CTRI/2021/09/036713尚未招募2 期
"Natural Killer(NK) Cell-based Immunotherapy for Acute Leukemia withAbatacept (CTLA4-Ig): Exploring the Crosstalk between NK cellsand Monocyte/ Macrophages."
Manashi Chakrabarti Foundation1 个研究点 分布在 1 个国家目标入组 20 人开始时间: 2021年1月10日最近更新:
试验速览
- 阶段
- 2 期
- 状态
- 尚未招募
- 发起方
- 入组人数
- 20
- 试验地点
- 1
- 主要终点
- The potential of CTLA4Ig in sparing and/or potentiating NK cell cytotoxicity is an unexplored and yet an exciting possibility in the field of cellular therapy with initial clinical data strongly suggesting a favourable impact of the molecule on NK cell function. This study will help in establishment of the mechanistic pathway underlying this phenomenon.
研究概览
简要总结
- Hematopoietic Cell Transplantation (HCT) remains the only curative option for majority of the patients with acute leukemia. However, disease progression (DP) remains the major cause for treatment failure in these patients. The advent of post-transplantation cyclophosphamide (PTCy) has resulted in an explosion of HCT from a Haploidentical family donor (HFD) over the last few years. Yet, the incidence of relapse after PTCy-based HFD-HCT has remained extremely high. Innovative and yet affordable cellular therapies, which would provide a potent anti-leukemia effect without increase in toxicity are an unmet need.
- Since its first use in late 1980, donor lymphocyte infusions (DLI) has been the only proven approach for treatment as well as prevention of DP after HCT. However, the use of DLI has been largely restricted to the treatment of overt or impending relapse, due to concerns regarding graft-versus-host disease (GVHD) mediated by T cells. On the other hand, the major non-T cell lymphocytes, the natural killer (NK) cells have shown to have strong anti-leukemia effect.
- In the context of allogeneic HCT, NK cells are the first lymphoid population to recover. However, the recovering NK cells belong to an immature phenotype with high expression of CD56 and inhibitory receptors. With maturation i.e. acquisition of CD56dim phenotype, the NK cells loose NKG2A expression as these cells are now ‘licensed’. It has been shown repeatedly that immature NK cells fail to exert cytotoxicity and might in-fact increase the risk of GVHD following an allogeneic HCT.
- Abatacept (CTLA4Ig) is a fusion construct of CTLA4 and Fc region of human IgG, which blocks T cell activation by avidly binding to CD80/86 and thus preventing the ligation of CD28. Animal studies had established the fact that NK cells were inherently resistant of to CTLA4Ig. We conjectured that CTLA4Ig if given before DLI might prevent T cell mediated GVHD and yet allow NK cell mediated anti-leukemia effect.
- We explored the efficacy of prophylactic DLI following CTLA4Ig (CTLA4Ig-DLI group, n=75), compared to conventional DLI (DLI group, n=50), in patients with advanced hematological malignancies receiving PTCy-based haploidentical transplantation. CTLA4Ig-DLI group had reduced incidence of GVHD as well as DP, with a superior recovery of mature NK cells. The next question that arose was if CTLA4Ig merely spared the NK cells or it augmented NK cell mediated cytotoxicity in any way.
- The mechanism through which CTLA4Ig influences proliferation and cytotoxicity of NK cells has not been elucidated. CTLA4Ig ligates with CD80 and CD86 ligands on monocyte/macrophages and dendritic cells. Macrophage polarisation has been shown to influence NK cell functions. The current study aims to explore the mechanistic pathway of crosstalk between NK cells and monocyte/macrophages in the presence of CTLA4Ig. Elucidation of this pathway might provide a unique platform for adoptive cellular therapy for acute leukemia.
研究设计
- 研究类型
- Interventional
- 分配方式
- Not Applicable
- 盲法
- Not Applicable
入排标准
- 年龄范围
- 2.00 Year(s) 至 65.00 Year(s)（—）
- 性别
- All
入选标准
- •Â· First allogeneic transplant.
- •Â· Age between 2 and 65 years.
- •Â· Patients must have a related donor that is HLA-matched at least 5 of 10 HLA A, B, C, DRB1, DQB.
- •Â· Cardiac function: Shortening fraction >25%; ejection fraction >40% · Estimated creatinine clearance greater than 50 mL/minute · Pulmonary function: DLCO ≥40% (adjusted for hemoglobin) and FEV1≥70%, oxygen saturation>91% · Liver function: direct (conjugated) bilirubin < 2x the upper limit of normal and ALT/AST < 2.5x the upper normal limit · No major organ disfunction · Signed informed consent.
排除标准
- •Â· Life expectancy less than 6 months · Patients with uncontrolled bacterial, viral or fungal infections (undergoing appropriate treatment and with progression of clinical symptoms) within 1 month prior to conditioning.
- •Patients with febrile illness or suspected minor infection should await clinical resolution prior to starting conditioning.
- •Â· Pregnant or breastfeeding patients · Patients seropositive for the human immunodeficiency virus (HIV) · Patient with active Hepatitis B or C determined by serology and/or NAAT not on treatment · Active hepatitis, bridging fibrosis or cirrhosis on liver biopsy (biopsy required for patients on chronic transfusion therapy for > 1 year and evidence of iron overload with ferritin >1000 ng/mL) · Patients with suitable 10/10 HLA matched related and unrelated donors.
结局指标
主要结局
The potential of CTLA4Ig in sparing and/or potentiating NK cell cytotoxicity is an unexplored and yet an exciting possibility in the field of cellular therapy with initial clinical data strongly suggesting a favourable impact of the molecule on NK cell function. This study will help in establishment of the mechanistic pathway underlying this phenomenon.
时间窗: 24 months
The exploration of the crosstalk between NK cells and monocyte/macrophages might uncover hitherto unknown pathways by which anti-leukemia activity of NK cells is potentiated.
时间窗: 24 months
次要结局
- The translational impact of unraveling the interaction between NK cells and monocyte/macrophages on exposure to CTLA4Ig might have a far-reaching impact in the field of cellular therapy, wherein a unique and more importantly, an affordable scalable platform for NK cell-based immunotherapy could be established, both in the context of HCT and without HCT.(24 months)
研究者
研究点 (1)
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