Introduction: Tumor necrosis factor-alpha (TNFα) is a pleiotropic cytokine, with known antitumor activity, produced mainly by activated immune cells. Cancer cells can neutralize TNFα by shedding soluble TNF receptors 1&2 (sTNFRs), which act as TNFα-binding decoys. In addition, sTNFRs can directly promote proliferation, survival, and chemoresistance of cancer cells by binding to membrane-bound TNFα and initiating retrograde signaling. Therefore, the reduction of systemic and intratumoral concentrations of sTNFRs represents a novel and unique anticancer strategy, since systemic recombinant TNFα treatment strategies require very high doses to achieve antitumor activity, and are feasible only in an isolated limb perfusion setting.

Methods: We developed an extracorporeal sTNFR-scavenging approach, Immunopheresis™, which combines apheresis with the novel LW-02 immunoadsorption column (LW-02) that employs a recombinant single chain TNFα (scTNF) as the sTNFR-scavenger ligand. The LW-02 column has received FDA breakthrough designation for potential treatment of advanced metastatic solid tumors, based on data from a comparative oncology study in canines with naturally occurring melanoma and solid tumors. For our first-in-human experience we chose to study patients with advanced, chemo-refractory metastatic triple-negative breast cancer (mTNBC) in a multi-center Phase I/II clinical trial (NCT04004910), assessing feasibility and safety of sTNFR-reduction, and preliminary clinical activity of LW-02-based immunopheresis alone and in combination with low-dose chemotherapy. Here we present data on the first cohort of mTNBC patients treated with LW-02 immunopheresis alone.

Results: Of 14 screened patients, due to ECOG PS deterioration in 4 pts, only 10 (median age - 52.9, ECOG≤1) underwent at least one LW-02 immunopheresis procedure involving processing of 2 plasma volumes (2PV). The highly specific LW-02 (no off-target capture) pulldown of sTNFRs exceeded 80%, leading to a ≥25% reduction in blood sTNFR levels after 2PV. Leaching of scTNF into circulation was minimal (<50 ng/min) and did not represent any hazard to patients. The most common AEs (mainly CTCAE G1-2) were transient electrolyte abnormalities, anemia, pain and leucopenia. Serious AEs were reported in 80% of patients but no SAE was related to the experimental treatment. Median duration of LW-02 immunopheresis treatment was 2.25 months in these patients who had failed multiple prior chemotherapy lines (median=4). Median survival was 4.38 months in patients receiving ≥4 wks of immunopheresis.

Conclusion: The LW-02-column immunopheresis procedure was shown to be generally safe and highly effective in specific sTNFR subtraction on a longer-term basis, with initial signals of clinical benefit in heavily pretreated mTNBC patients. Further clinical evaluation of the antitumor activity of LW02-based immunopheresis combined with low-dose chemotherapy is ongoing.

Citation Format: Piotr J. Wysocki, Adam Ostrowski, Robert Segal, Pawel M. Potocki, Lukasz Kwinta, Kamil Konopka, Lawrence B. Florin, Stephen M. Prince. Extracorporeal pulldown of soluble TNFRs to unleash the activity of endogenous TNFα in chemorefractory triple-negative breast cancer patients - first-in-human experience [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT135.