Retroviral replicating vector-mediated gene therapy achieves long-term control of tumor recurrence and leads to durable anticancer immunity.
Retroviral replicating vector-mediated gene therapy achieves long-term control of tumor recurrence and leads to durable anticancer immunity.
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逆转录病毒复制载体介导的基因治疗可长期控制肿瘤复发，并导致耐用的抗癌免疫力。
DOI：
10.1093/neuonc/nox038
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发表时间：
2017-07-01
期刊：
影响因子：
15.9
通讯作者：
Kasahara N
中科院分区：
文献类型：
--
作者：
Hiraoka K;Inagaki A;Kato Y;Huang TT;Mitchell LA;Kamijima S;Takahashi M;Matsumoto H;Hacke K;Kruse CA;Ostertag D;Robbins JM;Gruber HE;Jolly DJ;Kasahara N
正在复发性高级别胶质瘤患者中评价Toca 511（一种编码酵母胞嘧啶脱氨酶的肿瘤选择性逆转录病毒复制载体（RRV））的前药激活剂基因治疗。非裂解性逆转录病毒感染导致RRV永久整合到癌细胞基因组中，将感染的癌细胞和后代转化为稳定的载体生产细胞，从而使肿瘤内的持续转导和病毒持久性成为可能。受感染肿瘤细胞中的胞嘧啶脱氨酶将抗真菌前药5-氟胞嘧啶转化为抗癌药物5-氟尿嘧啶，介导局部肿瘤破坏而无显著的全身不良反应。在这里，我们研究了这种方法在原位脑肿瘤模型中的治疗效果的机制，采用免疫缺陷宿主中的人类胶质瘤异种移植物和免疫活性宿主中的同基因小鼠胶质瘤。在这两种模型中，单次注射复制载体，然后给予前药，实现了长期生存的好处。在免疫缺陷模型中，肿瘤反复复发，但肿瘤的生物发光成像能够定制多药前药给药的时间表，持续控制疾病负担和长期生存。在免疫活性模型中，在仅1-2个周期的前药后观察到肿瘤信号的完全丧失，随后尽管前药停止，但长期存活而无复发>300天。长期存活者拒绝未感染的胶质瘤细胞的挑战，表明对天然肿瘤抗原的免疫反应，和免疫细胞耗竭显示出CD 4 + T细胞的关键作用。这些结果支持了RRV介导的前体药物-激活剂基因疗法的功效的双重作用机制：通过前体药物转化介导的细胞减少的长期肿瘤控制和抗肿瘤免疫的诱导。
Prodrug-activator gene therapy with Toca 511, a tumor-selective retroviral replicating vector (RRV) encoding yeast cytosine deaminase, is being evaluated in recurrent high-grade glioma patients. Nonlytic retroviral infection leads to permanent integration of RRV into the cancer cell genome, converting infected cancer cell and progeny into stable vector producer cells, enabling ongoing transduction and viral persistence within tumors. Cytosine deaminase in infected tumor cells converts the antifungal prodrug 5-fluorocytosine into the anticancer drug 5-fluorouracil, mediating local tumor destruction without significant systemic adverse effects. Here we investigated mechanisms underlying the therapeutic efficacy of this approach in orthotopic brain tumor models, employing both human glioma xenografts in immunodeficient hosts and syngeneic murine gliomas in immunocompetent hosts. In both models, a single injection of replicating vector followed by prodrug administration achieved long-term survival benefit. In the immunodeficient model, tumors recurred repeatedly, but bioluminescence imaging of tumors enabled tailored scheduling of multicycle prodrug administration, continued control of disease burden, and long-term survival. In the immunocompetent model, complete loss of tumor signal was observed after only 1–2 cycles of prodrug, followed by long-term survival without recurrence for >300 days despite discontinuation of prodrug. Long-term survivors rejected challenge with uninfected glioma cells, indicating immunological responses against native tumor antigens, and immune cell depletion showed a critical role for CD4+ T cells. These results support dual mechanisms of action contributing to the efficacy of RRV-mediated prodrug-activator gene therapy: long-term tumor control by prodrug conversion-mediated cytoreduction, and induction of antitumor immunity.
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影响因子：
12.4
作者：
Perez, Omar D.;Logg, Christopher R.;Jolly, Douglas J.
通讯作者：
Jolly, Douglas J.
影响因子：
5.4
作者：
Johnson, Susan;Eller, Michael;Streeck, Hendrik
通讯作者：
Streeck, Hendrik
影响因子：
4.1
作者：
Smilowitz, Henry M.;Weissenberger, Jakob;Laissue, Jean A.
通讯作者：
Laissue, Jean A.
影响因子：
5.3
作者：
MILLER, DG;ADAM, MA;MILLER, AD
通讯作者：
MILLER, AD
影响因子：
7.3
作者：
Haabeth OA;Tveita AA;Fauskanger M;Schjesvold F;Lorvik KB;Hofgaard PO;Omholt H;Munthe LA;Dembic Z;Corthay A;Bogen B
通讯作者：
Bogen B