使用全源双阴性CD4-CAR-T细胞向T细胞恶性瘤
Karen Kai-Lin Fang1,2, Jongbok Lee1, Ismat Khatri1
1Toronto General Hospital Research Institute, Toronto, Ontario, Canada.
Journal for immunotherapy of cancer
|September 7, 2023
概括
用抗CD4仿真抗原受体 (CAR4) - DNTs进行基因工程的全原双阴性T细胞 (DNTs) 对T细胞恶性瘤具有强大的抗瘤活性. 这种CAR4-DNT疗法为患有复发/耐药T细胞急性淋巴细胞白血病和外围T细胞淋巴瘤的患者提供了一个有前途的新治疗方案.
科学领域:
- 免疫治疗是一种免疫疗法.
- 细胞疗法细胞疗法
- 在瘤学瘤学.
背景情况:
- 复发性/耐药性T细胞恶性瘤的治疗选择有限.
- 化学抗原受体 (CAR) -T细胞疗法在T细胞恶性瘤中面临挑战,原因是潜在的污染和兄弟杀戮.
- 全基双阴性T细胞 (DNTs) 是一个安全的,现成的细胞疗法候选人,可接受CAR转导.
研究的目的:
- 探索异性DNTs对T细胞恶性瘤的抗瘤活性.
- 评估抗CD4-CAR (CAR4) -DNTs在T细胞恶性瘤中采用细胞疗法的潜力.
主要方法:
- 健康的捐赠者衍生的异性DNTs的ex vivo扩张和CAR4转导.
- 使用细胞毒性测定和异种移植模型,评估DNT和CAR4-DNT对T细胞急性淋巴细胞白血病 (T-ALL) 和外围T细胞淋巴瘤 (PTCL) 的抗瘤活性.
- 通过过井和阻断测试来研究作用机制.
主要成果:
- 基DNTs在体外证明了对T-ALL和PTCL的内源性细胞毒性,在体内需要高剂量.
- CAR4转导显著增强了DNT功效,CAR4-DNTs对CD4+T-ALL和PTCL具有优越的细胞毒性.
- 在异种移植模型中,CAR4-DNTs有效地消除了T-ALL和PTCL细胞系和初级爆发,透瘤,延迟进展和延长存活. 用idelalisib进行预治疗提高了CAR4-DNT的持久性和有效性.
- 这些机制涉及LFA-1,NKG2D,以及穿孔素/granzyme B通路.
结论:
- 全基性CAR4-DNTs表明有效向T细胞恶性瘤.
- CAR4-DNTs代表了T细胞恶性瘤 (如T-ALL和PTCL) 的可行的采用细胞疗法.
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