Complete Remission with Reduction of High-Risk Clones following Haploidentical NK-Cell Therapy against MDS and AML

Björklund, Andreas; Carlsten, Mattias; Sohlberg, Ebba; Liu, Lisa L.; Clancy, Trevor; Karimi, Mohsen; Cooley, Sarah; Miller, Jeffrey S.; Klimkowska, Monika; Schaffer, Marie; Watz, Emma; Wikström, Kristina; Blomberg, Pontus; Wahlin, Björn Engelbrekt; Palma, Marzia; Hansson, Lotta; Ljungman, Per; Hellström‐Lindberg, Eva; Ljunggren, Hans Gustaf; Malmberg, Karl Johan

doi:10.1158/1078-0432.ccr-17-3196

Cited by 144 publications

(140 citation statements)

References 43 publications

(63 reference statements)

Supporting

Mentioning

129

Contrasting

Unclassified

Order By: Relevance

“…In poor prognosis acute myeloid leukemia (AML) patients, NK cell infusions in combination with high dose chemotherapy and IL2 infusion resulted in in vivo expansion of NK cells and complete hematologic remission in 5 out of 19 patients (102). Similar results were more recently shown in elderly high risk AML patients (103), and in high-risk myelodysplastic syndrome (MDS), and again in AML patients (104), where alloreactive NK cells were found in the periphery of all patients and in the bone marrow of some. In neuroblastoma, high doses of NK cell infusions followed by anti-GD2 immunotherapy improved progression free survival, and patient NK cells had increased NKG2A expression (105).…”

Section: Nk Cell Immunotherapysupporting

confidence: 56%

NK Cell Metabolism and TGFβ – Implications for Immunotherapy

Slattery

Gardiner

2019

Front. Immunol.

View full text Add to dashboard Cite

NK cells are innate lymphocytes which play an essential role in protection against cancer and viral infection. Their functions are dictated by many factors including the receptors they express, cytokines they respond to and changes in the external environment. These cell processes are regulated within NK cells at many levels including genetic, epigenetic and expression (RNA and protein) levels. The last decade has revealed cellular metabolism as another level of immune regulation. Specific immune cells adopt metabolic configurations that support their functions, and this is a dynamic process with cells undergoing metabolic reprogramming during the course of an immune response. Upon activation with pro-inflammatory cytokines, NK cells upregulate both glycolysis and oxphos metabolic pathways and this supports their anti-cancer functions. Perturbation of these pathways inhibits NK cell effector functions. Anti-inflammatory cytokines such as TGFβ can inhibit metabolic changes and reduce functional outputs. Although a lot remains to be learned, our knowledge of potential molecular mechanisms involved is growing quickly. This review will discuss our current knowledge on the role of TGFβ in regulating NK cell metabolism and will draw on a wider knowledge base regarding TGFβ regulation of cellular metabolic pathways, in order to highlight potential ways in which TGFβ might be targeted to contribute to the exciting progress that is being made in terms of adoptive NK cell therapies for cancer.

show abstract

Section: Nk Cell Immunotherapysupporting

confidence: 56%

NK Cell Metabolism and TGFβ – Implications for Immunotherapy

Slattery

Gardiner

2019

Front. Immunol.

View full text Add to dashboard Cite

show abstract

“…Clinical evidence for this hypothesis comes from clinical trials conducted by several independent groups, which showed that NK cell transfusion may induce complete remissions in patients with high-risk acute myeloid leukemia (AML). [1][2][3][4][5] Furthermore, several groups reported associations apply to specific transplant settings: In the setting of HLA class I mismatched HCT, the missing-self hypothesis provides a consistent explanation for NK-cell activation. If inhibitory KIRs do not encounter their cognate ligands on target cells, NK cells may become activated and kill their targets.…”

Section: Introductionmentioning

confidence: 99%

External validation of models for KIR2DS1/KIR3DL1-informed selection of hematopoietic cell donors fails

Schetelig

Baldauf

Heidenreich

et al. 2020

Blood

View full text Add to dashboard Cite

Several studies suggest that harnessing natural killer (NK) cell reactivity mediated through killer cell immunoglobulin-like receptors (KIRs) could reduce the risk of relapse after allogeneic hematopoietic cell transplantation. Based on one promising model, information on KIR2DS1 and KIR3DL1 and their cognate ligands can be used to classify donors as KIR-advantageous or KIR-disadvantageous. This study was aimed at externally validating this model in unrelated donor hematopoietic cell transplantation. The impact of the predictor on overall survival (OS) and relapse incidence was tested in a Cox regression model adjusted for patient age, a modified disease risk index, Karnofsky performance status, donor age, HLA match, sex match, cytomegalovirus match, conditioning intensity, type of T-cell depletion, and graft type. Data from 2222 patients with acute myeloid leukemia or myelodysplastic syndrome were analyzed. KIR genes were typed by using high-resolution amplicon-based next-generation sequencing. In univariable analyses and subgroup analyses, OS and the cumulative incidence of relapse of patients with a KIR-advantageous donor were comparable to patients with a KIR-disadvantageous donor. The adjusted hazard ratio from the multivariable Cox regression model was 0.99 (Wald test, P = .93) for OS and 1.04 (Wald test, P = .78) for relapse incidence. We also tested the impact of activating donor KIR2DS1 and inhibition by KIR3DL1 separately but found no significant impact on OS and the risk of relapse. Thus, our study shows that the proposed model does not universally predict NK-mediated disease control. Deeper knowledge of NK-mediated alloreactivity is necessary to predict its contribution to graft-versus-leukemia reactions and to eventually use KIR genotype information for donor selection.

show abstract

“…Additionally, 6 refractory patients became eligible for HSCT, suggesting the NK cell therapy may act as a bridge to transplant in otherwise refractory patients. [97] Trials currently enrolling with NK cells are shown in table 1. Chimeric-antigen receptor (CAR) T cells work similarly to NK cell therapy in that they both are endogenous immune regulators coopted to target malignant clones.…”

Section: Introductionmentioning

confidence: 99%

Disordered Immune Regulation and its Therapeutic Targeting in Myelodysplastic Syndromes

Ivy

Ferrell

2018

Curr Hematol Malig Rep

View full text Add to dashboard Cite

Immune alterations in MDS are complex, heterogeneous, and intertwined with clonal hematopoiesis and stromal cell dysfunction. Inflammation in MDS proceeds as a vicious cycle, mediated in large part by secreted factors, which induce cell death and activate innate immune signaling. Therapeutic targeting of this variable immune dysregulation has led to modest responses thus far, but incorporation of the growing repertoire of immunotherapy brings new potential for improved outcomes. The immune milieu is variable across the spectrum of MDS subtypes, with a changing balance of inflammatory and suppressive cellular forces from low- to high-risk disease.

show abstract

Complete Remission with Reduction of High-Risk Clones following Haploidentical NK-Cell Therapy against MDS and AML

Abstract: Experimental design: Sixteen patients received fludarabine/cyclophosphamide conditioning 68 combined with total lymphoid irradiation followed by adoptive immunotherapy with IL-2-69 activated haploidentical NK cells. 70

Cited by 144 publications

References 43 publications

NK Cell Metabolism and TGFβ – Implications for Immunotherapy

NK Cell Metabolism and TGFβ – Implications for Immunotherapy

External validation of models for KIR2DS1/KIR3DL1-informed selection of hematopoietic cell donors fails

Disordered Immune Regulation and its Therapeutic Targeting in Myelodysplastic Syndromes

Contact Info

Product

Resources

About