Natural killer cell therapy in children with relapsed leukemia

Rubnitz, Jeffrey E.; Inaba, Hiroto; Kang, Guolian; Gan, Kwan; Hartford, Christine; Dallas, Mari; Shook, David; Grüber, Tanja A.; Pui, Ching‐Hon; Leung, Wing

doi:10.1002/pbc.25555

Cited by 40 publications

(36 citation statements)

References 50 publications

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“…NK cells have been infused 2 months after related donor (matched or mismatched) HSCT 21 , 2 and 3 weeks after haploidentical HSCT 22 , or 3, 40, and 100 days after haploidentical HSCT 23 . 3 rd -party haploidentical NK cells have also been delivered approximately 3 months after autologous HSCT 15 or matched allogeneic HSCT 24 .…”

Section: Discussionmentioning

confidence: 99%

Haploidentical Natural Killer Cells Infused before Allogeneic Stem Cell Transplantation for Myeloid Malignancies: A Phase I Trial

Lee

Denman

Rondón

et al. 2016

Biology of Blood and Marrow Transplantation

123

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Allogeneic stem cell transplantation is an effective treatment for high-risk myeloid malignancies, but relapse remains the major post-transplant cause of treatment failure. Alloreactive NK cells mediate a potent antileukemic effect and may also enhance engraftment and reduce GvHD. Haploidentical transplants provide a setting in which NK cell alloreactivity can be manipulated, but are associated with high rates of GvHD. We performed a phase I study infusing escalating doses of NK cells from an HLA haploidentical related donor – selected for alloreactivity when possible – as a component of the preparative regimen for allotransplantation from a separate HLA identical donor. The goal of infusing third party alloreactive NK cells was to augment the antileukemic effect of the transplant without worsening GvHD, and thus improve the overall outcome of hematopoietic transplantation. Twenty-one patients with high-risk AML, MDS, or CML refractory or beyond first remission received a preparative regimen with busulfan and fludarabine followed by infusion of apheresis-derived, antibody-selected, and IL-2-activated NK cells. Doses were initially based on total nucleated cell content and later based on CD56+ cells to reduce variability. CD56+ content ranged from 0.02 to 8.32 × 106/kg. IL-2, 0.5 × 106 units/m2 SQ was administered daily for five days in the final cohort (n=10). CD3+ cells in the NK cell product were required to be <105/kg. Median relapse-free, overall, and GvHD-free/relapse-free survival for all patients enrolled was 102, 233, and 89 days, respectively. Five patients are alive, five patients died of transplant-related causes, and eleven patients died of relapse. Despite the small sample size, survival was highly associated with CD56+ cells delivered (p = 0.022) and development of ≥ Grade 3 GvHD (p = 0.006). There were nonsignificant trends toward higher survival rates in those receiving NK cells from KIR ligand mismatched donors and KIR-B haplotype donors. There was no association with disease type, remission at time of transplant, or KIR content. GvHD was not associated with TNC, CD56+, or CD3+ cells infused in the NK cell product or the stem cell product. This trial demonstrates a lack of major toxicity attributable to 3rd-party NK cell infusions delivered in combination with an HLA compatible allogeneic transplantation. The infusion of haploidentical alloreactive NK cells was well tolerated and did not interfere with engraftment or increase the rate of GvHD after allogeneic hematopoietic transplantation. Durable complete remissions occurred in five patients at high risk for disease recurrence. This approach is being further developed in a Phase I/II trial with ex vivo expanded NK cells to increase the NK cell dose with the objective of reducing relapse and improving the outcome of allogeneic hematopoietic transplantation for AML/MDS.

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Section: Discussionmentioning

confidence: 99%

Haploidentical Natural Killer Cells Infused before Allogeneic Stem Cell Transplantation for Myeloid Malignancies: A Phase I Trial

Lee

Denman

Rondón

et al. 2016

Biology of Blood and Marrow Transplantation

123

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“…NK cells have been shown to contribute significantly to the GVL effect, especially in haplo-identical MHC mismatched/KIR-mismatched settings[57–59]. Generally, NK Cells are considered to have lower allogenicity compared to T cells; nevertheless, NK-mediated…”

Section: Introductionmentioning

confidence: 99%

Challenges and opportunities of allogeneic donor-derived CAR T cells

Yang

Jacoby

Fry

2015

Current Opinion in Hematology

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Purpose of review As T cells engineered with chimeric antigen receptors (CARs) are entering advanced phases of clinical trial testing with promising results, the potential implications of use in an allogeneic environment is emerging as an important consideration. This review discusses the use of allogeneic CAR therapy, the potential effects of T cell receptor (TCR) signaling on CAR T cell efficacy, and the potential for TCR elimination to generate an off-the-shelf product. Recent findings The majority of preclinical and clinical data regarding allogeneic T cells are focused on safety of their use given the potential for graft versus host disease (GVHD) mediated by the T cell receptor expressed with the introduced CAR. Recent clinical trials using donor derived CAR T cells are using either rigorous patient selection or T cell selection (such as enrichment for virus-specific T cells, VST). Although no GVHD has been reported, the efficacy of the allogeneic CAR treatment needs to be optimized. Several pre-clinical models limit allogeneic CAR-driven GVHD by utilizing memory T cell selection, VST, gene-editing techniques or suicide gene engineering. Summary In the allogeneic environment, the potential effects of TCR signaling on the efficacy of CAR could affect the clinical responses with the use of donor-derived CAR T cells. Better understanding of the functionality of donor-derived T cells for therapy is essential for the development of universal effector cells for CAR therapy.

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“…In these other studies, the haploidentical NK cell products were processed in the same manner and the entirety of the purified NK cell product was administered without protocol defined NK cell dosing (doses administered ranged from 1.65 – 103 × 10 6 cells/kg CD56 + cells) 42, 44 . Consistent with our experience in these other trials, the use of haploidentical NKs in this experimental consolidation regimen was feasible and well tolerated.…”

Section: Discussionmentioning

confidence: 99%