Dynamic immune profiling identifies the stronger graft-versus-leukemia (GVL) effects with haploidentical allografts compared to HLA-matched stem cell transplantation

Guo, Huibin; Chang, Ying‐Jun; Hong, Yang; Xu, Lei; Wang, Yu; Zhang, Xiao-Hui; Wang, Ming; Chen, Huan; Chen, Yuhong; Wang, Feng-Rong; Wei-Han,; Sun, Yu‐Qian; Yan, Chen‐Hua; Tang, Fei‐Fei; Mo, Xiao‐Dong; Liu, Kai-Yan; Huang, Xiao‐Jun

doi:10.1038/s41423-020-00597-1

Cited by 59 publications

(49 citation statements)

References 44 publications

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“…Given the high IL-10 production observed after NK infusion, future studies should examine the contribution of IC in activating regulatory T cells and their role in GVT/GVHD/CRS in this model. In addition, increased TNF-α production by NK cells has been previously observed after haploidentical allogeneic HSCT ( 59 ), yet the decreased level noted in our model was still clinically significant. To determine if CRS was attenuating the GVT effect, adoptive transfer of purified, ex vivo activated TNFα -/- NK cells was performed and significantly attenuated tumor growth, suggesting that TNF-α production from ex vivo CD137L/IL-15/IL-15Rα activated NK cells may be contributing to a CRS that hinders anti-tumor effects.…”

Section: Discussionsupporting

confidence: 56%

Combining Immunocytokine and Ex Vivo Activated NK Cells as a Platform for Enhancing Graft-Versus-Tumor Effects Against GD2+ Murine Neuroblastoma

et al. 2021

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Management for high-risk neuroblastoma (NBL) has included autologous hematopoietic stem cell transplant (HSCT) and anti-GD2 immunotherapy, but survival remains around 50%. The aim of this study was to determine if allogeneic HSCT could serve as a platform for inducing a graft-versus-tumor (GVT) effect against NBL with combination immunocytokine and NK cells in a murine model. Lethally irradiated C57BL/6 (B6) x A/J recipients were transplanted with B6 bone marrow on Day +0. On day +10, allogeneic HSCT recipients were challenged with NXS2, a GD2+ NBL. On days +14-16, mice were treated with the anti-GD2 immunocytokine hu14.18-IL2. In select groups, hu14.18-IL2 was combined with infusions of B6 NK cells activated with IL-15/IL-15Rα and CD137L ex vivo. Allogeneic HSCT alone was insufficient to control NXS2 tumor growth, but the addition of hu14.18-IL2 controlled tumor growth and improved survival. Adoptive transfer of ex vivo CD137L/IL-15/IL-15Rα activated NK cells with or without hu14.18-IL2 exacerbated lethality. CD137L/IL-15/IL-15Rα activated NK cells showed enhanced cytotoxicity and produced high levels of TNF-α in vitro, but induced cytokine release syndrome (CRS) in vivo. Infusing Perforin-/- CD137L/IL-15/IL-15Rα activated NK cells had no impact on GVT, whereas TNF-α-/- CD137L/IL-15/IL-15Rα activated NK cells improved GVT by decreasing peripheral effector cell subsets while preserving tumor-infiltrating lymphocytes. Depletion of Ly49H+ NK cells also improved GVT. Using allogeneic HSCT for NBL is a viable platform for immunocytokines and ex vivo activated NK cell infusions, but must be balanced with induction of CRS. Regulation of TNFα or activating NK subsets may be needed to improve GVT effects.

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Section: Discussionsupporting

confidence: 56%

Combining Immunocytokine and Ex Vivo Activated NK Cells as a Platform for Enhancing Graft-Versus-Tumor Effects Against GD2+ Murine Neuroblastoma

et al. 2021

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“…It is conceivable at least from a theoretical standpoint that due to the broader HLA disparity in HaploSCT, the GVL effect is stronger in haploidentical compared with that of allogeneic transplantation from a sibling. We have recently observed a lower incidence of AML relapse with HaploSCT compared to MSD transplants with PTCy as GVHD prophylaxis [36], while we failed to demonstrate stronger GVL in haploidentical versus sibling allogeneic transplantation including in second allogeneic transplantation with haploidentical donors or broader GVHD prophylaxis protocols [33,34]. The magnitude of the GVL post-HaploSCT and thus post-transplantation RI may have to do with the type of anti-GVHD prophylaxis used [35].…”

Section: Discussionmentioning

confidence: 68%

“…Similar findings were reported by Li et al [18] comparing HaploSCT (n = 166) to MSD (n = 36) in Ph + ALL demonstrating a lower RI with HaploSCT of 14.8% vs 56.4% [17]. Importantly, in a very elegant recent paper Prof Xiao Jun Huang's group studied the immune cell dynamic response during leukemia development in a mouse model elucidating the immunological mechanism behind the stronger GVL in HaploSCT versus MSD transplants demonstrating decreased apoptosis and increased cytotoxic cytokine secretion by T and natural killer (NK) cells in the Haplo transplantation model [36]. Moreover, from a theoretical standpoint the strong anti-leukemia activity of the haploidentical allograft could be translated into superior survival by decreasing the NRM [37].…”

Section: Discussionmentioning

confidence: 99%

Outcome of haploidentical versus matched sibling donors in hematopoietic stem cell transplantation for adult patients with acute lymphoblastic leukemia: a study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation

et al. 2021

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Background Non-T-cell depleted haploidentical hematopoietic stem cell transplantation (HaploSCT) is being increasingly used in acute lymphoblastic leukemia (ALL) with improving patient outcomes. We have recently reported that outcomes of adult patients (pts) with ALL in complete remission (CR) receiving HaploSCT are comparable to unrelated donor transplants. We now compared HaploSCT and matched sibling donor (MSD) transplants in pts with ALL. Aim To assess transplantation outcomes of HaploSCT and MSD transplants in pts with ALL in CR. Methods We retrospectively analyzed adult patients (≥ 18 years) with ALL who underwent their first allogeneic stem cell transplantation (alloSCT) in first or second CR between 2012 and 2018, either from a T cell replete Haplo or MSD donor, and whose data were reported to the Acute Leukemia Working Party (ALWP) of the European Society for Blood and Marrow Transplantation (EBMT). Multivariate analysis (MVA) adjusting for differences between the groups was performed using the Cox proportional hazards regression model. Propensity score matching was also performed to reduce confounding effects. Results The analysis comprised 2304 patients: HaploSCT-413; MSD-1891. Median follow-up was 25 months. Median age was 37 (range 18–75) and 38 (18–76) years in HaploSCT and MSD, respectively. HaploSCT patients were transplanted more recently than those transplanted from MSD (2016 vs 2015, p < 0.0001). A higher rate of HaploSCT was in CR2 (33.4% vs 16.7%, p < 0.0001), respectively, and fewer received myeloablative conditioning (68% vs 83.2%, p < 0.0001). Cytomegalovirus (CMV) seropositivity was lower in HaploSCT patients (22% vs 28%, p = 0.01) and donors (27.1% vs 33%, p < 0.02), and a higher proportion of the HaploSCTs were performed using a bone marrow (BM) graft (46.2% vs 18.6%, p < 0.0001). The 2 groups did not differ with regard to gender, Karnofsky performance status score, ALL phenotype, Philadelphia chromosome (Ph) positivity and pre-alloSCT measurable residual disease (MRD). Graft versus host disease (GVHD) prophylaxis was mainly post-transplant cyclophosphamide (PTCy) based (92.7%) in the HaploSCT setting, while it was mostly pharmacologic in the setting of MSD (18.7% received ATG). Cumulative incidence of engraftment at day 60 was higher in MSD transplants compared to HaploSCT (98.7% vs 96.3%, p = 0.001), respectively. Day 180 incidence of acute (a) GVHD II-IV and III-IV was higher in HaploSCT vs. MSD: 36.3% vs 28.9% (p = 0.002 and 15.2% vs 10.5% (p = 0.005), respectively. Conversely, the 2-year chronic (c) GVHD and extensive cGVHD were 32% vs 38.8% (p = 0.009) and 11.9% vs 19.5% (p = 0.001) in HaploSCT vs MSD, respectively. Main causes of death were leukemia (31.8% vs 45%), infection (33.1% vs 19.7%) and GVHD (16.6% vs 19.7%) for HaploSCT and MSD, respectively. Two-year relapse incidence (RI), non-relapse mortality (NRM), leukemia-free survival (LFS), overall survival (OS) and GVHD-free, relapse-free survival (GRFS) were 26% vs 31.6%, 22.9% vs 13%, 51% vs 55.4%, 58.8% vs 67.4% and 40.6% vs 39% for HaploSCT and MSD, respectively. In the MVA, RI was significantly lower in HaploSCT in comparison with MSD, hazard ratio (HR) = 0.66 (95% CI 0.52–0.83, p = 0.004), while NRM was significantly higher, HR = 1.9 (95% CI 1.43–2.53, p < 0.0001). aGVHD grade II-IV and grade III-IV were higher in HaploSCT than in MSD HR = 1.53 (95% CI 1.23–1.9, p = 0.0002) and HR = 1.54 (95% CI 1.1–2.15, p = 0.011), respectively. Extensive cGVHD was lower in HaploSCT compared with MSD, HR = 0.61 (95% CI 0.43–0.88, p = 0.007), while total cGVHD did not differ significantly, HR = 0.94 (95% CI 0.74–1.18, p = 0.58). LFS, OS and GRFS did not differ significantly between the 2 transplant groups, HR = 0.96 (95% CI 0.81–1.14, p = 0.66); HR = 1.18 (95% CI 0.96–1.43, p = 0.11) and HR = 0.93 (95% CI 0.79–1.09, p = 0.37), respectively. These results were confirmed in a matched-pair analysis. Conclusions Outcomes of adult patients with ALL in CR receiving alloSCT from haploidentical donors are not significantly different from those receiving transplants from MSD in terms of LFS, OS and GRFS.

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“…There was higher percentage of cases in the positive pre-HSCT MRD group receiving haploidentical HSCT than in the negative pre-HSCT group (P=0.014). However, our previous studies demonstrated that, for ALL patients or acute myeloid leukemia patients, haploidentical HSCT had a superior anti-leukemia activity to MSDT [15,17,19,35] . Higher percentages of patients in the positive MRD groups received IFN-γ or DLI for relapse intervention than those of the negative MRD groups either pre-or post-HSCT (P=0.030 or <0.001, respectively) (table 1).…”

Section: Patient Characteristics and Transplant Outcomesmentioning

confidence: 94%

Predictive Value of Dynamic Peri-Transplantation MRD Assessed By MFC Either Alone or in Combination with Other Variables for Outcomes of Patients with T-Cell Acute Lymphoblastic Leukemia

Wang

et al. 2021

CURR MED SCI

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SummaryWe performed a retrospective analysis to investigate dynamic peri-hematopoietic stem cell transplantation (HSCT) minimal/measurable residual disease (MRD) on outcomes in patients with T-cell acute lymphoblastic leukemia (T-ALL). A total of 271 patients were enrolled and classified into three groups: unchanged negative MRD pre- and post-HSCT group (group A), post-MRD non-increase group (group B), and post-MRD increase group (group C). The patients in group B and group C experienced a higher cumulative incidence of relapse (CIR) (42% vs. 71% vs. 16%, P<0.001) and lower leukemia-free survival (LFS) (46% vs. 21% vs. 70%, P<0.001) and overall survival (OS) (50% vs. 28% vs. 72%, P<0.001) than in group A, but there was no significant difference in non-relapse mortality (NRM) among three groups (14% vs. 12% vs. 8%, P=0.752). Multivariate analysis showed that dynamic peri-HSCT MRD was associated with CIR (HR=2.392, 95% CI, 1.816–3.151, P<0.001), LFS (HR=1.964, 95% CI, 1.546–2.496, P<0.001) and OS (HR=1.731, 95% CI, 1.348–2.222, P<0.001). We also established a risk scoring system based on dynamic peri-HSCT MRD combined with remission status pre-HSCT and onset of chronic graft-verses-host disease (GVHD). This risk scoring system could better distinguish CIR (c=0.730) than that for pre-HSCT MRD (c=0.562), post-HSCT MRD (c=0.616) and pre- and post-MRD dynamics (c=0.648). Our results confirm the outcome predictive value of dynamic peri-HSCT MRD either alone or in combination with other variables for patients with T-ALL.

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Dynamic immune profiling identifies the stronger graft-versus-leukemia (GVL) effects with haploidentical allografts compared to HLA-matched stem cell transplantation

Cited by 59 publications

References 44 publications

Combining Immunocytokine and Ex Vivo Activated NK Cells as a Platform for Enhancing Graft-Versus-Tumor Effects Against GD2+ Murine Neuroblastoma

Combining Immunocytokine and Ex Vivo Activated NK Cells as a Platform for Enhancing Graft-Versus-Tumor Effects Against GD2+ Murine Neuroblastoma

Outcome of haploidentical versus matched sibling donors in hematopoietic stem cell transplantation for adult patients with acute lymphoblastic leukemia: a study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation

Predictive Value of Dynamic Peri-Transplantation MRD Assessed By MFC Either Alone or in Combination with Other Variables for Outcomes of Patients with T-Cell Acute Lymphoblastic Leukemia

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