提示: 手机请竖屏浏览!

儿童高级别胶质瘤的溶瘤HSV-1 G207免疫病毒疗法
Oncolytic HSV-1 G207 Immunovirotherapy for Pediatric High-Grade Gliomas


Gregory K. Friedman ... 肿瘤 • 2021.04.29
相关阅读
• 重组脊髓灰质炎病毒治疗复发性胶质母细胞瘤

儿童高级别胶质瘤溶瘤病毒免疫治疗

 

张扬,张力伟*

首都医科大学附属北京天坛医院神经外科;国家神经系统疾病临床研究中心

*通讯作者

 

近年来,儿童中枢神经系统肿瘤发病率逐年上升。据报道,中枢神经系统恶性肿瘤已仅次于白血病,成为我国第二常见儿童恶性肿瘤;而在美国,0~14岁儿童的中枢神经系统肿瘤发病率早已超过白血病,是第一常见儿童肿瘤。胶质瘤占儿童中枢神经系统肿瘤的51.6%(2020年CBTRUS报道),多为恶性;其中高级别胶质瘤(WHO Ⅲ~Ⅳ级)对包括手术、放疗和化疗等常规治疗反应差,治疗后早期复发,复发后的中位生存时间仅为5.6个月。受限于儿童这一特殊群体和脑恶性肿瘤新型治疗开发的整体滞后,儿童高级别胶质瘤治疗效果近30年未获得实质性提高。因此,亟需发现新型治疗手段,以期改善治疗预后。

查看更多

摘要


背景

儿童和青少年复发性或进行性高级别胶质瘤患者的结局不良,既往中位总生存期为5.6个月。儿童高级别胶质瘤基本上为免疫沉默或“冷”肿瘤,肿瘤浸润淋巴细胞极少。在临床前研究中,儿童脑肿瘤对以下溶瘤病毒疗法高度敏感:经过基因工程改造,缺乏在正常脑组织中复制所必需基因的单纯疱疹病毒1型(HSV-1)G207。


方法

我们应用3+3设计对G207开展了1期试验,该试验纳入经活检确诊为复发性或进行性幕上脑肿瘤的儿童和青少年患者,分成4个剂量队列。应用立体定向技术为患者置入最多4个肿瘤内导管。患者于第2日接受了G207(107或108个斑块形成单位)给药,给药过程中控制输入速度,使给药时间持续6小时。队列3和4的患者在G207给药后24小时内接受了大体肿瘤靶区放疗(5 Gy)。本试验通过培养和聚合酶链反应评估病毒通过唾液、结膜和血液排出的情况。通过免疫组化方法检查治疗前后对应组织样本的肿瘤浸润淋巴细胞。


结果

12例7~18岁的高级别胶质瘤患者接受了G207治疗。患者未发生被研究者归因于G207的剂量限制性毒性和严重不良事件。有20起1级不良事件可能与G207相关。未检测到病毒排出。本试验观察到11例患者达到影像学、神经病理学或临床缓解。中位总生存期为12.2个月(95%置信区间[CI],8.0~16.4);截至2020年6月5日,即G207治疗后18个月时,11例患者中有4例仍存活。G207明显增加了肿瘤浸润淋巴细胞数量。


结论

复发性或进行性儿童高级别胶质瘤患者接受G207瘤内给药和G207联合放疗后,不良事件可接受,且有证据表明患者达到缓解。G207将免疫“冷”肿瘤转化为“热”肿瘤(由美国食品药品管理局等资助,在ClinicalTrials.gov注册号为NCT02457845)。





作者信息

Gregory K. Friedman, M.D., James M. Johnston, M.D, Asim K. Bag, M.B., B.S., M.D., Joshua D. Bernstock, M.D., Ph.D., M.P.H., Rong Li, M.D., Ph.D., Inmaculada Aban, Ph.D., Kara Kachurak, C.R.N.P., Li Nan, B.S., Kyung-Don Kang, Ph.D., Stacie Totsch, Ph.D., Charles Schlappi, M.D., Allison M. Martin, M.D., Devang Pastakia, M.D., Rene McNall-Knapp, M.D., Sameer Farouk Sait, M.D., Yasmin Khakoo, M.D., Matthias A. Karajannis, M.D., Karina Woodling, M.D., C.C.R.P., Joshua D. Palmer, M.D., Diana S. Osorio, M.D., M.P.H., Jeffrey Leonard, M.D., Mohamed S. Abdelbaki, M.D., Avi Madan-Swain, Ph.D., T. Prescott Atkinson, M.D., Ph.D., Richard J. Whitley, M.D., John B. Fiveash, M.D., James M. Markert, M.D., M.P.H., and G. Yancey Gillespie, Ph.D.
From the Department of Pediatrics, Divisions of Pediatric Hematology–Oncology (G.K.F., K.K., L.N., K.-D.K., S.T., C.S., A.M.-S.), Pediatric Allergy and Immunology (T.P.A.), and Pediatric Infectious Disease (R.J.W.), and the Departments of Neurosurgery (G.K.F., J.M.J., J.M.M., G.Y.G.), Pathology (R.L.), Biostatistics (I.A.), and Radiation Oncology (J.B.F.), University of Alabama at Birmingham, and Children’s of Alabama (G.K.F., J.M.J., R.L., K.K., A.M.-S., T.P.A., R.J.W.) — both in Birmingham; the Department of Diagnostic Imaging, St. Jude Children’s Research Hospital, Memphis (A.K.B.), and the Department of Pediatrics, Vanderbilt University Medical Center, Nashville (D.P.) — both in Tennessee; the Department of Neurosurgery, Brigham and Women’s Hospital and Boston Children’s Hospital, Harvard Medical School, Boston (J.D.B.); the Department of Pediatrics, Albert Einstein College of Medicine (A.M.M.), and the Departments of Pediatrics (S.F.S., Y.K., M.A.K.) and Neurology (Y.K.), Memorial Sloan Kettering Cancer Center — both in New York; the Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City (R.M.-K.); the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant (K.W., D.S.O., M.S.A.) and the Department of Pediatric Neurosurgery (J.L.), Nationwide Children’s Hospital, and the Department of Radiation Oncology, Ohio State University Comprehensive Cancer Center (J.D.P.) — both in Columbus; and the Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant, Washington University School of Medicine, St. Louis (M.S.A.). Address reprint requests to Dr. Friedman at the Department of Pediatrics, University of Alabama at Birmingham, 1600 7th Ave. S., Lowder 512, Birmingham, AL 35233, or at gfriedman@peds.uab.edu.

 

参考文献

1. Cohen KJ, Pollack IF, Zhou T, et al. Temozolomide in the treatment of high-grade gliomas in children: a report from the Children’s Oncology Group. Neuro Oncol 2011;13:317-323.

2. Jakacki RI, Cohen KJ, Buxton A, et al. Phase 2 study of concurrent radiotherapy and temozolomide followed by temozolomide and lomustine in the treatment of children with high-grade glioma: a report of the Children’s Oncology Group ACNS0423 study. Neuro Oncol 2016;18:1442-1450.

3. Kline C, Felton E, Allen IE, Tahir P, Mueller S. Survival outcomes in pediatric recurrent high-grade glioma: results of a 20-year systematic review and meta-analysis. J Neurooncol 2018;137:103-110.

4. Jones C, Karajannis MA, Jones DTW, et al. Pediatric high-grade glioma: biologically and clinically in need of new thinking. Neuro Oncol 2017;19:153-161.

5. Mackay A, Burford A, Carvalho D, et al. Integrated molecular meta-analysis of 1,000 pediatric high-grade and diffuse intrinsic pontine glioma. Cancer Cell 2017;32(4):520-537.e5.

6. Mineta T, Rabkin SD, Yazaki T, Hunter WD, Martuza RL. Attenuated multi-mutated herpes simplex virus-1 for the treatment of malignant gliomas. Nat Med 1995;1:938-943.

7. He B, Gross M, Roizman B. The gamma(1)34.5 protein of herpes simplex virus 1 complexes with protein phosphatase 1alpha to dephosphorylate the alpha subunit of the eukaryotic translation initiation factor 2 and preclude the shutoff of protein synthesis by double-stranded RNA-activated protein kinase. Proc Natl Acad Sci U S A 1997;94:843-848.

8. Goldstein DJ, Weller SK. Herpes simplex virus type 1-induced ribonucleotide reductase activity is dispensable for virus growth and DNA synthesis: isolation and characterization of an ICP6 lacZ insertion mutant. J Virol 1988;62:196-205.

9. Toda M, Rabkin SD, Kojima H, Martuza RL. Herpes simplex virus as an in situ cancer vaccine for the induction of specific anti-tumor immunity. Hum Gene Ther 1999;10:385-393.

10. Todo T, Rabkin SD, Sundaresan P, et al. Systemic antitumor immunity in experimental brain tumor therapy using a multimutated, replication-competent herpes simplex virus. Hum Gene Ther 1999;10:2741-2755.

11. Benencia F, Courrèges MC, Fraser NW, Coukos G. Herpes virus oncolytic therapy reverses tumor immune dysfunction and facilitates tumor antigen presentation. Cancer Biol Ther 2008;7:1194-1205.

12. Leddon JL, Chen CY, Currier MA, et al. Oncolytic HSV virotherapy in murine sarcomas differentially triggers an antitumor T-cell response in the absence of virus permissivity. Mol Ther Oncolytics 2015;1:14010-14010.

13. Advani SJ, Markert JM, Sood RF, et al. Increased oncolytic efficacy for high-grade gliomas by optimal integration of ionizing radiation into the replicative cycle of HSV-1. Gene Ther 2011;18:1098-1102.

14. Markert JM, Medlock MD, Rabkin SD, et al. Conditionally replicating herpes simplex virus mutant, G207 for the treatment of malignant glioma: results of a phase I trial. Gene Ther 2000;7:867-874.

15. Markert JM, Liechty PG, Wang W, et al. Phase Ib trial of mutant herpes simplex virus G207 inoculated pre-and post-tumor resection for recurrent GBM. Mol Ther 2009;17:199-207.

16. Markert JM, Razdan SN, Kuo H-C, et al. A phase 1 trial of oncolytic HSV-1, G207, given in combination with radiation for recurrent GBM demonstrates safety and radiographic responses. Mol Ther 2014;22:1048-1055.

17. Friedman GK, Bernstock JD, Chen D, et al. Enhanced sensitivity of patient-derived pediatric high-grade brain tumor xenografts to oncolytic HSV-1 virotherapy correlates with nectin-1 expression. Sci Rep 2018;8:13930-13930.

18. Friedman GK, Langford CP, Coleman JM, et al. Engineered herpes simplex viruses efficiently infect and kill CD133+ human glioma xenograft cells that express CD111. J Neurooncol 2009;95:199-209.

19. Friedman GK, Moore BP, Nan L, et al. Pediatric medulloblastoma xenografts including molecular subgroup 3 and CD133+ and CD15+ cells are sensitive to killing by oncolytic herpes simplex viruses. Neuro Oncol 2016;18:227-235.

20. Bernstock JD, Vicario N, Li R, et al. Safety and efficacy of oncolytic HSV-1 G207 inoculated into the cerebellum of mice. Cancer Gene Ther 2020;27:246-255.

21. Carceller F, Fowkes LA, Khabra K, et al. Pseudoprogression in children, adolescents and young adults with non-brainstem high grade glioma and diffuse intrinsic pontine glioma. J Neurooncol 2016;129:109-121.

22. Andtbacka RHI, Kaufman HL, Collichio F, et al. Talimogene laherparepvec improves durable response rate in patients with advanced melanoma. J Clin Oncol 2015;33:2780-2788.

23. Desjardins A, Gromeier M, Herndon JE II, et al. Recurrent glioblastoma treated with recombinant poliovirus. N Engl J Med 2018;379:150-161.

24. Lang FF, Conrad C, Gomez-Manzano C, et al. Phase I study of DNX-2401 (Delta-24-RGD) oncolytic adenovirus: replication and immunotherapeutic effects in recurrent malignant glioma. J Clin Oncol 2018;36:1419-1427.

25. Kaufman HL, Amatruda T, Reid T, et al. Systemic versus local responses in melanoma patients treated with talimogene laherparepvec from a multi-institutional phase II study. J Immunother Cancer 2016;4:12-12.

26. Okada H, Weller M, Huang R, et al. Immunotherapy response assessment in neuro-oncology: a report of the RANO working group. Lancet Oncol 2015;16(15):e534-e542.

27. Taipale K, Liikanen I, Koski A, et al. Predictive and prognostic clinical variables in cancer patients treated with adenoviral oncolytic immunotherapy. Mol Ther 2016;24:1323-1332.

28. Marotel M, Hasim MS, Hagerman A, Ardolino M. The two-faces of NK cells in oncolytic virotherapy. Cytokine Growth Factor Rev 2020;56:59-68.

29. Kieran MW, Goumnerova L, Manley P, et al. Phase I study of gene-mediated cytotoxic immunotherapy with AdV-tk as adjuvant to surgery and radiation for pediatric malignant glioma and recurrent ependymoma. Neuro Oncol 2019;21:537-546.

30. Chiocca EA, Yu JS, Lukas RV, et al. Regulatable interleukin-12 gene therapy in patients with recurrent high-grade glioma: results of a phase 1 trial. Sci Transl Med 2019;11(505):eaaw5680-eaaw5680.

31. Foreman PM, Friedman GK, Cassady KA, Markert JM. Oncolytic virotherapy for the treatment of malignant glioma. Neurotherapeutics 2017;14:333-344.

32. Xu F, Lee FK, Morrow RA, et al. Seroprevalence of herpes simplex virus type 1 in children in the United States. J Pediatr 2007;151:374-377.

33. Lang A, Nikolich-Zugich J. Development and migration of protective CD8+ T cells into the nervous system following ocular herpes simplex virus-1 infection. J Immunol 2005;174:2919-2925.

34. Whitley RJ, Kern ER, Chatterjee S, Chou J, Roizman B. Replication, establishment of latency, and induced reactivation of herpes simplex virus gamma 1 34.5 deletion mutants in rodent models. J Clin Invest 1993;91:2837-2843.

35. Mackay A, Burford A, Molinari V, et al. Molecular, pathological, radiological, and immune profiling of non-brainstem pediatric high-grade glioma from the HERBY phase II randomized trial. Cancer Cell 2018;33(5):829-842.e5.

服务条款 | 隐私政策 | 联系我们