Background Humanized IgG1 mAb NEO-201 binds core 1 O-glycans and showed antibody-dependent cell-mediated cytotoxicity (ADCC) activity against cancer cells expressing core 1 O-glycans.1 NEO-201 kills cancer cells, neutrophils, and immune suppressor cells (iSCs), including regulatory T cells (Tregs) and granulocytic myeloid-derived suppressor cells (gMDSCs) via ADCC and complement-dependent cytotoxicity.2 Resistance to PD-1/PDL1 blockade may be due to accumulation of iSCs in the tumor microenvironment.3 Elevated neutrophil-to-lymphocyte ratio (NLR) correlates with poor prognosis.4 We evaluated post-treatment NLR and depletion of gMDSCs as prognostic markers in patients treated with NEO201 and pembrolizumab.
Methods PBMCs and serum from cancer patients on the Phase II trial combining NEO-201 with Pembrolizumab (NCT03476681) were used to evaluate the percentage of circulating gMDSCs (flow cytometry) and arginase-1 levels (ELISA). Patients with chemo-resistant solid tumors, who were resistant to prior checkpoint inhibitor therapy, received NEO-201 1.5mg/kg every 2 weeks with pembrolizumab 400mg IV every 6 weeks (1 cycle), and were imaged for response every 2 cycles. gMDSCs percentage in PBMCs and Arginase-1 levels in serum were analyzed before treatment (C1D1), 14 days after first infusion with NEO-201 (C1D15), before cycle 2 (C2D1), and before of cycle 3 (C3D1). gMDSC population was defined as HLA-DRneg/CD33+/CD15+/CD14neg/CD66b+.
Results We compared cancer patients with SD and PD at first radiological assessment. Among patients with SD, 1 patient (SD > 8 months) showed reduced gMDSCs (93.86%) at C3D1 compared to baseline (0.014% vs 0.228%) (figure 1). Similarly, another patient with SD showed a marked reduction of gMDSCs (87.42%) at C1D15 compared to C1D1 PRE (0.074% vs 0.588%). The other patient with SD > 8 months showed initial increase of gMDSCs at C1D15 and C2D1 compared to C1D1 but trended down at C3D1 (0.146% vs 0.114%). On the other hand, there was a general uptrend of circulating gMDSCs in patients with PD. Additionally, patients with PD had NLR >10 at C2D1, suggesting moderate to severe physiological stress compared to patients with SD who had NLR level <10 (table 1).
Conclusions Recent studies highlight the host’s inflammatory response in tumor development and progression of various cancers. In our study, patients with SD had a downtrend of circulating gMDSCs, arginase-1 levels and normal to mild NLR compared to patients with PD, suggestive of good prognosis for treatment with NEO-201 and pembrolizumab (figures 1 and 2). Ongoing enrollment in this clinical trial will validate these findings in larger cohorts.
Trial RegistrationClinical trial information NCT03476681
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Ethics Approval The study was approved by NCI, NIH, Institutional Review Board (protocol code NCT03476681, first approved 2/26/2018; combination of NEO-201 and pembrolizumab approved 10/5/2021; latest update 02/13/2023) and all participants signed a written informed consent.
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