Phase 1 clinical trial of adoptive immunotherapy using “off-the-shelf” activated natural killer cells in patients with refractory and relapsed acute myeloid leukemia

Boyiadzis, Michael; Agha, Mounzer; Redner, Robert L.; Sehgal, Alison R.; Im, Annie; Hou, Jing-Zhou; Farah, Rafic; Dorritie, Kathleen A.; Raptis, Anastasios; Lim, Seah H.; Wang, Hong; Lapteva, Natalia; Mei, Zhuyong; Butterfield, Lisa H.; Rooney, Cliona M.; Whiteside, Theresa L.

doi:10.1016/j.jcyt.2017.07.008

Cited by 126 publications

(111 citation statements)

References 22 publications

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“…16,17 As effector cells we employed continuously expanding human NK-92 cells. In several early stage clinical trials, unmodified NK-92 cells and a CD33-specific CAR-engineered variant have been safely applied as allogeneic off-the-shelf therapeutics to cancer patients, 41,[43][44][45][46] with clinical development of other CAR-expressing NK-92 derivatives ongoing (NCT03383978; clinicaltrials.gov). 47 Here, NK-92 cells were transduced with a lentiviral vector encoding an FLT3-specific CAR encompassing a scFv fragment of monoclonal antibody 4G8, 28 fused to a CD8α hinge region, the transmembrane domain of CD28, and CD28 and CD3ζ signaling domains.…”

Section: Discussionmentioning

confidence: 99%

“…47 Hence, in the murine model application of higher doses of the CAR NK cells, more frequent treatment intervals, or further extension of the treatment period may be necessary to achieve even more effective leukemia control. Prior to infusion into human cancer patients, NK-92 and CAR NK-92 cells have so far been irradiated with 10 Gy as a safety measure, 41,[43][44][45][46] which prevents further proliferation. Irradiation has no short-term effect on CAR-mediated cytotoxicity (Supporting Information Fig.…”

Section: Discussionmentioning

confidence: 99%

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Genetically engineered CAR NK cells display selective cytotoxicity against FLT3‐positive B‐ALL and inhibit in vivo leukemia growth

Oelsner

Waldmann

Billmeier

et al. 2019

Intl Journal of Cancer

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Chimeric antigen receptor (CAR)‐engineered natural killer (NK) cells represent a promising effector cell type for adoptive cancer immunotherapy. Both, genetically modified donor‐derived NK cells as well as continuously expanding NK‐92 cells are currently under clinical development. To enhance their therapeutic utility for the treatment of pre‐B‐cell acute lymphoblastic leukemia (B‐ALL), we engineered NK‐92 cells by lentiviral gene transfer to express a FMS‐like tyrosine kinase 3 (FLT3)‐specific CAR that contains a composite CD28‐CD3ζ signaling domain. FLT3 has primarily been described as a therapeutic target for acute myeloid leukemia, but overexpression of FLT3 has also been reported in B‐ALL. Exposure of FLT3‐positive targets to CAR NK‐92 cells resulted in conjugate formation between NK and leukemia cells, NK‐cell degranulation and selective cytotoxicity toward established B‐ALL cell lines and primary blasts that were resistant to parental NK‐92. In a SEM B‐ALL xenograft model in NOD‐SCID IL2R γnull mice, treatment with CAR NK‐92 but not parental NK‐92 cells markedly inhibited disease progression, demonstrating high antileukemic activity in vivo. As FLT3 is known to be also expressed on precursor cells, we assessed the feasibility of incorporating an inducible caspase‐9 (iCasp9) suicide switch to enhance safety of our approach. Upon addition of the chemical dimerizer AP20187 to NK‐92 cells coexpressing the FLT3‐specific CAR and iCasp9, rapid iCasp9 activation was observed, precluding further CAR‐mediated cytotoxicity. Our data demonstrate that B‐ALL can be effectively targeted by FLT3‐specific CAR NK cells which may complement CD19‐directed immunotherapies, particularly in cases of inherent or acquired resistance to the latter.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Genetically engineered CAR NK cells display selective cytotoxicity against FLT3‐positive B‐ALL and inhibit in vivo leukemia growth

Oelsner

Waldmann

Billmeier

et al. 2019

Intl Journal of Cancer

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“…The use of fresh versus cryopreserved cells is likely due to observed poor post-thaw viability and functionality of NK cells [49,50,58,59]. In one study directly comparing fresh NK cells and NK cells that had been frozen, thawed and re-cultured, it was shown that the cryopreserved cells did not show proliferation in the patients who received the cellular therapy [50].…”

Section: Cryopreserved Nk Cells In Clinical Trialsmentioning

confidence: 99%

“…Other clinical trials have opted for using fresh cells for the first infusion and cryopreserved cells for the rest, where it is challenging to provide consistent dosage and efficacy to patients between the fresh and cryopreserved cells [52]. Many of the clinical trials that did use cryopreserved NK cells referenced cell banks but made no mention of freezing medium formulation, freezing method, and so on [49,51,59,61].…”

Section: Cryopreserved Nk Cells In Clinical Trialsmentioning

confidence: 99%

Preservation of cell-based immunotherapies for clinical trials

Johnson

et al. 2019

Cytotherapy

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“…In addition, activated NK (aNK) cells generated from an IL-2-dependent human NK cell line (NK-92) have also undergone clinical evaluation. An ongoing Phase I trial of aNK in seven adult patients with RR-AML treated with two infusions of 1 to 3 × 10 9 cells/m 2 demonstrated no significant toxicities and clinical disease improvement in three patients (NCT00900809) [35].…”

Section: Alternative Sources Of Nk Cellsmentioning

confidence: 99%

Advances in Immunotherapy for Acute Myeloid Leukemia

2018

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Evasion of the host immune system is a key mechanism to promote malignant progression. Therapeutically targeting immune pathways has radically changed the treatment paradigm for solid and lymphoid tumors but has yet to be approved for myeloid malignancies. Here, we summarize the most recent advances in immunotherapy for acute myeloid leukemia. Topics reviewed here include adoptive cellular approaches (chimeric antigen receptor-T cells, natural killer and other immune cells), checkpoint inhibitors (anti-PD-1/PD-L1, anti-CTLA-4 and TIM-3) and vaccines (WT-1, HLA-A2 and hTERT). Emphasis is placed on agents with clear evidence of tumor-specific immune responses and/or clinical activity in early-phase trials. Despite concerns regarding heterogeneous antigen expression and cytokine release syndrome, immunotherapy remains a highly promising strategy for acute myeloid leukemia, particularly transplant-ineligible patients and minimal residual disease states.

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Phase 1 clinical trial of adoptive immunotherapy using “off-the-shelf” activated natural killer cells in patients with refractory and relapsed acute myeloid leukemia

Cited by 126 publications

References 22 publications

Genetically engineered CAR NK cells display selective cytotoxicity against FLT3‐positive B‐ALL and inhibit in vivo leukemia growth

Genetically engineered CAR NK cells display selective cytotoxicity against FLT3‐positive B‐ALL and inhibit in vivo leukemia growth

Preservation of cell-based immunotherapies for clinical trials

Advances in Immunotherapy for Acute Myeloid Leukemia

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