Ad-CD40L mobilizes CD4 T cells for the treatment of brainstem tumors.
Ad-CD40L mobilizes CD4 T cells for the treatment of brainstem tumors.
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AD-CD40L动员CD4 T细胞治疗脑干肿瘤。
DOI：
10.1093/neuonc/noaa126
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发表时间：
2020-12-18
期刊：
影响因子：
15.9
通讯作者：
Vile RG
中科院分区：
文献类型：
--
作者：
Wongthida P;Schuelke MR;Driscoll CB;Kottke T;Thompson JM;Tonne J;Stone C;Huff AL;Wetmore C;Davies JA;Parker AL;Evgin L;Vile RG
弥漫性中线胶质瘤，以前称为DIPG（弥漫性内在脑桥胶质瘤），是最致命的儿童脑干肿瘤，中位生存期不到一年。在此，我们研究了（i）将表达分化簇（CD）40配体（Ad-CD 40 L）的腺病毒直接递送至脑干肿瘤是否会诱导免疫介导的肿瘤清除，以及（ii）如果是，治疗是否与由于脑干中免疫介导的炎症引起的可管理的毒性相关。用Ad-CD 40 L治疗免疫活性小鼠脑干中的同基因胶质瘤，并测定存活率、毒性和免疫特征。在人类患者来源的弥漫性中线胶质瘤和免疫活性模型中测试了一种临床上可翻译的载体rAd-Δ24-CD 40 L，其复制将严格限制于肿瘤细胞。Ad-CD 40 L通过预先感染局限于脑干胶质瘤的表达诱导完全排斥反应，与免疫细胞浸润相关，其中CD 4 + T细胞是治疗的关键。直接瘤内注射Ad-CD 40 L到已建立的脑干肿瘤中可以提高生存率，并诱导一些完全治愈，但有一些急性毒性。RNA测序分析显示Ad-CD 40 L治疗诱导了与白细胞介素（IL）-6、IL-1β和肿瘤坏死因子α相关的神经炎性免疫应答。因此，为了产生其复制和转基因表达将严格限制于肿瘤细胞的载体，我们构建了rAd-Δ24-CD 40 L，其骨架已经进入弥漫性中线胶质瘤的临床试验。直接瘤内注射rAd-Δ24-CD 40 L，全身阻断IL-6和IL-1β，产生大量治愈，毒性易于控制。病毒介导的CD 40 L递送有可能有效治疗弥漫性中线胶质瘤，而不会产生强制性神经炎症相关毒性。
Diffuse midline glioma, formerly DIPG (diffuse intrinsic pontine glioma), is the deadliest pediatric brainstem tumor with median survival of less than one year. Here, we investigated (i) whether direct delivery of adenovirus-expressing cluster of differentiation (CD)40 ligand (Ad-CD40L) to brainstem tumors would induce immune-mediated tumor clearance and (ii) if so, whether therapy would be associated with a manageable toxicity due to immune-mediated inflammation in the brainstem. Syngeneic gliomas in the brainstems of immunocompetent mice were treated with Ad-CD40L and survival, toxicity, and immune profiles determined. A clinically translatable vector, whose replication would be tightly restricted to tumor cells, rAd-Δ24-CD40L, was tested in human patient–derived diffuse midline gliomas and immunocompetent models. Expression of Ad-CD40L restricted to brainstem gliomas by pre-infection induced complete rejection, associated with immune cell infiltration, of which CD4+ T cells were critical for therapy. Direct intratumoral injection of Ad-CD40L into established brainstem tumors improved survival and induced some complete cures but with some acute toxicity. RNA-sequencing analysis showed that Ad-CD40L therapy induced neuroinflammatory immune responses associated with interleukin (IL)-6, IL-1β, and tumor necrosis factor α. Therefore, to generate a vector whose replication, and transgene expression, would be tightly restricted to tumor cells, we constructed rAd-Δ24-CD40L, the backbone of which has already entered clinical trials for diffuse midline gliomas. Direct intratumoral injection of rAd-Δ24-CD40L, with systemic blockade of IL-6 and IL-1β, generated significant numbers of cures with readily manageable toxicity. Virus-mediated delivery of CD40L has the potential to be effective in treating diffuse midline gliomas without obligatory neuroinflammation-associated toxicity.
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DOI：
10.1083/jcb.85.3.890
发表时间：
1980-06
期刊：
The Journal of cell biology
影响因子：
--
作者：
McCarthy KD;de Vellis J
通讯作者：
de Vellis J
DOI：
10.1164/rccm.201309-1611oc
发表时间：
2014-04-01
影响因子：
24.7
作者：
Germain, Claire;Gnjatic, Sacha;Dieu-Nosjean, Marie-Caroline
通讯作者：
Dieu-Nosjean, Marie-Caroline
影响因子：
9.8
作者：
He L;Vanlandewijck M;Mäe MA;Andrae J;Ando K;Del Gaudio F;Nahar K;Lebouvier T;Laviña B;Gouveia L;Sun Y;Raschperger E;Segerstolpe Å;Liu J;Gustafsson S;Räsänen M;Zarb Y;Mochizuki N;Keller A;Lendahl U;Betsholtz C
通讯作者：
Betsholtz C
TNFRS OX40、4-1BB和CD40作为癌症免疫疗法的靶标。
影响因子：
7
作者：
Moran AE;Kovacsovics-Bankowski M;Weinberg AD
通讯作者：
Weinberg AD
DOI：
10.1016/j.neo.2015.12.002
发表时间：
2016-01
期刊：
Neoplasia (New York, N.Y.)
影响因子：
--
作者：
Misuraca KL;Hu G;Barton KL;Chung A;Becher OJ
通讯作者：
Becher OJ