Phase I study of MetXia-P450 gene therapy and oral cyclophosphamide for patients with advanced breast cancer or melanoma
Phase I study of MetXia-P450 gene therapy and oral cyclophosphamide for patients with advanced breast cancer or melanoma
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DOI：
10.1158/1078-0432.ccr-04-0155
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发表时间：
2005-02-15
影响因子：
11.5
通讯作者：
Harris, AL
中科院分区：
文献类型：
--
作者：
Braybrooke, JP;Slade, A;Harris, AL
目的：MetXa-P450是一种新型重组逆转录病毒载体，编码人细胞色素P450 2116型基因（CYP 2B 6）、大肠杆菌lacZ和新霉素抗性标记基因。细胞色素P450酶主要在肝脏中表达，并将前药环磷酰胺转化为活性磷酰胺芥末和丙烯醛。基于基因的CYP 2136到肿瘤部位的传递导致局部前体药物活化和在靶位点更高浓度的活性代谢物。实验设计：MetXa-P450在第1天和第2天直接注射到转移性皮肤肿瘤结节中，并在第7天对结节进行活检。第8 - 22天口服环磷酰胺（100 mg/m2）。重复口服环磷酰胺的后续周期2/4周。通过组织学和定量PCR分析测定活检样品中的基因转移水平。安全性评估是使用PCR进行的，用于注射后载体传播到血液中，并使用PCR和血清学分析检测复制病毒。次要终点包括临床反应、毒性以及通过测量癌胚抗原和5 T4抗体来评估抗肿瘤免疫反应。12名患有乳腺癌（n = 9）和黑素瘤（n = 3）的患者接受三种剂量水平的MetXa-P450（类似于8 × 10（5）、类似于8 × 10（6）和类似于8 × 10（7）lacZ转移单位/ mL）。该产品安全且耐受性良好。12例患者中有10例通过免疫组化在活检材料中检测到lacZ转基因，6例患者中有3例通过PCR检测到整合的病毒序列。1例（8%）乳腺癌患者有部分缓解，并接受了7个月的口服环磷酰胺治疗。4例（33%）患者病情稳定≥ 3个月，其余患者病情进展。初步的免疫学分析表明，在两名患者的抗肿瘤反应（部分反应在一名患者和稳定的疾病在一名patient）。结论：MetXia是安全和耐受性良好。在所有剂量水平下均检测到基因转移，并且抗肿瘤反应的初步建议表明MetXiaP 450应进行进一步的临床评估。
Purpose: MetXia-P450 is a novel recombinant retroviral vector that encodes the human cytochrome P450 type 2116 gene (CYP2B6), Escherichia coli lacZ, and neomycin resistance marker genes. Cytochrome P450 enzymes are primarily expressed in the liver and convert the prodrug cyclophosphamide to an active phosphoramide mustard and acrolein. Gene-based delivery of CYP2136 to the tumor site leads to local prodrug activation and higher concentrations of the active metabolites at the target site.Experimental Design: MetXia-P450 was directly injected into metastatic cutaneous tumor nodules on days I and 2 and nodules biopsied on day 7. Oral cyclophosphamide (100 mg/m(2)) was administered between days 8 and 22. Subsequent cycles of oral cyclophosphamide were repeated for 2 of 4 weeks. Gene transfer levels in biopsy samples were measured by histologic and quantitative PCR analyses. Safety assessments were made using PCR for vector dissemination to the blood after injection and using PCR and serologic analyses to detect replicating virus. Secondary end points included clinical response, toxicity, and evaluation of antitumor immune responses by measurement of carcinoembryonic antigen and 5T4 antibodies.Results: Twelve patients with breast cancer (n = 9) and melanoma (n = 3) received three dose levels of MetXia-P450 (similar to8 x 10(5), similar to8 x 10(6), and similar to8 x 10(7) lacZ transferring units/ mL). The product was safe and well tolerated. The lacZ transgene was detected in biopsy material by immunohistochemistry in 10 of 12 patients and integrated viral sequences by PCR in 3 of 6 patients. One (8 %) patient with breast cancer had a partial response and received 7 months of oral cyclophosphamide. Four (33 %) patients had stable disease for greater than or equal to 3 months and the rest had progressive disease. Preliminary immunologic analyses were suggestive of an antitumor response in two patients (partial response in one patient and stable disease in one patient).Conclusion: MetXia was safe and well tolerated. Gene transfer was detected at all dose levels, and the initial suggestion of an antitumor response indicates that MetXiaP450 should undergo further clinical assessment.