FcεRIγ-negative NK cells and association with improved outcomes in trastuzumab-treated patients.

person Vincent Michael Perez Tempus Labs, Inc., Durham, NC info_outline Vincent Michael Perez, Sara R. Selitsky, Bin Yao, Austin Bigley, Sungjin Kim, Mark Walter Frohlich

Authors person Vincent Michael Perez Tempus Labs, Inc., Durham, NC info_outline Vincent Michael Perez, Sara R. Selitsky, Bin Yao, Austin Bigley, Sungjin Kim, Mark Walter Frohlich Organizations Tempus Labs, Inc., Durham, NC, Statagize LLC, Thousand Oaks, CA, Indapta Therapeutics Inc., San Francisco, CA, University of California Davis, Davis, CA, Indapta Therapeutics, San Francisco, CA Abstract Disclosures Research Funding Pharmaceutical/Biotech Company Indapta Therapeutics, Inc. Background: A subset of natural killer cells lacking FcεRIγ expression (g-NK cells) demonstrate enhanced expansion, cytokine production, antibody-dependent cytotoxicity, and enhanced efficacy of therapeutic antibodies in preclinical models (Bigley, Blood Advances 2021). The monoclonal antibody, trastuzumab, is standard of care for treatment of HER2+ breast cancer in adjuvant and metastatic settings. We sought to determine whether the abundance of g-NK cells is associated with improved outcomes in trastuzumab-treated patients. Methods: We identified g-NK cells in single-cell (scRNA-seq) datasets from melanoma (n=47), renal (n=8), breast (n=29), and lung cancer (n=36) samples using predefined markers and defined a g-NK gene signature. We split the scRNA-seq cohorts into training and test sets and estimated cell-type compositions in pseudo bulk using MuSiC bulk tissue deconvolution (Wang, Nature Communications, 2019). We deconvoluted g-NK cells in 8 bulk RNA-seq HER2+ breast cancer cohorts (Table 1) and used Cox proportional hazard models to assess clinical outcomes stratified by g-NK and trastuzumab status. We reproduced our findings using real-world cohorts from patients sequenced via the Tempus xT test (Table 1). Results: The Spearman’s correlation coefficient between true and estimated pseudo bulk proportion of g-NK cells was 0.71 (p≤0.05). In a meta-analysis, the abundance of g-NK cells was associated with a lower hazard ratio (HR) for overall survival (OS) in trastuzumab-treated patients (cohorts 1-4; HR = 0.61; 95% CI, 0.37-0.99; p=0.04) but not trastuzumab-naive patients (cohorts 5-8; HR = 0.96; 95% CI, 0.80-1.15; p=0.65). In real-world, HER2+ breast cancer cohorts treated with trastuzumab, higher real-world progression-free survival (rwPFS) was associated with abundance of g-NK cells (N=104, HR = 0.78; 95% CI, 0.64-0.96; p=0.02). A similar trend was observed in real-world trastuzumab-treated gastric cancer patients (N=79, HR = 0.85; 95% CI, 0.72-1.00; p=0.06). Conclusions: G-NK cells are associated with improved OS and PFS in trastuzumab-treated patients from both clinical trials and real-world datasets, suggesting their presence may serve as a predictive marker for treatment efficacy. Adoptive transfer of g-NK cells is being explored to augment the efficacy of therapeutic monoclonal antibodies. Cohort # (n=) C1 104 C2 103 C3 49 C4 52 C5 57 C6 50 C7 50 C8 205 RWD1 104 RWD2 79 Trastuzumab x x x x x x Chemotherapy x x x x x x x Lapatinib x x Other x Study design NAT NAT AT AT NAT AT AT TB RWD RWD HR 0.97 0.46 0.31 0.80 0.78 0.94 0.99 1.16 0.79 0.86 Datasets used in analyses: CALGB 40601 trial, C1-2 and C5; Finland Herceptin trial, C3-4 and C6-7; Molecular Taxonomy of Breast Cancer International Consortium, C8; Tempus Labs, RWD1-2. Abbreviations: NAT, neoadjuvant therapy; AT, adjuvant therapy; TB, tumor bank; RWD, real-world data.