Apheresis of inhibitors of TNF disrupts tumor immunoevasion - Rigdon Lentz
Immune suppression has long been recognized as a hallmark of patients with advanced malignancies. Tumor necrosis factor (TNF) and interleukin-2 (IL-2) are pro-inflammatory cytokines produced by activated mononuclear white blood cells (WBC) that bind to tumor cells via specific receptors and induce cell death by both oxidative stress and apoptosis. This process constitutes a major part of the normal response of the immune system against cancer cells.
Overproduction and shedding by tumor cells of high levels of two soluble receptors for TNF (sTNF-R1 and sTNF-R2) and IL-2 (sIL2-R) are believed to be a fundamental mechanism by which tumor cells locally block attack and subsequent destruction by the immune system. These soluble receptors act as competitive inhibitors affecting the interaction of TNF and the surface receptors of cancer cells. This mechanism explains why high levels of sTNF-R1 and sTNF-R2 have been negatively associated with the prognosis of tumor patients in several clinical and epidemiological investigations.
My work involves the extracorporeal removal of these soluble inhibitors via a customized apheresis device and affinity column, with the goal of reducing local tissue inhibitor concentrations below the tumor-protective threshold. Multiple clinical trials and a recent mechanistic study have demonstrated that this treatment significantly reduces plasma concentrations of sTNF-R1, sTNF-R2, and sIL2-R receptors, and is well tolerated by patients.
Observed clinical effects are consistent with a treatment-induced immune response against the tumor, including tumor pain with tenderness of palpable tumors, tumor swelling, palpable heat in tumor regions, and low-grade fever. Longer observation shows that metastatic patients who receive multiple treatment cycles and demonstrate clinical signs and symptoms of tumor inflammation subsequently demonstrate signs of tumor necrosis and tumor reduction, as evidenced by X-ray imaging and CT scans, suggesting that lowering plasma levels of sTNF-R1, sTNF-R2, and sIL2-R is beneficial to patients with metastatic cancer.