P1426: Wu-nk-101, an Allogeneic Memory Nk Cell, for the Treatment of Relapse or Refractory (r/r) Acute Myeloid Leukemia (aml)
Year: 2022
Type: article
Abstract: Background: Memory NK cells have emerged as being safe and effective for the treatment of AML. Memory NK are significantly more potent than conventional NK cells (cNK) with enhanced activity and functional persistence. WU-NK-101 is an ‘off-the-shelf’ Memory NK cell therapy product derived from healthy donor cells, generated using Wugen’s proprietary MONETA™ process and scaled for commercial utility. WU-NK-101 overcomes several limitations associated with NK cell therapy in AML and furthermore displays enhanced trafficking, metabolic fitness and functionality within the TME. Aims: To characterize WU-NK-101 and evaluate its anti-tumor activity in preclinical models of AML Methods: WU-NK-101 cells were phenotypically characterized using multidimensional mass cytometry (CyTOF). Functionality was evaluated using in vitro cytotoxicity assays against AML cell lines (TF-1, THP-1, and HL-60). Cells were characterized in conventional and tumor microenvironment (TME)-aligned media. Proteomic analysis of WU-NK-101 was performed using tandem-mass spectrometry. In vivo efficacy was evaluated in NSG mice bearing THP-1 AML tumors. Results: A recent clinical study of CIML-NK cells in R/R AML (NCT01898793) showed a CR/CRh/CRi rate of 47% with a median DOR of 9.4 months following a single dose. As a scaled-up off-the-shelf product, multiple infusions of WU-NK-101 may be administered to increase the area under the curve, enhance persistence, and improve depth of remission. WU-NK-101 displays elevated expression levels of activating receptors (NKG2D, NKp30, NKp44, DNAM-1, and TRAIL), as well as cytotoxic and functional markers (CD25, CD69, Ki67, and granzyme B), compared with cNK cells. In addition, WU-NK-101 exhibits enhanced in vitro potency against multiple leukemic cell lines versus cNK cells. In culture conditions that mimic the TME, an immunosuppressive, acidic and hypoglycemic environment, cNK cell function was strongly inhibited, while WU-NK-101 maintained its enhanced cytotoxic activity. Furthermore, WU-NK-101 exhibited enhanced glycolytic and mitochondrial oxidative phosphorylation capacity (i.e., metabolic fitness) compared with cNK cells. Proteomic analysis revealed that glucose metabolism pathways were augmented at basal state in conventional media whereas amino acid metabolism was upregulated in hypoglycemic and nutrient depleted TME conditions. These findings suggest that WU-NK-101 cells are highly resistant to immunosuppression and can overcome adverse tumor microenvironments. In vivo activity of WU-NK-101 was confirmed in an AML THP-1 xenograft model, where a single dose effectively reduced tumor burden relative to vehicle controls. Long-term persistence of WU-NK-101 and anti-THP-1 efficacy could be further enhanced upon repeated dosing and using fluorescently labeled WU-NK-101 cells, homing and penetration into the BM was observed. Summary/Conclusion: CIML-NK cells have been shown to be clinically safe, tolerable, and effective in patients with AML. WU-NK-101 is an optimized off-the-shelf Memory-like NK cell therapy being developed for AML and will soon be tested in patients. Pre-clinically, WU-NK-101 displayed improved homing to the BM, resistance to an adverse and immunosuppressive TME, and activity against AML cell lines both in vitro and in vivo. Repeated dosing further enhanced efficacy in vivo. The data presented here augur well for R/R AML patients who will be treated in the upcoming clinical study, WUN101-01. Furthermore, the functional characteristics of WU-NK-101 described here support consideration of additional indications including solid tumors.
Source: HemaSphere
Authors: J. J. Muth, M. E. Mathyer, B. Cruz, C. DuFour, T. Leedom, A. S. Hamil, S. Pouyanfard, M. Berrien-Elliot, L. Luukkonen, M. Tran, B. Tumala, N. Pomper, L. Arthur, M. Foster, J. Gorrochategui, P. Comune Pennacchi, D. Primo, J. Ballesteros, V. Tolstikov, M. A. Kiebish, P. Shah, J. Vadakekolathu, S. Rutella, T. A. Fehniger, R. Sullivan, A. Kabakibi, M. L. Cooper, J. Davidson-Moncada
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,480
OpenAlex ID: W4283324314