CAR-T（CAR-T）细胞疗法在非肿瘤性疾病中的应用
Chimeric antigen receptor T (CAR-T) cell therapy in non-oncological diseases.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
疫苗增强的 CAR-T 与宿主免疫交互排斥抗原异质性肿瘤
英文原题：Vaccine-boosted CAR T crosstalk with host immunity to reject tumors with antigen heterogeneity.
查看英文原题
Vaccine-boosted CAR T crosstalk with host immunity to reject tumors with antigen heterogeneity.
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中文摘要
嵌合抗原受体（CAR）T细胞疗法可有效治疗人类癌症，但CAR所识别抗原的丢失构成了主要障碍。我们发现，对CAR-T 细胞进行体内疫苗增强可触发内源性免疫系统的参与，从而规避抗原阴性肿瘤逃逸。疫苗增强的CAR-T 可促进树突状细胞（DC）向肿瘤的募集，增加DC对肿瘤抗原的摄取，并引发内源性抗肿瘤T细胞的初始激活。这一过程伴随着CAR-T 代谢向氧化磷酸化（OXPHOS）的转变，并且关键依赖于CAR-T 来源的IFN-γ。疫苗增强的CAR-T 所诱导的抗原扩散（AS）使得即使初始肿瘤有50%为CAR抗原阴性，也能实现一定比例的完全缓解，而通过基因扩增CAR-T 的IFN-γ表达可进一步增强对异质性肿瘤的控制。因此，CAR-T 细胞来源的IFN-γ在促进AS中发挥关键作用，而疫苗增强提供了一种可在临床上转化的策略，以驱动针对实体瘤的此类反应。
展开英文摘要原文
Chimeric antigen receptor (CAR) T cell therapy effectively treats human cancer, but the loss of the antigen recognized by the CAR poses a major obstacle.
We found that in vivo vaccine boosting of CAR T cells triggers the engagement of the endogenous immune system to circumvent antigen-negative tumor escape. Vaccine-boosted CAR T promoted dendritic cell (DC) recruitment to tumors, increased tumor antigen uptake by DCs, and elicited the priming of endogenous anti-tumor T cells.
This process was accompanied by shifts in CAR T metabolism toward oxidative phosphorylation (OXPHOS) and was critically dependent on CAR-T-derived IFN- . Antigen spreading (AS) induced by vaccine-boosted CAR T enabled a proportion of complete responses even when the initial tumor was 50% CAR antigen negative, and heterogeneous tumor control was further enhanced by the genetic amplification of CAR T IFN- expression.
Thus, CAR-T-cell-derived IFN- plays a critical role in promoting AS, and vaccine boosting provides a clinically translatable strategy to drive such responses against solid tumors.
论文信息
- 作者
- Ma L、Hostetler A、Morgan DM、Maiorino L、Sulkaj I、Whittaker CA、Neeser A、Pires IS
- 第一作者单位
- David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; The Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. Electronic address: leyuan.ma@pennmedicine.upenn.edu.United Kingdom
- 通讯作者单位
- David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA; Department of Materials Science and Engineering, MIT, Cambridge, MA 02139, USA; Department of Biological Engineering, MIT, Cambridge, MA 02139, USA; Ragon Institute of Massachusetts General Hospital, Cambridge, MA 02139, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. Electronic address: djirvine@mit.edu.United Kingdom
- 文献类型
- 非美国政府资助研究 · 美国 NIH 资助研究
- 期刊
- Cell2023 Jul 20
- 原文标识
- PubMed 37413990 · DOI 10.1016/j.cell.2023.06.002
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