{"title":"人血小板裂解物通过减少细胞衰老和凋亡增强 CAR-Vδ2 T 细胞的体内活性","authors":"","doi":"10.1016/j.jcyt.2024.03.006","DOIUrl":null,"url":null,"abstract":"<div><h3>Background aims</h3><p>Vγ9Vδ2 T cells are an attractive cell platform for the off-the-shelf cancer immunotherapy as the result of their lack of alloreactivity and inherent multi-pronged cytotoxicity, which could be further amplified with chimeric antigen receptors (CARs). In this study, we sought to enhance the <em>in vivo</em> longevity of CAR-Vδ2 T cells by modulating <em>ex vivo</em> manufacturing conditions and selecting an optimal CAR costimulatory domain.</p></div><div><h3>Methods</h3><p>Specifically, we compared the anti-tumor activity of Vδ2 T cells expressing anti-CD19 CARs with costimulatory endodomains derived from CD28, 4-1BB or CD27 and generated in either standard fetal bovine serum (FBS)- or human platelet lysate (HPL)-supplemented medium.</p></div><div><h3>Results</h3><p>We found that HPL supported greater expansion of CAR-Vδ2 T cells with comparable <em>in vitro</em> cytotoxicity and cytokine secretion to FBS-expanded CAR-Vδ2 T cells. HPL-expanded CAR-Vδ2 T cells showed enhanced <em>in vivo</em> anti-tumor activity with longer T-cell persistence compared with FBS counterparts, with 4-1BB costimulated CAR showing the greatest activity. Mechanistically, HPL-expanded CAR Vδ2 T cells exhibited reduced apoptosis and senescence transcriptional pathways compared to FBS-expanded CAR-Vδ2 T cells and increased telomerase activity.</p></div><div><h3>Conclusions</h3><p>This study supports enhancement of therapeutic potency of CAR-Vδ2 T cells through a manufacturing improvement.</p></div>","PeriodicalId":50597,"journal":{"name":"Cytotherapy","volume":null,"pages":null},"PeriodicalIF":3.7000,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1465324924000951/pdfft?md5=6a0a4066a5ed48c9747f78a3f38ad023&pid=1-s2.0-S1465324924000951-main.pdf","citationCount":"0","resultStr":"{\"title\":\"Human platelet lysate enhances in vivo activity of CAR-Vδ2 T cells by reducing cellular senescence and apoptosis\",\"authors\":\"\",\"doi\":\"10.1016/j.jcyt.2024.03.006\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Background aims</h3><p>Vγ9Vδ2 T cells are an attractive cell platform for the off-the-shelf cancer immunotherapy as the result of their lack of alloreactivity and inherent multi-pronged cytotoxicity, which could be further amplified with chimeric antigen receptors (CARs). In this study, we sought to enhance the <em>in vivo</em> longevity of CAR-Vδ2 T cells by modulating <em>ex vivo</em> manufacturing conditions and selecting an optimal CAR costimulatory domain.</p></div><div><h3>Methods</h3><p>Specifically, we compared the anti-tumor activity of Vδ2 T cells expressing anti-CD19 CARs with costimulatory endodomains derived from CD28, 4-1BB or CD27 and generated in either standard fetal bovine serum (FBS)- or human platelet lysate (HPL)-supplemented medium.</p></div><div><h3>Results</h3><p>We found that HPL supported greater expansion of CAR-Vδ2 T cells with comparable <em>in vitro</em> cytotoxicity and cytokine secretion to FBS-expanded CAR-Vδ2 T cells. HPL-expanded CAR-Vδ2 T cells showed enhanced <em>in vivo</em> anti-tumor activity with longer T-cell persistence compared with FBS counterparts, with 4-1BB costimulated CAR showing the greatest activity. 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引用次数: 0
摘要
Vγ9Vδ2 T细胞因其缺乏异体活性和固有的多管齐下的细胞毒性而成为现成的癌症免疫疗法的一个有吸引力的细胞平台，嵌合抗原受体（CAR）可进一步增强这种毒性。在这项研究中，我们试图通过调节制造条件和选择最佳的 CAR costimulatory domain 来提高 CAR-Vδ2 T 细胞的寿命。具体来说，我们比较了在标准胎牛血清（FBS）或人血小板裂解液（HPL）补充培养基中生成的表达抗 CD19 CAR、具有来自 CD28、4-1BB 或 CD27 的成本刺激内域的 Vδ2 T 细胞的抗肿瘤活性。我们发现，HPL 支持 CAR-Vδ2 T 细胞的更大扩增，其细胞毒性和细胞因子分泌量与 FBS 扩增的 CAR-Vδ2 T 细胞相当。与FBS扩增的CAR-Vδ2 T细胞相比，HPL扩增的CAR-Vδ2 T细胞显示出更强的抗肿瘤活性，T细胞持续时间更长，其中4-1BB成本刺激的CAR显示出最强的活性。从机理上讲，与 FBS 扩增的 CAR-Vδ2 T 细胞相比，HPL 扩增的 CAR-Vδ2 T 细胞的凋亡和衰老转录通路减少，端粒酶活性增加。这项研究支持通过改进制造工艺来提高 CAR-Vδ2 T 细胞的治疗效力。
Human platelet lysate enhances in vivo activity of CAR-Vδ2 T cells by reducing cellular senescence and apoptosis
Background aims
Vγ9Vδ2 T cells are an attractive cell platform for the off-the-shelf cancer immunotherapy as the result of their lack of alloreactivity and inherent multi-pronged cytotoxicity, which could be further amplified with chimeric antigen receptors (CARs). In this study, we sought to enhance the in vivo longevity of CAR-Vδ2 T cells by modulating ex vivo manufacturing conditions and selecting an optimal CAR costimulatory domain.
Methods
Specifically, we compared the anti-tumor activity of Vδ2 T cells expressing anti-CD19 CARs with costimulatory endodomains derived from CD28, 4-1BB or CD27 and generated in either standard fetal bovine serum (FBS)- or human platelet lysate (HPL)-supplemented medium.
Results
We found that HPL supported greater expansion of CAR-Vδ2 T cells with comparable in vitro cytotoxicity and cytokine secretion to FBS-expanded CAR-Vδ2 T cells. HPL-expanded CAR-Vδ2 T cells showed enhanced in vivo anti-tumor activity with longer T-cell persistence compared with FBS counterparts, with 4-1BB costimulated CAR showing the greatest activity. Mechanistically, HPL-expanded CAR Vδ2 T cells exhibited reduced apoptosis and senescence transcriptional pathways compared to FBS-expanded CAR-Vδ2 T cells and increased telomerase activity.
Conclusions
This study supports enhancement of therapeutic potency of CAR-Vδ2 T cells through a manufacturing improvement.
期刊介绍：
The journal brings readers the latest developments in the fast moving field of cellular therapy in man. This includes cell therapy for cancer, immune disorders, inherited diseases, tissue repair and regenerative medicine. The journal covers the science, translational development and treatment with variety of cell types including hematopoietic stem cells, immune cells (dendritic cells, NK, cells, T cells, antigen presenting cells) mesenchymal stromal cells, adipose cells, nerve, muscle, vascular and endothelial cells, and induced pluripotential stem cells. We also welcome manuscripts on subcellular derivatives such as exosomes. A specific focus is on translational research that brings cell therapy to the clinic. Cytotherapy publishes original papers, reviews, position papers editorials, commentaries and letters to the editor. We welcome "Protocols in Cytotherapy" bringing standard operating procedure for production specific cell types for clinical use within the reach of the readership.
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