2291P WU-NK-101, best in class memory-NK cell, has key features vital for adoptive cell therapy (ACT) in solid tumors (ST)

Desirable features for successful ACT include effective migration into tumors, overcoming immunosuppression and dearth of nutrients to survive/function within the tumor microenvironment (TME), not restricted by antigen exclusivity, impervious to antigen escape, and engages the recipient’s immune system. WU-NK-101 (WUNK) is a non-engineered cytokine-reprogrammed, expanded, cryopreserved, off-the-shelf NK cell product derived from PBMCs. We have previously shown that WUNK traffic to, and persist in tumor models, and enhanced by mAb combination. Additionally, compared to conventional NK (cNK), WUNK demonstrated improved cytotoxicity A549 (NSCLC): 0% vs. 79%, p=0.0001 and LoVo (CRC) 0% vs. 57%, p=0.01, respectively]. (Rutella et al., ESMO 2022). Cell phenotypes were evaluated by flow cytometry. Fluorescent Abs for CD3, CD56 were used to resolve BM architecture. Compared to cNK, WUNK expresses higher levels of cell surface nutrient transporters which adapted to the differing TMEs, suggesting metabolic fitness, and flexibility. Unlike cNK and T-cells, WUNK cytotoxic activity was preserved in TME-aligned media (WUNK: 96.5% vs. 88.2%, p=0.45; cNK: 44.1% vs. 13.5%, p=0.009; T-cell: 53.2 % vs.25.2%, p=0.041, TME vs. conventional media, respectively). Resistance to TME was further confirmed in native-TME-aligned 3D assays from primary tumor surgical samples. WUNK was effective in lysing malignant cells, while sparing benign cells, indicating that WUNK are not indiscriminate killers. This suggests lack of antigen exclusivity and portends resistance to antigen escape. Treatment with memory-NK cells led to T-cell infiltration and co-localization within TME, suggesting coordination with endogenous immune cells. Synergy of WUNK with the endogenous immune system was also documented in a humanized mouse (engrafted with hPBMCs) model, across a number of ST xenografts, which showed deeper anti-tumor responses. We show that WUNK cells exhibit features that overcome challenges for ACT and enhances anti-tumor activity in ST, heralding the promise of NK cell therapy for ST. The data presented augurs positively for pts to be treated in the upcoming phase I/b clinical study.