Abstract 2259: Novel metallotherapeutic BOLD-100 induces circulating cytokine changes when administered in combination with FOLFOX in advanced gastrointestinal cancer patients
Authors: Bazett Mark , Park Brian , McAllister E Russell , Pankovich Jim 
Published: April 2023

Abstract
Proven metallotherapeutics, such as cisplatin and oxaliplatin, alter immune responses as part of their multimodal mechanisms-of-action. These immune responses can drive efficacy in specific patient populations and/or in combination with other oncology drugs. BOLD-100, currently in a multinational Phase 2 trial, is a first-in-class metallotherapeutic that (1) alters the unfolded protein response (UPR) through selective GRP78 inhibition, and (2) induces reactive oxygen species (ROS), leading to DNA damage and cell cycle arrest. Collectively, these pathways result in cell death in both sensitive and resistant cancers, giving BOLD-100 the potential to significantly improve outcomes in a wide range of both solid and liquid tumors in combination with other anticancer therapies. BOLD-100 can also alter immune responses, including through induction of immunogenic cell death, but these responses have not been investigated in a clinical population. A recently completed Phase 1b trial investigating BOLD-100 in combination with FOLFOX demonstrated a 3X improvement in progression-free survival (PFS) in 3rd line or later metastatic colorectal cancer patients compared to existing therapies, with a favorable safety profile. In this Phase 1b study, BOLD-100 was administered via IV infusion for 60-90 minutes immediately prior to FOLFOX on a 2-week cycle. To investigate the pharmacodynamics of immune markers, plasma samples were collected at baseline and 1, 6, 24, and 48 hours after initiation of BOLD-100 plus FOLFOX treatment for each of the first 4 cycles, and then at baseline for all subsequent cycles. In 326 samples collected from 15 patients, 48 cytokines were measured via multiplex. Multiple cytokines showed short-term (1 to 48 hours) transient increases in plasma concentration levels, including IL-10, IL-27, G-CSF, MIP-1β, IP-10, IL-2, IL-18 and TNFα. IL-10, a cytokine previously investigated as an anticancer therapeutic, increased significantly by 1 hour (6.7X increase) and by 6 hours (84.5X increase) after treatment, before reverting to baseline levels by 48 hours. Despite large acute increases in specific cytokines, no changes to baseline levels over multiple treatment cycles were observed. Correlation analysis showed that baseline MCP-1 and MIP-1α levels were negatively correlated with overall survival; and the maximum change in concentration over the first dosage cycle of RANTES, IL-17F, Eotaxin, TGFα and MDC were positively correlated with overall survival. These results show that BOLD-100 in combination with FOLFOX can induce immune responses, and that these immune responses may predict clinical outcome. Analysis of additional patient samples from the Phase 2 trial is ongoing.
Citation Format: Mark Bazett, Brian Park, E Russell McAllister, Jim Pankovich. Novel metallotherapeutic BOLD-100 induces circulating cytokine changes when administered in combination with FOLFOX in advanced gastrointestinal cancer patients [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 2259.