Abstract 4252: Evaluation of NXI-101 in non-small cell lung cancer (NSCLC) using patient-derived organotypic tumor spheroids (PDOTS): Targeting a novel tumorigenic pathway

Abstract ONCOKINE-1 (OK-1), a soluble protein that is released by tumor cells, is implicated in the resistance of immunotherapy. Here we evaluated the efficacy of NXI-101, a monoclonal antibody that binds and neutralizes OK-1, in a model of patient-derived organotypic tumor spheroids (PDOTS) derived from non-small cell lung carcinoma (NSCLC) patients. NSCLC PDOTS were treated with NXI-101 and the effects of the drug were evaluated on day 3 post-treatment. Cytotoxicity was measured by Hoechst/Propidium Iodide staining and quantified by measuring the area-weighted percentage of cell death. Significant cytotoxicity was observed in 2 out of 10 patient tumors (20%) as a monotherapy and 4 out of 10 (40%) when used in combination with atezolizumab. The therapeutic response for both treatments was positively correlated (p0. 05) with the level of OK-1 expression, determined by immunohistochemistry using tissue sections taken on the day of tumor specimen collection. NXI-101 alone and in combination with atezolizumab had immunomodulatory effects that were associated with cytotoxic response. For example, transcriptomic analysis, Nanostring IO 360 Panel, indicated that the drug treatments resulted in the inhibition of TGF-β pathways and stimulated a number of immune pathways in 3 of the 4 responsive PDOTS. These pathways include interferon-α, JAK-STAT, and dendritic cell activation markers. We also observed evidence of activation of these same pathways in 2 of the 6 non-responsive PDOTS. These data support the prospects of NXI-101 as a first-in-class therapeutic for the treatment of NSCLC when used alone or in combination with an immune checkpoint inhibitor. Moreover, the findings highlight the PDOTS platform's substantial value in capturing patient-specific tumor response variability and providing robust support for the mechanistic evaluation of cancer therapeutics. Citation Format: Julia Vail, Hyung Gun Maeng, Je Woong Jang, Kyungjin Boo, Je-In Youn, Alyssa Martin, Aaron Goldman, Kyoung Wan Yoon, Michael A. Perricone. Evaluation of NXI-101 in non-small cell lung cancer (NSCLC) using patient-derived organotypic tumor spheroids (PDOTS): Targeting a novel tumorigenic pathway abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 4252.