Bifunctional cancer cell-based vaccine concomitantly drives direct tumor killing and antitumor immunity.
Bifunctional cancer cell-based vaccine concomitantly drives direct tumor killing and antitumor immunity.
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DOI：
10.1126/scitranslmed.abo4778
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发表时间：
2023-01-04
影响因子：
17.1
通讯作者：
中科院分区：
文献类型：
--
作者：
已知施用灭活的肿瘤细胞可诱导有效的抗肿瘤免疫应答;然而，这种方法的功效受限于其在诱导免疫应答之前不能杀死肿瘤细胞。与灭活的肿瘤细胞不同，活的肿瘤细胞具有追踪和靶向肿瘤的能力。在这里，我们开发了一种基于全癌细胞的双功能治疗剂，具有直接肿瘤杀伤和免疫刺激作用。我们使用CRISPR-Cas9通过敲除干扰素-β特异性受体将肿瘤细胞从干扰素-β（IFN-β）敏感性重新定位为抗性，随后将其工程化以释放免疫调节剂IFN-β和粒细胞-巨噬细胞集落刺激因子。这些工程化治疗性肿瘤细胞（ThTC）通过诱导半胱天冬酶介导的癌细胞凋亡、下调癌症相关成纤维细胞表达的血小板源性生长因子受体β以及激活抗肿瘤免疫细胞运输和抗原特异性T细胞活化信号传导，消除小鼠中已建立的胶质母细胞瘤肿瘤。ThTC的这种基于机制的功效转化为免疫活性和人源化小鼠的原发性、复发性和转移性癌症模型中的生存益处和长期免疫。在ThTC中掺入包含单纯疱疹病毒-1胸苷激酶和雷帕霉素激活的半胱天冬酶9的双开关确保了我们方法的安全性。用双功能疗法武装天然富含新抗原的肿瘤细胞代表了一种有前途的基于细胞的实体瘤免疫疗法，并建立了临床转化的路线图。
The administration of inactivated tumor cells is known to induce a potent antitumor immune response; however, the efficacy of such an approach is limited by its inability to kill tumor cells before inducing the immune responses. Unlike inactivated tumor cells, living tumor cells have the ability to track and target tumors. Here, we developed a bifunctional whole cancer cell–based therapeutic with direct tumor killing and immunostimulatory roles. We repurposed the tumor cells from interferon-β (IFN-β) sensitive to resistant using CRISPR-Cas9 by knocking out the IFN-β–specific receptor and subsequently engineered them to release immunomodulatory agents IFN-β and granulocyte-macrophage colony-stimulating factor. These engineered therapeutic tumor cells (ThTCs) eliminated established glioblastoma tumors in mice by inducing caspase-mediated cancer cell apoptosis, down-regulating cancer-associated fibroblast-expressed platelet-derived growth factor receptor β, and activating antitumor immune cell trafficking and antigen-specific T cell activation signaling. This mechanism-based efficacy of ThTCs translated into a survival benefit and long-term immunity in primary, recurrent, and metastatic cancer models in immunocompetent and humanized mice. The incorporation of a double kill-switch comprising herpes simplex virus–1 thymidine kinase and rapamycin-activated caspase 9 in ThTCs ensured the safety of our approach. Arming naturally neoantigen-rich tumor cells with bifunctional therapeutics represents a promising cell-based immunotherapy for solid tumors and establishes a road map toward clinical translation.
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DOI：
10.1084/jem.20120532
发表时间：
2012-10-22
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Hirschhorn-Cymerman D;Budhu S;Kitano S;Liu C;Zhao F;Zhong H;Lesokhin AM;Avogadri-Connors F;Yuan J;Li Y;Houghton AN;Merghoub T;Wolchok JD
通讯作者：
Wolchok JD
影响因子：
6.7
作者：
Burel JG;Apte SH;Groves PL;Klein K;McCarthy JS;Doolan DL
通讯作者：
Doolan DL
影响因子：
3.4
作者：
Dillman, RO;Beutel, LD;Nayak, SK
通讯作者：
Nayak, SK
影响因子：
3.4
作者：
Dillman, RO;Barth, NM;Nayak, SK
通讯作者：
Nayak, SK
原发性脑肿瘤的临床前肿瘤模型：挑战和机遇。
DOI：
10.1016/j.bbcan.2020.188458
发表时间：
2021-01
期刊：
Biochimica et biophysica acta. Reviews on cancer
影响因子：
--
作者：
Akter F;Simon B;de Boer NL;Redjal N;Wakimoto H;Shah K
通讯作者：
Shah K