James Cancer Hospital/Ohio State University Medical Center, N-1017 Doan Hall, 410 W. 10th Ave, Columbus, OH 43210, USA.
J Clin Oncol. 2011 Sep 20;29(27):3611-9. doi: 10.1200/JCO.2011.35.5222. Epub 2011 Aug 15.
Despite aggressive therapies, median survival for malignant gliomas is less than 15 months. Patients with unmethylated O(6)-methylguanine-DNA methyltransferase (MGMT) fare worse, presumably because of temozolomide resistance. AdV-tk, an adenoviral vector containing the herpes simplex virus thymidine kinase gene, plus prodrug synergizes with surgery and chemoradiotherapy, kills tumor cells, has not shown MGMT dependency, and elicits an antitumor vaccine effect.
Patients with newly diagnosed malignant glioma received AdV-tk at 3 × 10(10), 1 × 10(11), or 3 × 10(11) vector particles (vp) via tumor bed injection at time of surgery followed by 14 days of valacyclovir. Radiation was initiated within 9 days after AdV-tk injection to overlap with AdV-tk activity. Temozolomide was administered after completing valacyclovir treatment.
Accrual began December 2005 and was completed in 13 months. Thirteen patients were enrolled and 12 completed therapy, three at dose levels 1 and 2 and six at dose level 3. There were no dose-limiting or significant added toxicities. One patient withdrew before completing prodrug because of an unrelated surgical complication. Survival at 2 years was 33% and at 3 years was 25%. Patient-reported quality of life assessed with the Functional Assessment of Cancer Therapy-Brain (FACT-Br) was stable or improved after treatment. A significant CD3(+) T-cell infiltrate was found in four of four tumors analyzed after treatment. Three patients with MGMT unmethylated glioblastoma multiforme survived 6.5, 8.7, and 46.4 months.
AdV-tk plus valacyclovir can be safely delivered with surgery and accelerated radiation in newly diagnosed malignant gliomas. Temozolomide did not prevent immune responses. Although not powered for efficacy, the survival and MGMT independence trends are encouraging. A phase II trial is ongoing.
尽管采用了积极的治疗方法，恶性神经胶质瘤患者的中位生存期仍不足 15 个月。未甲基化 O(6)-甲基鸟嘌呤-DNA 甲基转移酶（MGMT）的患者预后更差，推测这是由于替莫唑胺耐药所致。携带单纯疱疹病毒胸苷激酶基因的腺病毒载体 AdV-tk 联合手术和放化疗具有协同作用，能杀伤肿瘤细胞，与 MGMT 无关，并且能引发抗肿瘤疫苗效应。
新诊断为恶性神经胶质瘤的患者在手术时于肿瘤床内注射 AdV-tk，剂量分别为 3×10(10)、1×10(11)或 3×10(11) 病毒颗粒（vp），同时在注射 AdV-tk 后 14 天内给予伐昔洛韦。放疗在注射 AdV-tk 后 9 天内开始，以与 AdV-tk 活性重叠。替莫唑胺在完成伐昔洛韦治疗后给予。
入组于 2005 年 12 月开始，在 13 个月内完成。共入组 13 例患者，12 例完成治疗，3 例接受剂量水平 1 和 2，6 例接受剂量水平 3。无剂量限制性毒性或显著附加毒性。1 例患者因无关的手术并发症在完成前体药物治疗前退出。2 年生存率为 33%，3 年生存率为 25%。用癌症治疗功能评估-脑（FACT-Br）量表评估的患者报告的生活质量在治疗后保持稳定或改善。治疗后对 4 例肿瘤中的 4 例进行分析，发现有明显的 CD3(+)T 细胞浸润。3 例未甲基化的胶质母细胞瘤多形性恶性神经胶质瘤患者分别存活了 6.5、8.7 和 46.4 个月。
AdV-tk 联合伐昔洛韦可与新诊断的恶性神经胶质瘤患者的手术和加速放疗安全联合应用。替莫唑胺不能预防免疫反应。尽管未进行疗效评价，但生存和 MGMT 独立性的趋势令人鼓舞。一项二期临床试验正在进行中。
