Abstract 11P
Background
The efficacy of adoptive cell therapies against solid tumors has been limited by the immune-suppressive TME, which aids immune escape. WU-NK-101, manufactured using the MONETATM platform, is an NK product derived from healthy donor NK cells that addresses challenges of adoptive cell therapy in the setting of an adverse TME.
Methods
Cell phenotypes were evaluated by mass cytometry. Cytotoxicity was assessed in vitro in 2 culture conditions: IMDM-20 and TME-aligned media. Multi-omic studies were performed by mass spectrometry. Cell trafficking/penetration to the TME was measured in NSG mice by tracking labeled WU-NK-101 cells ± mAb.
Results
WU-NK-101 has a unique phenotype vs. conventional NK cells (cNK), with higher expression of activating receptors, which enable rapid activation and improved activity. The latter was confirmed by cytotoxicity assays, with lower Effector:Target (E:T) ratio required to kill 50% of target cells (EC50) for WU-NK-101 vs. cNK, mEC50 1.7 vs. 5.2 (p= 0.032). Importantly, TME-aligned media had a strong impact on cNK killing but negligible impact on WU-NK-101 cytotoxicity, mEC50 16.3 vs. 2.0 (p= 0.018). Potentially explaining this improved killing, WU-NK-101 has metabolic profile consistent with aerobic glycolysis, which may counteract the inhibition of the TME. In IMDM-20, WU-NK-101 uses glucose as its main nutritional source; while in hypoglycemic TME-aligned media, amino acid metabolic pathways were upregulated: this metabolic adaptability augurs improved in vivo efficacy in solid tumor microenvironments. To confirm anti-tumor activity in mouse models, WU-NK-101 was able to infiltrate tumors with robust persistence and anti-tumor activity, which was enhanced with mAb pre-dosing (p = 0.016).
Conclusions
WU-NK-101 has potent cytotoxicity against tumor cells and enhanced/adaptive metabolic fitness contributing to resilience toward the immunosuppressive TME, relative to cNK cells. mAb addition further enhances anti-tumor activity by improved NK trafficking and tumor penetration, taking advantage of these enhanced metabolic features of WU-NK-101. These data suggest that WU-NK-101 may overcome the limitations of adoptive cellular therapy and supports clinical development in the setting of solid tumor.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Wugen, Inc.
Disclosure
S. Rutella: Financial Interests, Institutional, Research Grant: Wugen. J. Muth A. Carter: Non-Financial Interests, Institutional, Full or part-time Employment: Wugen, Inc. M.E. Mathyer, B.R. Tumala K. Magee: Non-Financial Interests, Institutional, Full or part-time Employment: Wugen. J. Baughman: Financial Interests, Personal, Other, Clinical Research Consultant: Wugen; Financial Interests, Personal, Stocks/Shares: MacroGenics, Inc. M. Kiebish: Financial Interests, Institutional, Full or part-time Employment: BERG LLC; Financial Interests, Institutional, Stocks/Shares: BERG LLC. M.L. Cooper: Financial Interests, Personal, Ownership Interest: Wugen; Financial Interests, Personal, Full or part-time Employment: Wugen; Financial Interests, Personal, Royalties: Washington University. M. Berrien-Elliott: Financial Interests, Personal, Ownership Interest, Equity: Wugen; Financial Interests, Personal, Royalties, Possible Royalties Based on Inventorship: Wugen; Financial Interests, Personal, Other, Consulting: Wugen; Financial Interests, Institutional, Licensing Fees, Licensing Fees and Possible Royalties: Wugen; Financial Interests, Institutional, Other, John Dipersio also has equity interest: Wugen. T.A. Fehniger: Financial Interests, Personal, Ownership Interest, Equity: Wugen; Financial Interests, Personal, Other, Possible Royalties Based on Patents by Washington University: Wugen; Financial Interests, Personal, Advisory Board, Consulting: Wugen, Takeda; Financial Interests, Institutional, Funding, SRA and Partial Clinical Trial Funding: Wugen; Financial Interests, Institutional, Other, John DiPersio also has Ownership interest, possible royalties: Wugen; Financial Interests, Personal, Ownership Interest, SAB: OrcaBio, Indapta; Financial Interests, Institutional, Funding, SRA: Affimed, HCW Biologics; Financial Interests, Institutional, Funding, Clinical trial funding: ImmunityBio; Financial Interests, Personal, Advisory Board, SAB: Affimed. J.K. Davidson-Moncada: Financial Interests, Personal and Institutional, Stocks/Shares: Wugen. All other authors have declared no conflicts of interest.