肿瘤细胞治疗研究
英文原题：A phase I/II trial of WT1-specific TCR gene therapy for patients with acute myeloid leukemia and active disease post-allogeneic hematopoietic cell transplantation: skewing towards NK-like phenotype impairs T cell function and persistence.
这些发现提示AML驱动一种独特的T细胞功能障碍形式，凸显了需要采取保留T细胞适应性的靶向策略，从而最终提高AML细胞疗法的疗效。
异基因造血细胞移植（HCT）后复发和/或难治性急性髓系白血病（AML）通常是致命的。我们此前报道，HCT后使用表达Wilms肿瘤抗原1特异性T细胞受体（T TCR-C4）的EB病毒（EBV）特异性供者CD8+ T细胞进行免疫治疗，似乎可预防高危患者的复发。在这项I/II期临床试验（NCT01640301）中，我们评估了EBV或巨细胞病毒（CMV）特异性T TCR-C4在15例HCT后活动性AML患者中的安全性（主要终点）、持久性和疗效（次要终点）。输注耐受良好，未发生剂量限制性毒性或与产品相关的严重不良事件。然而，尽管EBV特异性T TCR-C4细胞相比CMV特异性T TCR-C4显示出更强的长期持久性潜力，T TCR-C4细胞并未明确改善结局。通过研究持久存在的T TCR-C4的命运，我们发现其向自然杀伤样（NKL）终末分化转变，这不同于实体瘤相关的经典耗竭程序。在一例患者中，阿扎胞苷治疗似乎减轻了这种NKL偏移，促进了T TCR-C4的持久性。这些发现表明，AML驱动了一种独特形式的T细胞功能障碍，凸显了需要采用靶向方法以保持T细胞适应性，最终提高AML细胞治疗的疗效。
Relapsed and/or refractory acute myeloid leukemia (AML) post-allogeneic hematopoietic cell transplantation (HCT) is usually fatal. We previously reported that post-HCT immunotherapy with Epstein-Barr virus (EBV)-specific donor CD8 + T cells engineered to express a Wilms Tumor Antigen 1-specific T-cell receptor (T TCR-C4 ) appeared to prevent relapse in high-risk patients. In this phase I/II clinical trial (NCT01640301), we evaluated safety (primary endpoint), persistence and efficacy (secondary endpoints) of EBV- or Cytomegalovirus (CMV)-specific T TCR-C4 in fifteen patients with active AML post-HCT. Infusions were well tolerated, with no dose-limiting toxicities or serious adverse events related to the product. However, T TCR-C4 cells did not clearly improve outcomes despite EBV-specific T TCR-C4 cells showing enhanced potential for prolonged persistence compared to CMV-specific T TCR-C4 . Investigating the fate of persisting T TCR-C4 , we identified a shift towards natural killer-like (NKL) terminal differentiation, distinct from solid tumor-associated canonical exhaustion programs. In one patient, treatment with azacitidine appeared to mitigate this NKL skewing, promoting T TCR-C4 persistence. These findings suggest that AML drives a distinct form of T-cell dysfunction, highlight the need for targeted approaches that preserve T-cell fitness, ultimately improving the efficacy of cellular therapies for AML.
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