Abstract PO001: Results from a preclinical study to evaluate the efficacy of polyvalent immunoglobulins on the imbalance of (anti-)inflammatory immune cell responses in clinical colorectal cancer
Authors: Gasser Martin , Lissner Reinhard , Hsiao Li-Li , Waaga-Gasser Ana Maria 
Published: February 2021

Abstract
Introduction: The purpose of this study was to determine the efficacy of an immunoglobulin concentrate on dysregulated inflammatory responses in patients with colorectal cancer (CRC). Recent findings have shown that CRC is associated with dysbiosis of the gut microbiome and frequently a compromised gut barrier, resulting in prolonged and smoldering endotoxin leakage into the circulation. Subclinical local and systemic microinflammation is suggested to facilitate metastasis formation. Previous studies have pointed to the capacity of polyvalent immunoglobulins to neutralize endotoxins and pathogens on gut epithelial surfaces to abrogate inflammatory responses and thereby tumor recurrence. The effects of KMP01D, a colostrum preparation with a multitude of immunoglobulins against gram-negative/positive bacteria and viruses, on pro-/anti-inflammatory cytokine responses and apoptosis were determined ex vivo.
Methods: Peripheral blood and tumor-derived mononuclear cells (MNC) from CRC patients at UICC stages I–IV (n=48) operated at our Center for Operative Medicine/Comprehensive Cancer Center and treated under current guidelines for (neo-)adjuvant therapy were further investigated. Expression of CD14, CD68, Toll-like receptor(TLR) 4, and insulin-like growth factor (IGF)-1 with/without co-incubation of KMP01D as well as immune cell apoptosis was analyzed by flow cytometry, RT PCR, immunohistochemistry, and Elisa in each patient.
Results: KMP01D increased interleukin (IL)-10 and IL-13 anti-inflammatory cytokine expression in peripheral blood MNCs (UICC I-III). More interestingly, it likewise decreased secretion of IL-1β, IL-6, IFN-γ, TNF-α, and IL-12 driven inflammation as well as IGF-1. Moreover, CD14/CD68 and TLR4 expression critically involved in endotoxin signaling was downregulated in PBMCs and tumor-infiltrating MNCs. CD14+Fas+/TUNEL+ PBMCs and tumor-derived MNCs indicating apoptosis were likewise enhanced under KMP01D co-incubation. Addition of vitamin D3 known as a regulatory factor in immune responses demonstrated additive anti-inflammatory effects in vitro.
Conclusions: Inflammatory immune responses are significantly and stage-dependently upregulated which negatively impacts anti-tumor-specific immune reactivity, immune cell apoptosis and prognosis in CRC patients despite modern adjuvant treatment protocols. KMP01D produced from natural bovine sources and composed of a multitude of immunoglobulin activity (IgG1/2 and Lactoferrin) demonstrates highly ex vivo efficacy on downregulation of inflammatory cytokine responses in PBMCs and normalized immune cell apoptosis in CRC patients. Together with previous clinical data our results strongly suggest that KMP01-mediated endotoxin and pathogen neutralization and thereby mitigated chronic inflammation can be a highly valuable add-on instrument in the treatment of CRC patients to downregulate stage-dependently their local and systemic inflammation and risk for metastasis formation.
Citation Format: Martin Gasser, Reinhard Lissner, Li-Li Hsiao, Ana Maria Waaga-Gasser. Results from a preclinical study to evaluate the efficacy of polyvalent immunoglobulins on the imbalance of (anti-)inflammatory immune cell responses in clinical colorectal cancer [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2020 Oct 19-20. Philadelphia (PA): AACR; Cancer Immunol Res 2021;9(2 Suppl):Abstract nr PO001.