Cancer immunotherapy with enveloped self-amplifying mRNA CARG-2020 that modulates IL-12, IL-17 and PD-L1 pathways to prevent tumor recurrence.
Cancer immunotherapy with enveloped self-amplifying mRNA CARG-2020 that modulates IL-12, IL-17 and PD-L1 pathways to prevent tumor recurrence.
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DOI：
10.1016/j.apsb.2023.08.034
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发表时间：
2024-01
期刊：
影响因子：
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靶向多种免疫机制可以克服治疗耐药性，并进一步改善人类的癌症免疫治疗。在这里，我们描述了应用病毒样囊泡（VLV）单独和联合递送三种免疫调节剂，作为一种有前途的癌症免疫治疗方法。设计VLV载体以递送单链白细胞介素（IL）-12、靶向程序性死亡配体1（PD-L1）的短发夹RNA（shRNA）和显性阴性形式的IL-17受体A（dn-IL 17 RA）作为单一有效载荷或作为组合有效载荷。单独表达IL-12的VLV载体以及三价载体（命名为CARG-2020）的病灶内递送根除了大的已建立的肿瘤。然而，只有CARG-2020预防了肿瘤复发，并为荷瘤小鼠提供了长期生存益处，表明联合免疫调节的益处。CARG-2020对非注射对侧肿瘤的远位效应以及对肿瘤细胞再激发的保护作用表明免疫介导的保护机制和免疫记忆的建立。从机制上讲，CARG-2020有效激活Th 1免疫机制，抑制与T细胞耗竭和促癌炎症相关的基因表达。CARG-2020预防肿瘤复发和提供生存益处的能力使其成为开发人类癌症免疫疗法的有希望的候选者。CARG-2020递送单链IL-12、针对PD-L1的shRNA和IL-17 RA的拮抗剂。这些有效载荷刺激Th 1武装免疫，减少PD-L1表达，并抑制促癌炎症。
Targeting multiple immune mechanisms may overcome therapy resistance and further improve cancer immunotherapy for humans. Here, we describe the application of virus-like vesicles (VLV) for delivery of three immunomodulators alone and in combination, as a promising approach for cancer immunotherapy. VLV vectors were designed to deliver single chain interleukin (IL)-12, short-hairpin RNA (shRNA) targeting programmed death ligand 1 (PD-L1), and a dominant-negative form of IL-17 receptor A (dn-IL17RA) as a single payload or as a combination payload. Intralesional delivery of the VLV vector expressing IL-12 alone, as well as the trivalent vector (designated CARG-2020) eradicated large established tumors. However, only CARG-2020 prevented tumor recurrence and provided long-term survival benefit to the tumor-bearing mice, indicating a benefit of the combined immunomodulation. The abscopal effects of CARG-2020 on the non-injected contralateral tumors, as well as protection from the tumor cell re-challenge, suggest immune-mediated mechanism of protection and establishment of immunological memory. Mechanistically, CARG-2020 potently activates Th1 immune mechanisms and inhibits expression of genes related to T cell exhaustion and cancer-promoting inflammation. The ability of CARG-2020 to prevent tumor recurrence and to provide survival benefit makes it a promising candidate for its development for human cancer immunotherapy. CARG-2020 delivers a single chain IL-12, shRNA against PD-L1, and an antagonist of IL-17RA. These payloads stimulate Th1-armed immunity, reduce PD-L1 expression, and suppress cancer-promoting inflammation.
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影响因子：
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作者：
Capece D;Verzella D;Fischietti M;Zazzeroni F;Alesse E
通讯作者：
Alesse E
影响因子：
5.4
作者：
Gaddy, Daniel F.;Lyles, Douglas S.
通讯作者：
Lyles, Douglas S.
白细胞介素12对小鼠血管肉瘤的治疗作用与抗肿瘤细胞毒性T-淋巴细胞活性的增加无关。
影响因子：
8.8
作者：
Vizler, C;Rosato, A;Calderazzo, F;Quintieri, L;Fruscella, P;Wainstok de Calmanovici, R;Mantovani, A;Vecchi, A;Zanovello, P;Collavo, D
通讯作者：
Collavo, D
DOI：
10.4049/jimmunol.0902574
发表时间：
2010-03-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
He D;Li H;Yusuf N;Elmets CA;Li J;Mountz JD;Xu H
通讯作者：
Xu H
影响因子：
64.8
作者：
Coffelt, Seth B.;Kersten, Kelly;Doornebal, Chris W.;Weiden, Jorieke;Vrijland, Kim;Hau, Cheei-Sing;Verstegen, Niels J. M.;Ciampricotti, Metamia;Hawinkels, Lukas J. A. C.;Jonkers, Jos;de Visser, Karin E.
通讯作者：
de Visser, Karin E.