Phase IB Study of Gene-Mediated Cytotoxic Immunotherapy Adjuvant to Up-Front Surgery and Intensive Timing Radiation for Malignant Glioma
Phase IB Study of Gene-Mediated Cytotoxic Immunotherapy Adjuvant to Up-Front Surgery and Intensive Timing Radiation for Malignant Glioma
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DOI：
10.1200/jco.2011.35.5222
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发表时间：
2011-09-20
影响因子：
45.3
通讯作者：
New, Pamela Z.
中科院分区：
文献类型：
--
作者：
Chiocca, E. Antonio;Aguilar, Laura K.;New, Pamela Z.
目的尽管采用积极的治疗方法，恶性胶质瘤的中位生存期不到15个月。未甲基化的O-6-甲基鸟嘌呤-DNA甲基转移酶(MGMT)患者的病情更差，可能是因为替莫唑胺耐药。ADV-tk是一种含有单纯疱疹病毒胸苷激酶基因的腺病毒载体，与手术和放化疗具有协同作用，可杀伤肿瘤细胞，未表现出对MGMT的依赖，并产生抗肿瘤疫苗效应。患者和方法新诊断的恶性胶质瘤患者在手术时经肿瘤床注射ADV-tk 3×10(10)、1×10(11)或3×10(11)载体颗粒(VP)，然后服用万乃洛韦14天。在注射Adv-tk后9d内开始放射治疗，以与Adv-tk活性重叠。替莫唑胺在万乃洛韦治疗结束后使用。结果应计从2005年12月开始，在13个月内完成。13名患者入选，12名患者完成治疗，其中3名患者剂量水平为1和2，6名患者剂量水平为3。没有剂量限制或显著的附加毒性。一名患者因无关的手术并发症在完成前药前停药。2年生存率为33%，3年生存率为25%。患者报告的用癌症治疗脑功能评估(FACT-BR)评估的生活质量在治疗后稳定或改善。在治疗后分析的四个肿瘤中，有四个发现了显著的CD3(+)T细胞浸润。3例MGMT未甲基化的多形性胶质母细胞瘤患者分别存活6.5、8.7和46.4个月。结论AdV-tk联合万乃洛韦治疗新诊断的恶性胶质瘤是安全的。替莫唑胺不能阻止免疫反应。虽然不是为了疗效，但生存和MGMT独立的趋势是令人鼓舞的。第二阶段的试验正在进行中。
PurposeDespite 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 and MethodsPatients with newly diagnosed malignant glioma received AdV-tk at 3 x 10(10), 1 x 10(11), or 3 x 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.ResultsAccrual 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.ConclusionAdV-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.