Natural killer cell activity influences outcome after T cell depleted stem cell transplantation from matched unrelated and haploidentical donors

Lang, Peter; Pfeiffer, Mat­thias; Teltschik, Heiko‐Manuel; Schlegel, Patrick; Feuchtinger, Tobias; Ebinger, Martin; Klingebiel, Thomas; Bader, Peter; Schlegel, Paul-Gerhard; Beck, James F.; Greil, Johann; Handgretinger, Rupert

doi:10.1016/j.beha.2011.04.009

Cited by 23 publications

(16 citation statements)

References 23 publications

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“…In several studies it was shown that NK-mediated leukemia control plays an important role after autologous and allogeneic transplantation (Lowdell et al, 2002; Ruggeri et al, 2002; Leung et al, 2004). Furthermore, reconstitution pattern of NK cell receptors and NK-mediated cytotoxic activity were correlated to relapse rate after haploidentical SCT in children (Pfeiffer et al, 2010; Lang et al, 2011). Studies with several solid tumor entities and AML have shown that treatment with HDACi and DNMTi could up regulate the expression of activating NK cell ligands, contributing to an enhanced NK cell-mediated killing of the different tumor entities (Rohner et al, 2007; Diermayr et al, 2008; López-Soto et al, 2009; Chávez-Blanco et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Influence of Histone Deacetylase Inhibitors and DNA-Methyltransferase Inhibitors on the NK Cell-Mediated Lysis of Pediatric B-Lineage Leukemia

Pfeiffer¹,

Burow²,

Schleicher³

et al. 2013

Front. Oncol.

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Epigenetic drugs like histone deacetylase inhibitors (HDACi) and DNA-methyltransferase inhibitors (DNMTi) have been shown to be effective against a variety of tumor entities. Among different molecular anticancer activities of epigenetic active substances, up-regulation of natural killer (NK) cell ligands was described to contribute to an enhanced NK cell-mediated killing of tumor cell lines. So far, no data is available on this effect in childhood acute lymphoblastic leukemia. We investigated the effect of two HDACi [vorinostat, valproic acid (VPA)] and two DNMTi (azacytidine, decitabine) on the viability, expression of NK ligands, and NK susceptibility of the pre-B-cell-ALL cell line MHH-CALL-4. Whereas vorinostat, azacytidine, and decitabine directly reduced viability of the cell line, VPA had no direct cytotoxic effect. NKG2D-ligands were expressed only at very low levels and not affected by epigenetic treatment. Higher expression was found for the DNAM-1 ligands with significant up regulation of CD112 after treatment with VPA (p = 0.02). No significant increase in lysis mediated by resting NK cells could be observed, whereas incubation of target cells with decitabine resulted in a significant increase in lysis mediated by IL-2 activated NK cells (p = 0.0051, p = 0.06 for azacytidine). Vorinostat and VPA could increase the lysis by expanded NK cells which was statistically not significant due to high inter-individual variability. Furthermore, HDACi but not DNMTi reduced the NK-mediated lysis of MHH-CALL-4 after incubation of effector cells. In conclusion, there is a synergistic effect between epigenetic drugs and NK cells against MHH-CALL-4 which is not as strong as in other tumor entities. In situations where NK-mediated control of leukemia is assumed or wanted, a sophisticated combination of single epigenetic drugs and ex vivo expanded NK cells is needed to maximize the synergistic effect of both treatment strategies and DNMTIs may be preferred based on the direct inhibitory effect of HDACi on NK cell cytotoxicity.

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Section: Discussionmentioning

confidence: 99%

Influence of Histone Deacetylase Inhibitors and DNA-Methyltransferase Inhibitors on the NK Cell-Mediated Lysis of Pediatric B-Lineage Leukemia

Pfeiffer¹,

Burow²,

Schleicher³

et al. 2013

Front. Oncol.

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“…In AML, a role for NK cells in controlling disease is supported by the association of improved outcome of patients who have high levels of NK cells following allogeneic stem cell transplant. 20, 21 Of note, it has been found that NK cells developing post chemotherapy and post transplant can have an immature phenotype; it has been suggested that these immature post-transplant NK cells have a reduced ability to kill recipient blast cells. 22, 23, 24 In the present study we found that post chemotherapy autologous NK cells and NK cells from HDs produced comparable lysis of AML blast cells treated with CSL362.…”

Section: Introductionmentioning

confidence: 99%

CD123 target validation and preclinical evaluation of ADCC activity of anti-CD123 antibody CSL362 in combination with NKs from AML patients in remission

et al. 2017

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Despite the heterogeneity of acute myeloid leukemia (AML), overexpression of the interleukin-3 receptor-α (CD123) on both the more differentiated leukemic blast and leukemic stem cells (LSCs) provides a therapeutic target for antibody treatment. Here we present data on the potential clinical activity of the monoclonal antibody CSL362, which binds to CD123 with high affinity. We first validated the expression of CD123 by 100% (52/52) of patient samples and the correlation of NPM1 and FLT3-ITD mutations with the high frequency of CD123 in AML. In vitro studies demonstrated that CSL362 potently induced antibody-dependent cell cytotoxicity (ADCC) of AML blasts including CD34+CD38−CD123+ LSCs by natural killer cells (NKs). Importantly, compared with healthy donor (HD) NKs, NKs drawn from AML patients in remission had a comparable ADCC activity against leukemic cells; of note, during remission, immature NKs were five times higher in AML patients than that in HDs. Significantly, we report a case where leukemic cells were resistant to autologous ADCC; however, the blasts were effectively lysed by CSL362 together with donor-derived NKs after allogeneic hematopoietic stem cell transplantation. These studies highlight CSL362 as a promising therapeutic option following chemotherapy and transplant so as to improve the outcome of AML patients.

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“…Here, NK-cells are regenerated from the transplant, and participate in the graft-versus-leukemia response. The effect can further be strengthened by additional adoptive transfer of enriched NK-cells, and this is frequently used in the post-transplant treatment of both adult and pediatric patients with acute leukemia [120][121][122][123][124]. This use of NK-cells as cellular therapeutics trough transplantation and/or adoptive transfer is an entirely different therapeutic modality from the recruitment of resident NK-cells through the administration of therapeutic anti-tumor abs, the focus of the present paragraph, although both effects can be combined.…”

Section: Nk-cells For Cancer Therapymentioning

confidence: 99%

Natural Killer (NK)- and T-Cell Engaging Antibody-Derived Therapeutics

2012

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Unmodified antibodies (abs) have been successful in the treatment of hematologic malignancies, but less so for the treatment of solid tumors. They trigger anti-tumor effects through their Fc-domains, and one way to improve their efficacy is to optimize their interaction with the effectors through Fc-engineering. Another way to empower abs is the design of bispecific abs and related fusion proteins allowing a narrower choice of effector cells. Here we review frequently chosen classes of effector cells, as well as common trigger molecules. Natural Killer (NK)-and T-cells are the most investigated populations in therapeutical approaches with bispecific agents until now. Catumaxomab, the first bispecific ab to receive drug approval, targets the tumor antigen Epithelial Cell Adhesion Molecule (EpCAM) and recruits T-cells via a binding site for the cell surface protein CD3. The next generation of recombinant ab-derivatives replaces the broadly reactive Fc-domain by a binding domain for a single selected trigger. Blinatumomab is the first clinically successful member of this class, targeting cancer cells via CD19 and engaging T-cells by CD3. Other investigators have developed related recombinant fusion proteins to recruit effectors, such as NK-cells and macrophages. The first such agents currently in preclinical and clinical development will be discussed.

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Natural killer cell activity influences outcome after T cell depleted stem cell transplantation from matched unrelated and haploidentical donors

Cited by 23 publications

References 23 publications

Influence of Histone Deacetylase Inhibitors and DNA-Methyltransferase Inhibitors on the NK Cell-Mediated Lysis of Pediatric B-Lineage Leukemia

Influence of Histone Deacetylase Inhibitors and DNA-Methyltransferase Inhibitors on the NK Cell-Mediated Lysis of Pediatric B-Lineage Leukemia

CD123 target validation and preclinical evaluation of ADCC activity of anti-CD123 antibody CSL362 in combination with NKs from AML patients in remission

Natural Killer (NK)- and T-Cell Engaging Antibody-Derived Therapeutics

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