scholarly journals Outcomes with Natural Killer Cells Infusion after Allogeneic Hematopoietic Stem Cell Transplantation: A Systematic Review and Meta-Analysis

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1847-1847
Author(s):  
Muhammad Umair Mushtaq ◽  
Moazzam Shahzad ◽  
Amna Y Shah ◽  
Muhammad Usman Zafar ◽  
Ezza Tariq ◽  
...  
Keyword(s):  
Systematic Review ◽  
Stem Cell ◽  
Natural Killer Cells ◽  
Nk Cells ◽  
Natural Killer ◽  
Research Funding ◽  
Meta Analysis ◽  
Killer Cells ◽  
Hematopoietic Stem ◽  
Relapsed Disease

Abstract Background: Natural killer cells (NK) are known to be the first cells that recover after allogeneic hematopoietic stem cell transplant (HCT). NK cells have anti-leukemic and anti-viral properties and are also implicated in the graft versus leukemia (GVL) effect without causing graft versus host disease (GVHD). There is emerging evidence supporting the use of NK cells post-transplant as adoptive immunotherapy to prevent or treat the relapse of hematologic malignancies. Here, we present a systematic review and meta-analysis aimed to investigate the outcomes with NK cells infusion after HCT. Methods: A detailed literature search was conducted for the systematic review and meta-analysis according to the guidelines mentioned in the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA). Population, intervention, comparison, and outcome (PICO) table was developed and three electronic databases (PubMed, Cochrane Library, and ClinicalTrials.gov) were searched through January 2021 using MeSH terms and keywords for "hematologic malignancy and natural killer cells" and "hematopoietic stem cell transplantation and natural killer cells". No filters or publication time limits were applied for the search. A total of 988 records were identified through database searching. After excluding duplicates, review, and non-relevant articles, we selected 9 studies that reported outcomes with NK cells infusion after HCT. Quality evaluation was done using the NIH quality assessment tool and Inter-study variance was calculated using the Der Simonian-Laird Estimator. Pooled analysis was done using the 'meta' package (Schwarzer et al, R programming language) and proportions with 95% confidence intervals (CI) were computed. Results: We identified 9 studies with a total of 149 participants. Out of these, 53 patients were from 4 studies using NK cells for the treatment of relapsed disease after HCT (therapeutic studies) and 96 patients were from 5 studies using NK cells to prevent relapse after HCT (pre-emptive studies). Therapeutic use of NK cells for relapsed disease after HCT: A total of 53 patients from 4 studies were evaluated. The median age of patients was 44.5 (1.9-69) years, and 40% patients were male. The median follow-up was 20 (1-69) months. Overall survival (OS) was reported by two studies at 2 years and was 36.3% and 55%. The pooled complete response (CR) was 18% (95% CI 0.06-0.33, I 2 =0%, n=37) and overall response rate (ORR) was 45% (95% CI 0.20-0.71, I 2 =71%, n=53). The pooled relapse rate was 65% (95% CI 0.32-0.92, I 2 =75%, n=42). The pooled incidence of acute GVHD and chronic GVHD was 15% (95% CI 0.03-0.31, I 2 =41%, n=53) and 8% (95% CI 0.01-0.18, I 2 =0%, n=53) respectively. Pre-emptive use of NK cells to prevent relapse after HCT: A total of 96 patients from 5 studies were evaluated. The median age of patients was 33.5 (2-75) years, and 48% patients were males. The median follow-up was 23.1 (8-81.6) months. The median OS was 1 (0.63-5) years. The pooled CR was 45% (95% CI 0.21-0.70, I 2 =76%, n=83) and ORR was 89% (95% CI 0.57-1.00, I 2 =77%, n=42). The pooled relapse rate was 35% (95% CI 0.20-0.52, I 2 =55%, n=96). The pooled incidence of acute GVHD and chronic GVHD was 30% (95%CI 0.14-0.48, I 2 =61%, n=96) and 8% (95%CI 0.00-0.24, I 2 =73%, n=96) respectively. Conclusion: Infusion of NK cells after HCT to prevent relapsed disease results in favorable outcomes with an acceptable toxicity profile. Optimal use of NK cells infusions after HCT is in a pre-emptive fashion to prevent relapsed disease and the efficacy of NK cells infusions after HCT in the setting of overt hematologic relapse is modest. Our findings suggest the need for large prospective clinical trials to establish the potential benefit of NK cells infusion after HCT to prevent relapse of hematologic malignancies without increased non-relapse mortality. Figure 1 Figure 1. Disclosures Abhyankar: Incyte/Therakos: Consultancy, Research Funding, Speakers Bureau. McGuirk: Bellicum Pharmaceuticals: Research Funding; Gamida Cell: Research Funding; Novartis: Research Funding; Novartis: Research Funding; EcoR1 Capital: Consultancy; Fresenius Biotech: Research Funding; Astelllas Pharma: Research Funding; Magenta Therapeutics: Consultancy, Honoraria, Research Funding; Juno Therapeutics: Consultancy, Honoraria, Research Funding; Allovir: Consultancy, Honoraria, Research Funding; Pluristem Therapeutics: Research Funding; Kite/ Gilead: Consultancy, Honoraria, Other: travel accommodations, expense, Kite a Gilead company, Research Funding, Speakers Bureau.

scholarly journals Impact of Natural Killer Cells Reconstitution on Outcomes after Allogenic Hematopoietic Stem Cell Transplantation: A Systematic Review and Meta-Analysis

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4880-4880
Author(s):  
Moazzam Shahzad ◽  
Amna Y Shah ◽  
Muhammad Usman Zafar ◽  
Ezza Tariq ◽  
Anam Hamid ◽  
...  
Keyword(s):  
Stem Cell ◽  
Nk Cells ◽  
Natural Killer ◽  
Hematopoietic Stem Cell ◽  
Research Funding ◽  
Hematopoietic Stem Cell Transplant ◽  
Acute Gvhd ◽  
Meta Analysis ◽  
Cell Transplant ◽  
Hematopoietic Stem

Abstract Background: Natural killer (NK) cells are the first cells to recover following allogeneic hematopoietic stem cell transplant (HSCT) and play a crucial role in enabling engraftment, preventing post-transplant infection and tumor relapse. In addition, NK cells also reduce the risk of graft versus host disease (GvHD) and increase the graft versus leukemia effect (GVL). The purpose of this systematic review and meta-analysis is to know the impact of NK cells reconstitution on outcomes of allogeneic HSCT. Methods: Following Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, a comprehensive literature search was conducted on PubMed, Cochrane Library, and ClinicalTrials.gov through January 2021. We used MeSH terms and keywords for "hematologic malignancies" OR "hematopoietic stem cell transplantation" AND "natural killer cells." No filters or publication time limits were applied for the search. A total of 13 studies were included after screening 988 records and excluding duplicates, review, and non-relevant articles. An arbitrary value of NK cell count of 22.2 cell/ul was set as a cut-off to divide between high and low groups of NK where applicable. Quality evaluation was done using the NIH quality assessment tool and Inter-study variance was calculated using Der Simonian-Laird Estimator. Pooled analysis was done using the 'meta' package (Schwarzer et al. R programming language), and proportions with 95% confidence intervals (CI) were computed. Results: A total of 1623 patients were evaluated from 13 studies. (Table 1) The median age of patients was 44 (8.6-63) years and 33.5% were males. The median duration of follow-up was 18 (0.3-122) months. The median 2-year overall survival (OS) for high NK cohort and low NK cohort was 77% (95%CI 0.70-0.83, I 2 =82%, n=982) and 52%(95%CI 0.38-0.67, I 2 =95%, n=982), respectively. The pooled rate of relapse in high NK group was 8% (95%CI 0.01-0.19, I 2 =83%, n=226) and it was 20% (95%CI 0.06-0.39, I 2 =90%, n=226) for low NK group. The pooled incidence of acute GvHD was 24% (95%CI 0.09-0.42, I 2 =91%, n=336) and 44% (95%CI 0.26-0.62, I 2 =91%, n=336) for high and low NK cohorts, respectively. The pooled incidence for viral infection for high NK group was 17% (95%CI 0.01-0.47, I 2 =98%, n=508) while it was 29% (95%CI 0.04-0.65, I 2 =98%, n=508) for low NK group, respectively. Conclusion: Higher reconstitution of NK cells after allogeneic hematopoietic stem cell transplant has a favorable impact on outcomes, including better overall survival and low incidence of relapse, acute GvHD, and viral infections. Our findings suggest the need for further prospective studies to investigate utility of NK cells infusion early post-transplant to improve clinical outcomes and survival. Figure 1 Figure 1. Disclosures McGuirk: Bellicum Pharmaceuticals: Research Funding; Novartis: Research Funding; EcoR1 Capital: Consultancy; Astelllas Pharma: Research Funding; Allovir: Consultancy, Honoraria, Research Funding; Novartis: Research Funding; Fresenius Biotech: Research Funding; Gamida Cell: Research Funding; Magenta Therapeutics: Consultancy, Honoraria, Research Funding; Kite/ Gilead: Consultancy, Honoraria, Other: travel accommodations, expense, Kite a Gilead company, Research Funding, Speakers Bureau; Juno Therapeutics: Consultancy, Honoraria, Research Funding; Pluristem Therapeutics: Research Funding.

Traditional Oriental Herbal Medicine and Natural Killer Cells for Cancer Patients: A Systematic Review and Meta-analysis

2017 ◽  
Vol 31 (4) ◽  
pp. 519-532 ◽  
Author(s):  
Kyeore Bae ◽  
Ji-hye Park ◽  
Jeehye Kim ◽  
Chong-kwan Cho ◽  
Byeongsang Oh ◽  
...  
Keyword(s):  
Systematic Review ◽  
Natural Killer Cells ◽  
Herbal Medicine ◽  
Natural Killer ◽  
Cancer Patients ◽  
Meta Analysis ◽  
Killer Cells

Circulating CD56 Bright Natural Killer Cells after Allogeneic Stem Cell Trasnplantation Express Functional TRAIL; Implication for a Novel Target of Immunotherapy.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5403-5403
Author(s):  
Sumiko Takao ◽  
Takayuki Ishikawa ◽  
Katsuyuki Ohmori ◽  
Atsumi Ishida ◽  
Takashi Uchiyama
Keyword(s):  
Stem Cell ◽  
Natural Killer Cells ◽  
Healthy Volunteers ◽  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Killer Cells ◽  
Concanamycin A ◽  
Group 2 ◽  
Group 1

Abstract Relapse of malignancies remains to be one of the major problems after allogeneic stem cell transplantation (allo-SCT). It is well-recognized that natural killer cells (NK-cells) are predominated in early phase of immune reconstitution after allo-SCT, and several studies demonstrated that CD56 bright CD16 negative (CD56++CD16−) NK-cells, which account for only a few percentage of peripheral NK-cells in healthy individuals, constitute a large subset of NK-cells at this phase. Although CD56++CD16− NK-cells possess unique ability to proliferate and produce proinflammatory cytokines in response to monokines or IL-2, they have been regarded to be less cytotoxic and unfavorable for graft-versus leukemia effects. To verify this issue, we compared the frequency of peripheral CD56++ NK-cells among total NK-cells with subsequent relapse in 25 allo-SCT recipients. Although the ratio of CD56++ NK-cells was gradually decreased as the increased duration between phlebotomy and allo-SCT, we could divide these patients into two groups. Group 1 was consisted of patients who showed consistently elevated ratio of CD56++ NK-cells, and the remainder was categorized into group 2. The relapse after allo-SCT was seen in 1 out of 8 patients in group 1, whereas it was documented in 5 out of 17 patients in group 2. This finding suggested that CD56++ NK-cells might also have a role in preventing relapse. We have found that peripheral CD56++CD16− NK-cells from patients after allo-SCT consistently expressed TNF-related apoptosis-inducing ligand (TRAIL), although its expression was faintly detectable on circulating NK-cells from healthy volunteers. As reported, stimulation with IL-2 or IL-15 resulted in the increased expression of TRAIL on NK-cells from healthy volunteers as well as the recipients of allo-SCT. However, its expression was always stronger in the CD16- subset than CD16+ in both groups. Cultivation of purified NK-cells from healthy volunteers with 0.5 nM of IL-2 for more than 2 weeks resulted in the expansion of both NK-cell subsets, and after sorting into CD16− and CD16+ NK-cells, cytotoxic assays against Jurkat were performed in the presence or absence of concanamycin A, neutralizing anti-Fas antibody, and neutralizing anti-TRAIL antibody. Cytotoxicity was more prominent in the CD16− subset than CD16+, and blocking study revealed that TRAIL expressed on CD16− NK-cells was strongly involved in the killing of Jurkat. We could not detect TRAIL-mediated cytotoxicity in the CD16+ subset, because the expression of TRAIL was much lower in the CD16+ subset than CD16−. Next, NK-cells purified from allo-SCT recipients and healthy volunteers were overnight cultured with 0.5 nM of IL-2 and their cytotoxicity against Jurkat was examined. NK-cells from patients who received allo-SCT within 3 months and those from healthy volunteers showed equivalent cytotoxicity. In patients who showed increased ratio of CD56++CD16− NK-cells, TRAIL was strongly expressed on overnight cultured CD56++CD16− NK cells, and TRAIL-mediated cytotoxicity was also detected. In murine models, TRAIL has been reported to exert strong graft-versus-tumor effects without causing GVHD. As CD56++CD16− NK cells readily express functional TRAIL on cytokine stimulation, and they usually reconstituted shortly early after allo-SCT, they may become promising targets for immunological intervention.

Jagged2 promotes the development of natural killer cells and the establishment of functional natural killer cell lines

Blood ◽  
2005 ◽  
Vol 105 (9) ◽  
pp. 3521-3527 ◽  
Author(s):  
Sarah L. DeHart ◽  
Marc J. Heikens ◽  
Schickwann Tsai
Keyword(s):  
Natural Killer Cells ◽  
Nk Cells ◽  
Natural Killer ◽  
Cell Lines ◽  
Nk Cell ◽  
Killer Cell ◽  
Interleukin 2 ◽  
Lymphoid Cells ◽  
Killer Cells ◽  
Hematopoietic Stem

AbstractEmerging evidence indicates that Notch receptors and their ligands play important roles in the development of T cells and B cells. However, little is known about their possible roles in the development of other lymphoid cells. Here we demonstrate that Jagged2, a Notch ligand, stimulates the development of natural killer (NK) cells from Lin- Sca-1+ c-kit+ hematopoietic stem cells. Our culture system supports NK cell development for 2 to 3 months, often leading to the establishment of continuous NK cell lines. The prototype of such cell lines is designated as KIL. KIL depends on interleukin-7 for survival and proliferation and is NK1.1+ CD3- TCRαβ- TCRδγ- CD4- CD8- CD19- CD25+ CD43+ CD45+ CD49b- CD51+ CD94+ NKG2D+ Mac-1-/low B220- c-kit+ perforin I+ granzyme B+ Notch-1+, and cytotoxic. Like normal natural killer cells, the T-cell receptor-β loci of KIL remain in the germ-line configuration. In response to interleukin-2, KIL proliferates extensively (increasing cell number by approximately 1010-fold) and terminally differentiates into adherent, hypergranular NK cells. Our findings indicate that Jagged2 stimulates the development of natural killer cells and the KIL cell line preserves most properties of the normal NK precursors. As such, KIL provides a valuable model system for NK cell research.

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