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Feasibility of intracerebrally administering multiple doses of genetically modified neural stem cells to locally produce chemotherapy in glioma patients.
Cancer Gene Therapy ( IF 4.8 ) Pub Date : 2020-09-08 , DOI: 10.1038/s41417-020-00219-y
Jana Portnow 1 , Behnam Badie 2 , M Suzette Blanchard 3 , Julie Kilpatrick 4 , Revathiswari Tirughana 5, 6 , Marianne Metz 5 , Shu Mi 7 , Vivi Tran 7 , Julie Ressler 8 , Massimo D'Apuzzo 9 , Karen S Aboody 5 , Timothy W Synold 7
Affiliation  

Neural stem cells (NSCs) are tumor tropic and can be genetically modified to produce anti-cancer therapies locally in the brain. In a prior first-in-human study we demonstrated that a single dose of intracerebrally administered allogeneic NSCs, which were retrovirally transduced to express cytosine deaminase (CD), tracked to glioma sites and converted oral 5-fluorocytosine (5-FC) to 5-fluorouracil (5-FU). The next step in the clinical development of this NSC-based anti-cancer strategy was to assess the feasibility of administering multiple intracerebral doses of CD-expressing NSCs (CD-NSCs) in patients with recurrent high-grade gliomas. CD-NSCs were given every 2 weeks using an indwelling brain catheter, followed each time by a 7-d course of oral 5-FC (and leucovorin in the final patient cohort). Fifteen evaluable patients received a median of 4 (range 2–10) intracerebral CD-NSC doses; doses were escalated from 50 × 106 to 150 × 106 CD-NSCs. Neuropharmacokinetic data confirmed that CD-NSCs continuously produced 5-FU in the brain during the course of 5-FC. There were no clinical signs of immunogenicity, and only three patients developed anti-NSC antibodies. Our results suggest intracerebral administration of serial doses of CD-NSCs is safe and feasible and identified a recommended dose for phase II testing of 150 × 106 CD-NSCs.



中文翻译:

脑内给予多剂量转基因神经干细胞以在胶质瘤患者中局部产生化学疗法的可行性。

神经干细胞 (NSC) 具有肿瘤嗜性,可以通过基因改造在大脑中局部产生抗癌疗法。在之前的首次人体研究中,我们证明了单剂量脑内给药的同种异体 NSC,经逆转录病毒转导表达胞嘧啶脱氨酶 (CD),追踪到胶质瘤部位并将口服 5-氟胞嘧啶 (5-FC) 转化为 5 -氟尿嘧啶(5-FU)。这种基于 NSC 的抗癌策略临床开发的下一步是评估在复发性高级别胶质瘤患者脑内给予多剂量表达 CD 的 NSC (CD-NSC) 的可行性。使用留置脑导管每 2 周给予 CD-NSC,然后每次口服 5-FC(最后一个患者队列中使用亚叶酸)的 7 天疗程。15 名可评估患者接受中位数为 4(范围 2-10)的脑内 CD-NSC 剂量;剂量从 50 × 106到 150 × 10 6 个CD-NSC。神经药代动力学数据证实,CD-NSCs 在 5-FC 过程中不断在大脑中产生 5-FU。没有免疫原性的临床迹象,只有 3 名患者产生了抗 NSC 抗体。我们的结果表明,脑内连续给药 CD-NSCs 是安全可行的,并确定了 150 × 10 6 CD-NSCs 的 II 期测试的推荐剂量。

更新日期:2020-09-08
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