A phase I study of OncoVEXGM-CSF, a second-generation oncolytic herpes simplex virus expressing granulocyte macrophage colony-stimulating factor
A phase I study of OncoVEXGM-CSF, a second-generation oncolytic herpes simplex virus expressing granulocyte macrophage colony-stimulating factor
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DOI：
10.1158/1078-0432.ccr-06-0759
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发表时间：
2006-11-15
影响因子：
11.5
通讯作者：
Coombes, R. Charles
中科院分区：
文献类型：
--
作者：
Hu, Jennifer C. C.;Coffin, Robert S.;Coombes, R. Charles
目的：用表达粒细胞巨噬细胞集落刺激因子（OncoVEX（GM-CSF））的第二代溶瘤单纯疱疹病毒（HSV）进行I期临床试验，以确定病毒的安全性特征，寻找生物活性的证据，并确定后续研究的给药方案。乳腺癌、头颈癌和胃肠道癌以及先前治疗失败的恶性黑色素瘤。13例患者是在一个单一的剂量组，其中剂量为10（6），10（7）和10（8）空斑形成单位（pfu）/mL进行了测试，和17例患者是在一个多剂量组测试了一些剂量regiments.Results：病毒一般耐受性良好，局部炎症，红斑，发热反应的主要副作用。HSV血清阴性患者在10（7）pfu/mL时对注射的局部反应是剂量限制性的。因此，多次给药阶段以10（6）pfu/mL随后多次更高剂量（高达10（8）pfu/mL）测试血清转化HSV血清阴性患者，所有患者均耐受良好。观察生物活性（病毒复制、局部反应、粒细胞巨噬细胞集落刺激因子表达和HSV抗原相关肿瘤坏死）。局部反应和病毒复制的持续时间表明，每2至3周给药一次是适当的。26例患者治疗后活检中有19例含有残留肿瘤，其中14例显示肿瘤坏死，在某些情况下是广泛的，或凋亡。在所有病例中，坏死区域也被HSV强烈染色。对治疗的总体反应是，3例患者病情稳定，6例患者肿瘤变平（注射和/或未注射病变），4例患者显示未注射以及注射肿瘤的炎症，几乎在所有情况下，都变得inflamed.Conclusions：OncoVEX（GM-CSF）耐受性良好，可以安全地使用所述的多剂量方案给药。观察到抗肿瘤作用的证据。
Purpose: To conduct a phase I clinical trial with a second-generation oncolytic herpes simplex virus (HSV) expressing granulocyte macrophage colony-stimulating factor (OncoVEX(GM-CSF)) to determine the safety profile of the virus, look for evidence of biological activity, and identify a dosing schedule for later studies.Experimental Design: The virus was administered by intratumoral injection in patients with cutaneous or s.c. deposits of breast, head and neck and gastrointestinal cancers, and malignant melanoma who had failed prior therapy. Thirteen patients were in a single-dose group, where doses of 10(6), 10(7) and 10(8) plaque-forming units (pfu)/mL were tested, and 17 patients were in a multidose group testing a number of dose regimens.Results: The virus was generally well tolerated with local inflammation, erythema, and febrile responses being the main side effects. The local reaction to injection was dose limiting in HSV-seronegative patients at 10(7) pfu/mL. The multidosing phase thus tested seroconverting HSV-seronegative patients with 10(6) pfu/mL followed by multiple higher doses (up to 10(8) pfu/mL), which was well tolerated by all patients. Biological activity (virus replication, local reactions, granulocyte macrophage colony-stimulating factor expression, and HSV antigen-associated tumor necrosis), was observed. The duration of local reactions and virus replication suggested that dosing every 2 to 3 weeks was appropriate. Nineteen of 26 patient posttreatment biopsies contained residual tumor of which 14 showed tumor necrosis, which in some cases was extensive, or apoptosis. In all cases, areas of necrosis also strongly stained for HSV. The overall responses to treatment were that three patients had stable disease, six patients had tumors flattened (injected and/or uninjected lesions), and four patients showed inflammation of uninjected as well as the injected tumor, which, in nearly all cases, became inflamed.Conclusions: OncoVEX(GM-CSF) is well tolerated and can be safely administered using the multidosing protocol described. Evidence of an antitumor effect was seen.