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一种用于ErbB(+)实体瘤肿瘤细胞CAR免疫治疗的创新型PTD-IVT-mRNA递送平台。

An Innovative PTD-IVT-mRNA Delivery Platform for CAR Immunotherapy of ErbB(+) Solid Tumor Neoplastic Cells.

作者信息

Georgiou-Siafis Sofia K, Miliotou Androulla N, Ntenti Charikleia, Pappas Ioannis S, Papadopoulou Lefkothea C

机构信息

Laboratory of Pharmacology, School of Pharmacy, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54124 Thessaloniki, Macedonia, Greece.

Laboratory of Pharmacology and Toxicology, Faculty of Veterinary Medicine, University of Thessaly, 43100 Karditsa, Thessaly, Greece.

出版信息

Biomedicines. 2022 Nov 10;10(11):2885. doi: 10.3390/biomedicines10112885.

DOI:10.3390/biomedicines10112885
PMID:36359405
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9687928/
Abstract

Chimeric antigen receptor (CAR) immunotherapy includes the genetic modification of immune cells to carry such a receptor and, thus, recognize cancer cell surface antigens. Viral transfection is currently the preferred method, but it carries the risk of -target mutagenicity. Other transfection platforms have thus been proposed, such the in vitro transcribed (IVT)-mRNAs. In this study, we exploited our innovative, patented delivery platform to produce protein transduction domain (PTD)-IVT-mRNAs for the expression of on NK-92 cells. CAR T1E-engineered NK-92 cells, harboring the sequence of T1E single-chain fragment variant (scFv) to recognize the ErbB receptor, bearing either CD28 or 4-1BB as co-stimulatory signaling domains, were prepared and assessed for their effectiveness in two different ErbB(+) cancer cell lines. Our results showed that the PTD-IVT-mRNA of was safely transduced and expressed into NK-92 cells. CAR T1E-engineered NK-92 cells provoked high levels of cell death (25-33%) as effector cells against both HSC-3 (oral squamous carcinoma) and MCF-7 (breast metastatic adenocarcinoma) human cells in the co-incubation assays. In conclusion, the application of our novel PTD-IVT-mRNA delivery platform to NK-92 cells gave promising results towards future CAR immunotherapy approaches.

摘要

嵌合抗原受体（CAR）免疫疗法包括对免疫细胞进行基因改造，使其携带这种受体，从而识别癌细胞表面抗原。病毒转染是目前的首选方法，但它存在靶向诱变的风险。因此，人们提出了其他转染平台，如体外转录（IVT）-mRNA。在本研究中，我们利用我们创新的专利递送平台生产蛋白转导结构域（PTD）-IVT-mRNA，用于在NK-92细胞中表达。制备了携带识别ErbB受体的T1E单链片段变体（scFv）序列、带有CD28或4-1BB作为共刺激信号结构域的CAR T1E工程化NK-92细胞，并评估了它们在两种不同的ErbB（+）癌细胞系中的有效性。我们的结果表明， 的PTD-IVT-mRNA被安全地转导并表达于NK-92细胞中。在共孵育试验中，CAR T1E工程化NK-92细胞作为效应细胞，对HSC-3（口腔鳞状癌）和MCF-7（乳腺转移性腺癌）两种人类细胞都引发了高水平的细胞死亡（25%-33%）。总之，我们新型的PTD-IVT-mRNA递送平台在NK-92细胞上的应用为未来的CAR免疫疗法带来了有希望的结果。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c77/9687928/930a70958a7b/biomedicines-10-02885-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c77/9687928/3abe68a0f2cc/biomedicines-10-02885-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c77/9687928/ae94d5195861/biomedicines-10-02885-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c77/9687928/0ecb647a2135/biomedicines-10-02885-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c77/9687928/0c6a0892c7ba/biomedicines-10-02885-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c77/9687928/b530e95b7bf9/biomedicines-10-02885-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c77/9687928/fb0e4d21832d/biomedicines-10-02885-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c77/9687928/15aa2befa9b7/biomedicines-10-02885-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c77/9687928/f12b8cd4c375/biomedicines-10-02885-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c77/9687928/930a70958a7b/biomedicines-10-02885-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c77/9687928/3abe68a0f2cc/biomedicines-10-02885-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c77/9687928/ae94d5195861/biomedicines-10-02885-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c77/9687928/0ecb647a2135/biomedicines-10-02885-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c77/9687928/0c6a0892c7ba/biomedicines-10-02885-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c77/9687928/b530e95b7bf9/biomedicines-10-02885-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c77/9687928/fb0e4d21832d/biomedicines-10-02885-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c77/9687928/15aa2befa9b7/biomedicines-10-02885-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c77/9687928/f12b8cd4c375/biomedicines-10-02885-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3c77/9687928/930a70958a7b/biomedicines-10-02885-g009.jpg

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