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首页> 外文期刊>The journal of clinical investigation >Gene therapy enhances chemotherapy tolerance and efficacy in glioblastoma patients
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Gene therapy enhances chemotherapy tolerance and efficacy in glioblastoma patients

机译：基因疗法增强胶质母细胞瘤患者的化疗耐受性和疗效

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BACKGROUND. Temozolomide (TMZ) is one of the most potent chemotherapy agents for the treatment of glioblastoma. Unfortunately, almost half of glioblastoma tumors are TMZ resistant due to overexpression of methylguanine methyltransferase (MGMT~(hi)). Coadministration of O~(6)-benzylguanine (O~(6)BG) can restore TMZ sensitivity, but causes off-target myelosuppression. Here, we conducted a prospective clinical trial to test whether gene therapy to confer O~(6)BG resistance in hematopoietic stem cells (HSCs) improves chemotherapy tolerance and outcome.METHODS. We enrolled 7 newly diagnosed glioblastoma patients with MGMT~(hi) tumors. Patients received autologous gene-modified HSCs following single-agent carmustine administration. After hematopoietic recovery, patients underwent O~(6)BG/TMZ chemotherapy in 28-day cycles. Serial blood samples and tumor images were collected throughout the study. Chemotherapy tolerance was determined by the observed myelosuppression and recovery following each cycle. Patient-specific biomathematical modeling of tumor growth was performed. Progression-free survival (PFS) and overall survival (OS) were also evaluated.RESULTS. Gene therapy permitted a significant increase in the mean number of tolerated O~(6)BG/TMZ cycles (4.4 cycles per patient, P < 0.05) compared with historical controls without gene therapy ( n = 7 patients, 1.7 cycles per patient). One patient tolerated an unprecedented 9 cycles and demonstrated long-term PFS without additional therapy. Overall, we observed a median PFS of 9 (range 3.5–57~(+)) months and OS of 20 (range 13–57~(+)) months. Furthermore, biomathematical modeling revealed markedly delayed tumor growth at lower cumulative TMZ doses in study patients compared with patients that received standard TMZ regimens without O~(6)BG.CONCLUSION. These data support further development of chemoprotective gene therapy in combination with O~(6)BG and TMZ for the treatment of glioblastoma and potentially other tumors with overexpression of MGMT.TRIAL REGISTRATION. Clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00669669","term_id":"NCT00669669"}}NCT00669669.FUNDING. R01CA114218, R01AI080326, R01HL098489, P30DK056465, K01DK076973, R01HL074162, R01CA164371, R01NS060752, U54CA143970.
机译：背景。替莫唑胺（TMZ）是治疗胶质母细胞瘤最有效的化疗药物之一。不幸的是，由于甲基鸟嘌呤甲基转移酶（MGMT_（hi））的过表达，几乎一半的胶质母细胞瘤肿瘤对TMZ具有抗性。 O〜（6）-苄基鸟嘌呤（O〜（6）BG）的共同给药可以恢复TMZ敏感性，但会引起脱靶性骨髓抑制。在这里，我们进行了一项前瞻性临床试验，以测试赋予造血干细胞（HSCs）O〜（6）BG耐药性的基因治疗是否能提高化疗耐受性和疗效。我们招募了7例新诊断为MGMT〜（hi）肿瘤的胶质母细胞瘤患者。在单剂卡莫司汀给药后，患者接受了自体基因修饰的HSC。造血恢复后，患者在28天的周期内接受了O〜（6）BG / TMZ化疗。在整个研究中收集了连续的血液样本和肿瘤图像。通过观察每个周期后的骨髓抑制和恢复来确定化疗耐受性。对肿瘤生长进行了患者特定的生物数学建模。还评估了无进展生存期（PFS）和总生存期（OS）。与没有基因治疗的历史对照组（n = 7例，每名患者1.7个周期）相比，基因治疗允许耐受的O〜（6）BG / TMZ周期的平均数显着增加（每名患者4.4个周期，P <0.05）。一名患者耐受史无前例的9个周期，并表现出长期的PFS而无需额外的治疗。总体而言，我们观察到PFS的中位数为9（3.5-57〜（+））个月，OS为20（13-57〜（+））个月。此外，生物数学模型显示，与未接受O〜（6）BG的标准TMZ方案的患者相比，研究患者以较低的累积TMZ剂量显着延迟了肿瘤的生长。这些数据支持与O〜（6）BG和TMZ联合使用的化学保护性基因疗法的进一步发展，用于治疗胶质母细胞瘤和可能具有MGMT过表达的其他肿瘤。 Clinicaltrials.gov {“ type”：“ clinical-trial”，“ attrs”：{“ text”：“ NCT00669669”，“ term_id”：“ NCT00669669”}} NCT00669669.FUNDING。 R01CA114218，R01AI080326，R01HL098489，P30DK056465，K01DK076973，R01HL074162，R01CA164371，R01NS060752，U54CA143970。

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