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嵌合抗原受体T细胞在恶性B淋巴瘤的治疗中疗效显著

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发表于 2015-8-30 11:21:42 | 显示全部楼层 |阅读模式
本帖最后由 爱康得 于 2015-8-30 11:28 编辑

Identification and selectiveexpansion of functionally superior T cells expressing chimeric antigenreceptors
Abstract
Background
T cells expressing chimeric antigen receptors (CARs)have shown exciting promise in cancer therapy, particularly in the treatment ofB-cell malignancies. However, optimization of CAR-T cell production remains atrial-and-error exercise due to a lack of phenotypic benchmarks that areclearly predictive of anti-tumor functionality. A close examination of thedynamic changes experienced by CAR-T cells upon stimulation can improveunderstanding of CAR–T-cell biology and identify potential points foroptimization in the production of highly functional T cells.
Methods Primary human T cells expressing asecond-generation, anti-CD19 CAR were systematically examined for changes inphenotypic and functional responses to antigen exposure over time. Multi-colorflow cytometry was performed to quantify dynamic changes in CAR-T cell viability,proliferation, as well as expression of various activation and exhaustionmarkers in response to varied antigen stimulation conditions.
Results
Stimulated CAR-T cells consistently bifurcate  into two distinct subpopulations, only one ofwhich (CARhi/CD25+) exhibit anti-tumor functions. The use of central memory Tcells as the
starting population and the resilience—but not antigendensity—of antigen-presenting cells used to expand CAR-T cells were identifiedas critical parameters that augment the production of functionally superior Tcells. We further demonstrate that the CARhi/CD25+subpopulation upregulatesPD-1 but is resistant to PD-L1-induced dysfunction.
Conclusions
CAR-T cells expanded ex vivo for adoptive T-cell therapy undergo dynamic phenotypic changesduring the expansion process and result in two distinct populations withdramatically different functional capacities. Significant and sustained CD25and CAR expression upregulation is predictive of robust anti-tumor functionalityin antigen-stimulated T cells, despite their correlation with persistent PD-1upregulation. The functionally superior subpopulation can be selectivelyaugmented by careful calibration of antigen stimulation and the enrichment ofcentral memory T-cell type.
爱康得生物编译:
背景
嵌合抗原受体T细胞在肿瘤的治疗中,特别是在恶性B淋巴瘤的治疗中显示出令人兴奋的疗效。然而由于缺乏可显著预测抗瘤功能的标准,因此CAR-T的生产优化仍处于探索阶段。通过密切监测CAR-T细胞激活时的动态变化,可帮助我们理解T细胞的生物学特点并发现那些可以用于优化生产高效CAR-T细胞的潜在点。
方式
表达第二代anti-CD19CAR分子的原代人类T细胞,被用于监测CAR-T在被抗原激活后表型的变化以及功能性的应答。多色流式细胞仪被用于定量监测CAR-T细胞在响应抗原时的增殖和存活力的动态变化,以及与与激活和耗竭有关的标记物的表达。
结果
经抗原激活的CAR-T细胞最终分化成两个不同的亚群,但只有CARhi/CD25 +亚群表达出抗肿瘤的作用,中枢记忆T细胞被认为是生产功能优越T细胞的关键点。我们进一步证明CARhi/ CD25 +亚群会上调的PD-1的表达,但是会耐受PD-L1引起的免疫抑制。
结论:
CAR-T细胞在体外扩增经历了动态的表型改变,并产生了两个具有不同功能的细胞亚群。显著的CD25CAR的表达量的上升预示着这些经抗体激活的T细胞将具备显著的抗肿瘤活性,与此同时也伴随着PD-1表达量的上升。这些具备优越功能的亚群细胞数量可通过调节抗原刺激和中枢记忆T细胞富集被选择性地扩大。

Identification and selective expansion of functionally superior T cells expressi.pdf

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