agent for cancer treatment. Those viruses kill tumor cells by a variety of mechanisms including direct cell lysis, cell–cell fusion, toxic proteins, and induction of antitumor immune responses. Commonly used oncolytic viruses include adenovirus, herpes simplex virus, and reovirus. H101 is an E1B-gene-deleted replication-selective adenovirus that preferentially replicates in malignant cells. In 2005, an adenovirus with E1B-55K gene deletion (H101) was approved in China as the world’s first oncolytic virus for head and neck cancer in combination with chemotherapy. Although encouraging results have been demonstrated in vitro and in animal models, most oncolytic viruses have failed to impress in the clinical setting. The explanation is multifactorial, determined by the complex interactions between the tumor and its microenvironment, the virus, and the host immune response.
To evaluate the efficacy and safety of intratumoral injection of E1B gene-deleted adenovirus (H101) combined with intravenous gemcitabine in treating pancreatic carcinomas and to research new treatment approach,we constructed an orthotopic animal model of pancreatic carcinoma through cancer cell injection, which was validated by anatomy and histology. Then, we proceeded a comparative study of the efficiency and reliability between ethanol and oncolytic virus on treating pancreatic cancer based on this model. We found that this kind of virus is effective on inhibiting the pancreatic cancer, in spite of its lower effectiveness than ethanol. The immune response induced by these two agent at exterior and interior of the tumor were different. More lymphocytes infiltration were observed in oncolytic virus group. This difference may affect the immune escape of the cancer tremendously. This conjecture were proved partly by the follow clinical trial. Meanwhile, we studied the distribution of this virus after intratumoral injection. The H101 was absent in all the other organs besides the pancreas, which means that the selectivity of the H101 was tremendous. Based on these results, we studied the modality of the oncolytic virus treatment on pancreatic cancer in PART III. We found that the therapeutic effect of single track injection was similar to multipoint injection. What’s more, intratumoral injection of oncolytic adenovirus combined with intravenous gemcitabine showed a more significant effect than intravenous virus and gemcitabine. These results may suggest the necessity of EUS-guided intratumoral injection in the therapy strategy of pancreatic cancer.
Based on the results above, to evaluate the efficacy and tolerability of EUS-guided intratumoral injection of E1B gene-deleted adenovirus (H101) combined with intravenous gemcitabine in treating unresectable pancreatic carcinomas, we carried the study of PART IV. Methods Forty-one patients with advanced adenocarcinoma of the pancreas enrolled in this study,who were allocated to two group randomly. Each one in virus group underwent two sessions of H101 intratumoral injection in combination with gemcitabine (i.v., 1000mg/m2, d3,10,17) at least. The control group undergone the chemotherapy of gemcitabine. The clinical indices, adverse effects and complications at one and four weeks after treatment were recorded respectively. The tumor size and the summation of the long diameter were calculated for efficacy assessment. The pain score and KPS were estimated before and one month after injection. Results All patients completed two cycles of treatment. Major adverse effects associated with H101 injection were fever and diarrhea. In virus group, among all the nineteen patients, 5 (26.3%) had partial response, 6 (31.6%) had progressive disease, 8 (42.1%) had stable disease, and none had complete response. The total effective power was 26.3%. While that were PR4.5%(1/22)、PD45.5%(10/22)、SD50.0%(11/22)、CR0 in control group. The total effective power was 4.5% in control group which was significantly different to that in virus group. The CA199 level of virus group was decreased deeper than control group(P=0.032). While CEA was similar(P=0.513). The pain score in virus group were decreased after 2 sessions with a significant statistical difference (3.1±1.7 vs 3.9±1.6, P=0.004). Meanwhile KPS had significant increase (68.4±12.1 vs 61.1±9.9, P=0.003). There were significant different between two groups on improvement rate of pain, aggratation of jaundice and improvement of KPS(P=0.000、0.017、0.003). The survival time and median survival time of virus group were 2.5 to 10 months and 9 months, respectively. Nine patients are still alive. While there were 3 to 10 months and 6 months in control group. The survival rate were significantly different(P=0.004). Conclusion EUS-guided E1B gene-deleted adenovirus intratumral injection in unresectable pancreatic carcinomas is efficient, feasible and well tolerable in combination with intravenous gemcitabine, which can improve the living quality and cut down the pain score of patients.
Our study showed the efficiency and reliability of intratumoral injection of oncolytic adenovirus combined with intravenous gemcitabine in treating unresectable pancreatic carcinomas based on the results from animal experiment and clinic trail. The oncolytic virus was predominant in pain release and other symptom reduction. The virus may play a more important role in pancreatic cancer therapy in future.
引文
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