Abstract: lmmunicom, Inc. has developed a novel subtractive immunotherapeutic apheresis method (lmmunopheresis®) to selectively remove soluble tumor necrosis factor receptors, sTNF-R1 and sTNF-R2 (sTNF-Rs) generated by tumors. sTNF-Rs block the tumoricidal activities, hence their removal restores the anticancer immunotherapeutic activity of native TNF-a. Past use of systemic administration of TNF-a to treat solid tumors resulted in unacceptable toxicities. lmmunicom’s LW-02 Column contains a bead matrix covalently bonded to a single-chain, TNF-a capture ligand (scTNF) with high affinity and selectivity to remove sTNF-Rs from plasma. Three clinical trials (NCT04004910, NCT04142931, NCT04690686) have been conducted in patients with various advanced-stage breast cancers (BC), melanoma (M), renal cell carcinoma (RCC) and non-small cell lung cancers (NSCLC). Patients were assigned to receive LW-02 Column lmmunopheresis® monotherapy or combined with various chemo- or immunotherapies. lmmunopheresis® was administered 3x/week for each trial’s 12 or 16-week Primary Treatment period with each procedure processing 2 plasma volumes (2PV). Patients with (at least) clinical stability and/or tumor responses could receive additional treatment. Compared to healthy persons, patients in all 3 trials were noted as having significantly elevated baseline blood concentrations of sTNF-R1 and sTNF-R2. For instance, sTNF-R1 plasma levels were 3.5 ng/mL, 3.5 ng/mL, 2.2 ng/mL and 2.1 ng/mL for BC, M, RCC and NSCLC, respectively, which were 5-8-fold higher than normal values. Likewise, sTNF-R2 plasma concentrations (which can be 4-fold, or more, greater than sTNF-R1) were 4-9-fold higher for BC (16.5 ng/mL), M (19.1 ), RCC (22.7) or NSCLC (11.1 ng/mL) than normal values. Through the data cutoff, >1,600 LW-02 Column lmmunopheresis® procedures were performed. On average, 95% of sTNF-R1 and 80% of sTNF-R2 are removed from plasma at the 30-minute procedure timepoint. At the 2PV timepoint, overall mean reductions of sTNF-R1 and sTNF-R2 in whole blood were 51 and 52%. Further, minimal leaching (mean of 113 ng per procedure), of the scTNF capture ligand was detected, a quantity that is insufficient to cause any meaningful clinical effects. In vitro testing determined that the LW-02 Column has no discernable evidence of unintended or “off-target” removal of other cytokines or blood constituents or any non-specific binding. Moreover, the trial results demonstrate lmmunopheresis® is safe with minimal side effects determined to be related to treatment with the column. Results from 3 trials indicate that cancer patients with advanced solid tumors present with significantly upregulated levels of immune inhibitory sTNF-Rs. LW-02 Column lmmunopheresis® can safely and selectively remove sTNF-Rs thus allowing endogenous TNF-a to instigate its multiple anticancer pathways.