Good manufacturing practice-compliant cell sorting and large-scale expansion of single KIR-positive alloreactive human natural killer cells for multiple infusions to leukemia patients

Siegler, Uwe; Meyer-Monard, Sandrine; Jörger, Simon; Stangel, Martin; Thewis, André; Gratwohl, Aloïs; Wodnar-Filipowicz, Aleksandra; Kalberer, Christian P.

doi:10.3109/14653241003786155

Cited by 83 publications

(84 citation statements)

References 51 publications

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“…Furthermore, in vitro NK cell activation and expansion to obtain higher doses of possibly more effective cell populations need to be studied. 26,27 Some single-center experiences showed a benefit of IL-2-stimulated NK cells compared with freshly isolated, resting NK cells with regard to the cytotoxicity against leukemic and tumor targets. 18,[28][29][30][31] This was due to a strong upregulation of the activating receptors NKp30, NKp44, NKp46 and NKG2D during IL-2 stimulation.…”

Section: Discussionmentioning

confidence: 99%

Pre-emptive immunotherapy with purified natural killer cells after haploidentical SCT: a prospective phase II study in two centers

Stangel

Passweg

Meyer-Monard

et al. 2012

Bone Marrow Transplant

163

124

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Adoptive immunotherapy with allogeneic purified natural killer (NK) cell products might exert graft-versus-tumor alloreactivity with little risk of GVHD. In a prospective phase II study in two centers, we administered purified NK cell products to high-risk patients treated with haploidentical T-cell-depleted SCT. Sixteen patients received a total of 29 NK cell infusions on days þ 3, þ 40 and þ 100 after transplantation. Median doses (and ranges) of infused NK-and T-cells per product were 1.21 (0.3-3.8) Â 10 7 /kg and 0.03 (0.004-0.72) Â 10 5 /kg, respectively. With a median follow-up of 5.8 years 4/16 patients are alive. Cause of death was relapse in five, GVHD in three, graft failure in three, and transplant related neurotoxicity in one patient. Four patients developed acute GVHDXgrade II, all receiving a total of X0.5 Â 10 5 T cells/kg. Compared with historical controls, NK cell infusions had no apparent effect on the rates of graft failure or relapse. Adoptive transfer of allogeneic NK cells is safe and feasible, but further studies are needed to determine the optimal dose and timing of NK cell therapy. Moreover, NK cell activation/expansion may be required to attain clinical benefit, while careful consideration must be given to the number of T cells infused.

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Section: Discussionmentioning

confidence: 99%

Pre-emptive immunotherapy with purified natural killer cells after haploidentical SCT: a prospective phase II study in two centers

Stangel

Passweg

Meyer-Monard

et al. 2012

Bone Marrow Transplant

163

124

View full text Add to dashboard Cite

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“…To overcome these limitations, this group is currently exploring ex vivo NK cell activation with 4-1BB ligand and IL-15, as well as alternative conditioning regimens, to enhance the expansion and persistence of transferred NK cells, 73 with ongoing clinical studies in relapsed/ refractory myeloma (NCT01313897). Ongoing pilot trials at other centers exploring alternative expansion techniques before infusion of haplo-identical NK cells derived from peripheral blood 74 (NCT01040026) or umbilical cord blood 75 (NCT01729091) following auto-HCT will provide further insight into the safety and potential efficacy of this approach in myeloma patients.…”

Section: Cellular Therapiesmentioning

confidence: 99%

Beyond consolidation: auto-SCT and immunotherapy for plasma cell myeloma

Lendvai

Cohen

Cho

2015

Bone Marrow Transplant

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Autologous hematopoietic cell transplantation (auto-HCT) is the standard consolidation therapy for plasma cell myeloma patients following induction therapy. Auto-HCT improves disease-free survival (DFS), but is generally not curative. The allogeneic HCT experience demonstrated that T-cell immunotherapy can confer long-term DFS. Preclinical and clinical data indicate that myelomaassociated Ags elicit humoral and cellular immune responses (IRs) in myeloma patients. These findings strongly suggest that the immunotherapeutic strategies, including immune checkpoint inhibitors, therapeutic cancer vaccines and adoptive cellular therapies, are promising avenues of clinical research that may be most applicable in the minimal residual disease state following auto-HCT. These strategies are designed to prime or augment antimyeloma IRs and promote a 'host-vs-myeloma' effect that may result in durable DFS. Innovative clinical trials investigating immune checkpoint inhibitors and cancer vaccines have demonstrated that robust immunity against myeloma-associated Ags can be elicited in the setting of auto-HCT. A diverse array of immunotherapeutic strategies have entered clinical trials in myeloma, including PD-1/PD-L1 inhibitors, DC/myeloma cell fusion vaccines and adoptive chimeric Ag receptor T-cell therapy, and further investigation of combinations of immunologic and pharmaceutical agents are expected in the near future. In this review, we will discuss the preclinical data supporting immunotherapy in auto-HCT for myeloma, clinical investigation of these strategies and the future prospects of immunotherapy in pursuit of the goal of curative therapy.

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“…Ex vivo expansion of NK cells, as previously mentioned, is one source of NK cells for immunotherapy. Progress has been made in this area: using CliniMACS-purified NK cells, Siegler et al 117 was able to expand single KIR-positive alloreactive NK cells for AML patients. In addition, Sutlu et al have designed an automated reactor able to expand NK cells from PB mononuclear cells and demonstrated that large amounts of high reactive NK cells can be produced and used for immunotherapy.…”

Section: Gmp Proceduresmentioning

confidence: 99%

Generation of natural killer cells from hematopoietic stem cells in vitro for immunotherapy

Luevano

Madrigal

2012

Cell Mol Immunol

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Good manufacturing practice-compliant cell sorting and large-scale expansion of single KIR-positive alloreactive human natural killer cells for multiple infusions to leukemia patients

Cited by 83 publications

References 51 publications

Pre-emptive immunotherapy with purified natural killer cells after haploidentical SCT: a prospective phase II study in two centers

Pre-emptive immunotherapy with purified natural killer cells after haploidentical SCT: a prospective phase II study in two centers

Beyond consolidation: auto-SCT and immunotherapy for plasma cell myeloma

Generation of natural killer cells from hematopoietic stem cells in vitro for immunotherapy

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