e15002 Background: NEO-201 is a humanized IgG1 mAb that targets tumor-associated variants of CEACAM-5/6. NEO201 exerts anti-tumor activity by (NK)-mediated ADCC, CDC, and by enhancing NK cell cytotoxicity through blockade of CEACAM5-CEACAM1 interaction. The first in human phase I clinical trial is ongoing. Neutropenia caused DLT and was observed at 2mg/kg (DL 2). At DL2, 2/6 patients with colorectal cancers had stable disease. In the present study we evaluated the correlation between response, NK status, and profiles of soluble factors. Methods: This is a classic 3+3 dose escalation. NEO-201 is administered intravenously every 2 weeks, with 4 dose levels planned (DL1 = 1mg/kg, DL2 = 2mg/kg, DL3 = 4mg/kg and DL4 = 6mg/kg). So far, 3 patients received DL1 and 6 patients DL2. Safety is evaluated according to CTCAEv5.0, and response according to RECISTv1.1. Biological samples are collected at baseline, at 4, 24 and 72 hours after the first dose, and before C1D15 dose to understand NEO-201 pharmacokinetics (PK), effects on immune profile and correlation with treatment toxicity and response. CD56+/CD16+ NK cells were evaluated for modulation of NKG2D, CD107a, NKp46 (activation markers), and CEACAM1 (inhibitory marker) by flow cytometry. Soluble factors (cytokines, sMICA and sCEACAM5) were evaluated by ELISA. Results: Among the 3 patients achieving radiological SD, one (DL1) had clinical progression (PD) without radiological progression after 2 cycles due to mucous producing disease, a second patient (DL2) went off study after 2 cycles for drug unrelated issues, and the third patient (DL2) has stable disease (SD) for 6 months without significant toxicity. All other patients had radiologic PD after 2 cycles. Interestingly, baseline CD56+/CD16+ NK cells from the two patients with SD showed an increase in NKG2D, CD107a and NKp46, and a low expression of CEACAM1. They also had low serum levels of sMICA, sCEACAM5 and IL-6. On contrary, CD56+/CD16+ NK cells from patients with PD had low expression of NKG2D and CD107a, high expression of CEACAM1, and high levels of sMICA. Conclusions: High expression of activating markers and low expression of CEACAM1 on CD56+/CD16+ NK cells, as well as low levels of sMICA and sCEACAM5 correlate with clinical response to NEO-201. Thus, the activity of NK cells may serve as predictors for efficacy of tumor-targeting antibody therapy. Further correlation of these biomarkers with PK and CEACAM1/5/6 expression in patients’ tissue samples will provide further support for optimizing the use of NEO201. Clinical trial information: NCT03476681 .