Engineering CD19-specific T lymphocytes with interleukin-15 and a suicide gene to enhance their anti-lymphoma/leukemia effects and safety.
Engineering CD19-specific T lymphocytes with interleukin-15 and a suicide gene to enhance their anti-lymphoma/leukemia effects and safety.
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表达靶向CD 19抗原（CAR.19）的嵌合抗原受体（CAR）的T淋巴细胞可能对B细胞恶性肿瘤的治疗有价值。由于即使CAR含有CD 28共刺激胞内结构域，CAR.19+ T细胞的体内存活、扩增和抗淋巴瘤活性仍然不理想，因此我们产生了一种新的构建体，其还掺入了白细胞介素-15（IL 15）基因和基于诱导型半胱天冬酶-9的自杀基因（iC 9/CAR.19/IL 15）。我们发现，与CAR.19+ T细胞相比，iC 9/CAR.19/IL 15 + T细胞具有：（i）在抗原刺激后更大的数值扩增（体外扩增10倍，和3至15倍的体内扩增）和降低的细胞死亡率（对于iC 9/CAR.19/IL 15 + T细胞，膜联蛋白-V +/7-AAD+细胞为10% ± 6%，而CAR.19+ T细胞为32% ± 19%）;（ii）抗原刺激后程序性死亡1（PD-1）受体的表达减少19/IL 15 + T细胞的PD-1+细胞<15%对比CAR. 19 + T细胞>40%）;（iii）改善的体内抗肿瘤作用（肿瘤生长减少4.7至5.4倍）。此外，iC 9/CAR.19/IL 15 + T细胞在自杀基因的药理学激活后被有效消除。总之，这种策略安全地增加了CAR.19重定向T淋巴细胞的抗淋巴瘤/白血病作用，可能是治疗B细胞恶性肿瘤患者的一种有用方法。
T lymphocytes expressing a chimeric antigen receptor (CAR) targeting the CD19 antigen (CAR.19) may be of value for the therapy of B-cell malignancies. Because the in vivo survival, expansion and anti-lymphoma activity of CAR.19+ T cells remain suboptimal even when the CAR contains a CD28 costimulatory endodomain, we generated a novel construct that also incorporates the interleukin-15 (IL15) gene and an inducible caspase-9-based suicide gene (iC9/CAR.19/IL15). We found that compared to CAR.19+ T cells, iC9/CAR.19/IL15+ T cells had: (i) greater numeric expansion upon antigen stimulation (10-fold greater expansion in vitro, and 3 to 15 fold greater expansion in vivo) and reduced cell death rate (Annexin-V+/7-AAD+ cells 10% ± 6% for iC9/CAR.19/IL15+ T cells and 32% ± 19% CAR.19+ T cells); (ii) reduced expression of the programmed death 1 (PD-1) receptor upon antigen stimulation (PD-1+ cells <15% for iC9/CAR.19/IL15+ T cells versus >40% for CAR.19+ T cells); (iii) improved anti-tumor effects in vivo (from 4.7 to 5.4-fold reduced tumor growth). In addition, iC9/CAR.19/IL15+ T cells were efficiently eliminated upon pharmacologic activation of the suicide gene. In summary, this strategy safely increases the anti-lymphoma/leukemia effects of CAR.19-redirected T lymphocytes and may be a useful approach for treatment of patients with B-cell malignancies.
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