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Abstract 3964: Mesothelin targeting immunotoxin LMB-100 alters the profile of tumor-secreted proteins

Recombinant immunotoxins are antibody-based therapies that carry a bacterial toxin payload. LMB-100 is a next generation immunotoxin currently being tested in clinical trial. It targets the human cell surface antigen mesothelin (MSLN). MSLN is made by many solid tumors but has no expression in the parenchyma of vital organs. LMB-100 carries a Pseudomonas exotoxin payload that works by irreversibly modifying elongation factor-2 (EF-2), inactivating it and halting protein synthesis. To determine whether non-lethal doses of LMB-100 might inhibit tumor cell secretion of cytokines and growth factors that maintain the pancreatic cancer microenvironment, human pancreatic cancer cells were treated with LMB-100 and conditioned medium was assayed for tumor-secreted factors by ELISA and Luminex assays. Decreased levels of multiple secreted factors were detected including VEGF, PDGF, MMP-1, SPARC, and OPN. Conversely, levels of MIF, a stored cytokine released under stress conditions, increased dramatically upon LMB-100 treatment. To determine whether this also occurs in vivo, tumor-bearing athymic nude mice were treated with LMB-100 and levels of tumor-secreted factors in intratumoral fluid were measured. A statistically significant decrease in the same factors was found in treated mice compared to control mice. To determine whether these decreases in tumor-secreted factors could change the tumor microenvironment and alter the immune milieu, a mouse syngeneic model of pancreas cancer sensitive to LMB-100 was developed. LMB-100 treatment of this mouse cell model caused a statistically significant decrease in the angiogenesis factors VEGF and Angiopoietin-2 in conditioned medium. To determine if this also occurs in vivo, immune-competent mice bearing intraperitoneal or orthotopic tumors were treated with immunotoxin or vehicle then intratumoral fluid was assayed for secreted proteins contributed by both tumor and stromal cells. No detectable change in intratumoral fluid concentration was seen for VEGF, Antiopoietin-2 or a panel of 11 other secreted factors. In conclusion, LMB-100 does inhibit tumor cell production of secreted proteins, but this change is insufficient to alter the total concentration of secreted factors in the tumor microenvironment. Citation Format: Salma El-Behaedi, Rebekah Landsman, Michael Rudloff, Emily Kolyvas, Rakan AlBalawy, Christine Alewine. Mesothelin targeting immunotoxin LMB-100 alters the profile of tumor-secreted proteins [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3964.