Abstract B023: Immunomodulatory telodendrimer nanomedicine in treating ovarian cancer

Abstract Introduction: Despite the advances in ovarian cancer (OC) treatment, the 5-year survival rate is still lower than 40%. Surgery and chemotherapy can result in cellular debris and damage-associated molecular patterns (DAMPs) roaming the body, activating the immune cells, and causing inflammation, which has a key role in tumor progression. Despite the survival benefits of hyperthermic intraperitoneal chemotherapy (HIPEC) during the debulking surgery, magnified tissue damages lead to overwhelming inflammation. Inflammatory responses are triggered by the activation of toll-like receptors (TLRs) expressed on both immune and cancer cells to secret proinflammatory cytokines, which promote tumor proliferation and metastasis. Moreover, paclitaxel (PTX) and cisplatin (CDDP) can stimulate TLR-4, and several studies have shown that TLR-4 blockade can enhance the treatment effects. Therefore, tackling inflammation in cancer by inhibition of TLRs (e.g., TLR-2,4,9) is a current interest. We have developed a library of telodendrimer (TD) nanoparticles (NPs) with a flexible scaffold decorated with different charged and hydrophobic moieties for both therapeutic delivery and immune modulation via TLR inhibition. Thus, we hypothesize that treatment with immunomodulatory TDs, which inhibit TLR through direct targeting of receptors or through ligands (DAMPs) scavenging, can control chemotherapy/surgery-induced inflammation and the consequent tumor progression. Results and Methods: We have shown that TD can specifically inhibit TLR-4/2 activations upon stimulation with OC- sonicated DAMPs using HEK Blue TLR-4 and TLR-2 cells. TD can significantly inhibit proinflammatory cytokines in immune, OC cell lines and co-culture of OC and immune cells using ELISA. TD can inhibit the cell viability of SKOV-3 directly and upon stimulation with LPS, LTA, DAMPs, and conditioned media of THP-1 macrophages treated with LPS (TCM/LPS) using MTS assay. TD can inhibit the migration of OC cell lines in a dose-dependent manner using scratch assay. TD shows inhibition of NF-kB activation in OC cell lines. Moreover, a positively charged TD (ligands scavenger) shows preferential coating for wound sites and mitigation of the OC engraftment promoted by a surgical wound. Conclusion: We believe that TD's effective control of inflammation induced by OC treatment can reduce tumor progression. In the future, we will investigate loading TD with frontline chemotherapy (PTX and CDDP) for targeted delivery. Citation Format: Hadil A Gadelrab, Changying Shi, Dandan Guo, Md Shanewaz Hossan, Rinki Agarwal, Sandra Orsulic, Juntao Luo. Immunomodulatory telodendrimer nanomedicine in treating ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr B023.