Abstract Immunicom, Inc. has developed a novel subtractive immunotherapeutic apheresis method (Immunopheresis®) 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-α. Past use of systemic administration of TNF-α to treat solid tumors resulted in unacceptable toxicities. Immunicom’s LW-02 Column contains a bead matrix covalently bonded to a single-chain, TNF-α 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 Immunopheresis® monotherapy or combined with various chemo- or immunotherapies. Immunopheresis® 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 Immunopheresis® 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 Immunopheresis® 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 Immunopheresis® can safely and selectively remove sTNF-Rs thus allowing endogenous TNF-α to instigate its multiple anticancer pathways. Citation Format: Piotr J. Wysocki, Piotr Tomczak, Tomasz Jankowski, Tomasz Nowikiewicz, Gal Markel, Ronnie Shapira, Gokhan Demir, Mustafa Bozkurt, Sameera Bilgrami, Annette Marleau, Adam Ostrowski, Lawrence Florin, Victoria Manax, Robert Segal. Removal of soluble TNF receptors as a novel form of immunotherapy for patients with advanced solid tumors. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4426.