Clinical effects of administering leukemia-specific donor T cells to patients with AML/MDS after allogeneic transplant
Clinical effects of administering leukemia-specific donor T cells to patients with AML/MDS after allogeneic transplant
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DOI：
10.1182/blood.2020009471
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发表时间：
2021-05-13
期刊：
影响因子：
20.3
通讯作者：
Leen, Ann M.
中科院分区：
文献类型：
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作者：
Lulla, Premal D.;Naik, Swati;Leen, Ann M.
异基因造血干细胞移植（HCT）后复发是急性髓细胞白血病（AML）或骨髓增生异常综合征（MDS）患者死亡的主要原因。供体淋巴细胞（DLI）的输注增强了移植物抗白血病（GVL）效应。然而，由于输注的淋巴细胞没有选择白血病特异性，GVL效应通常伴随着危及生命的移植物抗宿主病（GVHD），与同种异体反应性淋巴细胞的同时转移有关。因此，为了使GVHD最小化和GVL最大化，我们选择性地活化和扩增了对AML/MDS细胞表达的多种抗原（PRAME、WT 1、存活素和NY-ESO-1）具有反应性的干细胞供体来源的T细胞。证明白血病抗原特异性的产物由29个HCT供体产生。与DLIs相反，白血病特异性T细胞（mLSTs）选择性识别并杀死白血病抗原脉冲细胞，对受体的正常细胞没有体外活性。我们给25名试验入组者施用递增剂量的mLST（每平方米0.5至10 × 10（7）个细胞），其中17名具有高复发风险，8名患有复发性疾病。输注耐受性良好，未观察到>2级急性或广泛慢性GVHD。我们观察到体内抗白血病效应，转化为1.9年随访时尚未达到的中位无白血病生存期和总生存期以及活动性疾病队列的客观缓解（1例完全缓解和1例部分缓解）。总之，mLST用于预防和治疗HCT后的AML/MDS是安全且有前景的。
Relapse after allogeneic hematopoietic stemcell transplantation (HCT) is the leading cause of death in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Infusion of unselected donor lymphocytes (DLIs) enhances the graft-versus-leukemia (GVL) effect. However, because the infused lymphocytes are not selected for leukemia specificity, the GVL effect is often accompanied by life-threatening graft-versus-host disease (GVHD), related to the concurrent transfer of alloreactive lymphocytes. Thus, to minimize GVHD and maximize GVL, we selectively activated and expanded stem cell donor-derived T cells reactive to multiple antigens expressed by AML/MDS cells (PRAME, WT1, Survivin, and NY-ESO-1). Products that demonstrated leukemia antigen specificity were generated from 29 HCT donors. In contrast to DLIs, leukemia-specific T cells (mLSTs) selectively recognized and killed leukemia antigen-pulsed cells, with no activity against recipient's normal cells in vitro. We administered escalating doses of mLSTs (0.5 to 10 x 10(7) cells per square meter) to 25 trial enrollees, 17 with high risk of relapse and 8 with relapsed disease. Infusions were well tolerated with no grade >2 acute or extensive chronic GVHD seen. We observed antileukemia effects in vivo that translated into not-yet-reached median leukemia-free and overall survival at 1.9 years of follow-up and objective responses in the active disease cohort (1 complete response and 1 partial response). In summary, mLSTs are safe and promising for the prevention and treatment of AML/MDS after HCT.