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通过表达CD40L增强嵌合抗原受体修饰的T细胞的抗肿瘤活性

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发表于 2016-1-27 21:51:05 | 显示全部楼层 |阅读模式
Enhancing antitumor efficacy of chimeric antigen receptor T cells through constitutive CD40L expression.


Adoptive cell therapy with genetically modified T cells expressing a chimeric antigen receptor (CAR) is a promising therapy for patients with B-cell acute lymphoblastic leukemia. However, CAR-modified T cells (CAR T cells) have mostly failed in patients with solid tumors or low-grade B-cell malignancies including chronic lymphocytic leukemia with bulky lymph node involvement.Herein, we enhance the antitumor efficacy of CAR T cells through the constitutive expression of CD40 ligand (CD40L, CD154). T cells genetically modified to constitutively express CD40L (CD40L-modified T cells) demonstrated increased proliferation and secretion of proinflammatory TH1 cytokines. Further, CD40L-modified T cells augmented the immunogenicity of CD40(+) tumor cells by the upregulated surface expression of costimulatory molecules (CD80 and CD86), adhesion molecules (CD54, CD58, and CD70), human leukocyte antigen (HLA) molecules (Class I and HLA-DR), and the Fas-death receptor (CD95).
Additionally, CD40L-modified T cells induced maturation and secretion of the proinflammatory cytokine interleukin-12 by monocyte-derived dendritic cells. Finally, tumor-targeted CD19-specific CAR/CD40L T cells exhibited increased cytotoxicity against CD40(+) tumors and extended the survival of tumor-bearing mice in a xenotransplant model of CD19(+) systemic lymphoma. This preclinical data supports the clinical application of CAR T cells additionally modified to constitutively express CD40L with anticipated enhanced antitumor efficacy.


通过表达CD40L增强嵌合抗原受体修饰的T细胞的抗肿瘤活性
CAR-T细胞的过继细胞移植治疗已经成为一种治疗B细胞急性淋巴细胞白血病的有前途的治疗方式。然而,CAR-T细胞 对于实体肿瘤患者和初级B细胞恶性肿瘤患者包括慢性淋巴细胞性白血病,淋巴结肿大,淋巴结肿大等患者的治疗经常会出现失败。这篇文章中,我们通过CD40配体的结构性表达,能够增强CAR-T细胞的有效性。表达CD40L的T细胞证明了能够增加增殖能力和增加Th1型细胞因子的分泌。此外,通过上调肿瘤细胞表面表达的共刺激分子(CD80CD86),粘附分子(CD54CD58CD70),人类白细胞抗原(HLA)分子(I类和HLA-DR),和Fas死亡受体(CD95)。CD40L修饰的T细胞增加了对CD40阳性肿瘤细胞的免疫性。此外,通过单核细胞来源的树突状细胞,CD40L修饰的T细胞能够促进成熟和促炎性细胞因子白细胞介素12的分泌。最终,CD19 CAR-T细胞展示出了增强的细胞毒性,并且延长了CD19+)系统性淋巴瘤异种移植模型的荷瘤小鼠的生存期。
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