IL-2 activated NK cell immunotherapy of three children after haploidentical stem cell transplantation

Koehl, Ulrike; Sørensen, Jan Tind; Esser, Ruth; Zimmermann, Stefanie; Grüttner, Hans Peter; Tonn, Torsten; Seidl, Christian; Seifried, Erhard; Klingebiel, Thomas; Schwabe, Dirk

doi:10.1016/j.bcmd.2004.08.013

Cited by 125 publications

(111 citation statements)

References 23 publications

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“…17 We and others could show that NK cells can be used as adoptive immunotherapy after haploidentical SCT. 32,33 In addition, high levels of NK cells may be protective against the development of GvHD. 34 Immune reconstitution studies, to date, have not measured lymphocyte subsets in short intervals.…”

Section: Discussionmentioning

confidence: 99%

Immune recovery in children undergoing allogeneic stem cell transplantation: absolute CD8+CD3+ count reconstitution is associated with survival

Koehl

Bochennek

Zimmermann

et al. 2007

Bone Marrow Transplant

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To evaluate the correlation between kinetics of immune reconstitution and survival, we prospectively evaluated lymphocyte subsets in 32 paediatric patients undergoing allogeneic stem cell transplantation (SCT) for haematological malignancies. Four-colour flow cytometric analysis was performed at short intervals with a median follow-up of 4 years post SCT. A total of 50% of patients reached age-matched 5th percentile of natural killer, cytotoxic T, B and helper T cells 4, 9, 20 and 28 weeks after SCT, respectively, which increased to more than 80% within 1 year after SCT. Transplantation of peripheral blood stem cells (PBSC) seemed to elicit the fastest reconstitution of CD3 þ , CD4 þ CD3 þ , CD8 þ CD3 þ and naı¨ve T cells compared to bone marrow (BM) or CD34-selected PBSC, which did not differ. Most importantly, we observed a significantly higher number of survivors among patients whose CD8 þ CD3 þ absolute counts rose above the 5th percentile of age-matched normal levels during the first year post SCT compared to patients who never reached these levels (19/25 vs 0/7, Po0.001). This was still present in both subgroups, BM-and CD34-selected grafts (P ¼ 0.03, 0.02). These results from a small patient sample underline the importance of particular lymphocyte subsets for the outcome of children undergoing SCT. A larger study with detailed subset analysis is underway.

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Section: Discussionmentioning

confidence: 99%

Immune recovery in children undergoing allogeneic stem cell transplantation: absolute CD8+CD3+ count reconstitution is associated with survival

Koehl

Bochennek

Zimmermann

et al. 2007

Bone Marrow Transplant

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“…Following preliminary data from a pilot phase, 15,16 the primary objectives were to collect, purify and administer NK cell DLIs (NK-DLIs) pre-emptively in recipients of haploidentical stem cell transplants in a two-center phase II study (center A: Basel, Switzerland; center B: Frankfurt am Main, Germany). Target cell doses were X1.0 Â 10 7 /kg CD56 þ /CD3 À NK cells, with o1.0 Â 10 5 /kg contaminating CD3 þ T cells to address feasibility and toxicity of the procedure.…”

Section: Methodsmentioning

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

160

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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“…The two-step depletion procedure led to a median percentage of 0.04% CD3 þ cells associated with a median residual T-cell number of 280 Â 10 3 CD3 þ cells (range 45-1100 Â 10 3 CD3 þ ) in the final product. 43 Uharek reported on a yield of 42% with 74% purity and a 4 log T-cell depletion and a dose of 0.76 Â 10 7 /kg prior to activation with IL-2. This group infused NK cells that had been separated from the stem cell apheresis product on day þ 2 of haploidentical HSCT.…”

Section: Nk-cell Harvesting and Purificationmentioning

confidence: 99%

“…NK-cell infusion was well tolerated, two patients died of transplant-related complications, one patient died of relapse. 43 Data available so far show that ex vivo purification of donor NK cells from leukapheresis products is technically feasible, and large numbers of CD56-positive, highly CD3-depleted cells can be obtained using the CliniMACS s twostep procedure of T-cell depletion and NK-cell enrichment. NK cells are infused without immediate adverse events and without inducing GvHD.…”

Section: Nk-cell Infusionmentioning

confidence: 99%

Use of natural killer cells in hematopoetic stem cell transplantation

Passweg

Stangel

Koehl

et al. 2005

Bone Marrow Transplant

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IL-2 activated NK cell immunotherapy of three children after haploidentical stem cell transplantation

Cited by 125 publications

References 23 publications

Immune recovery in children undergoing allogeneic stem cell transplantation: absolute CD8+CD3+ count reconstitution is associated with survival

Immune recovery in children undergoing allogeneic stem cell transplantation: absolute CD8+CD3+ count reconstitution is associated with survival

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

Use of natural killer cells in hematopoetic stem cell transplantation

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