Abstract 5737: Enhancing cancer treatment Via a nanostructured chemoimmunotherapy gel facilitating interleukin-2 delivery and immunogenic cell death induction
Authors: Yu Mu Hsuan , Ta Yen-Nhi Ngoc , Tham Jing Rui Max , Hsu Fu-Fei , Lin Yu-Chieh , Huang Hsi-Chien , Sung Yun-Chieh , Huang Chih-I , Wu Ching-Ling , Chang Chao-Hung , Yang Sheng , Lee Tsung-Ying , Wang Jane , Duda Dan G. , Boucher Yves , Huang Jen-Huang , Ang Wee Han , Chen Yunching 
Published: March 2024

Background: The landscape of immunotherapy, employing recombinant cytokines like interleukin-2 (IL-2), confronts challenges marked by its short half-life, systemic toxicity, and constrained tumor accumulation. These hurdles are particularly evident in the context of the immunosuppressive milieu characterizing pancreatic ductal adenocarcinoma (PDAC). Chemo-immuno-therapeutic synergies, notably those provoking immunogenic cell death (ICD), have demonstrated superior efficacy. This investigation delves into Pt-NHC as a type II ICD inducer to surmount immunosuppression and amplify antitumor immunity within a highly tumor-accumulated liposomal drug delivery system. Additionally, the co-administration of the angiotensin receptor blocker, losartan, mitigates desmoplasia in PDAC, further augmenting the efficacy of immunotherapy.

Methods: To address the constraints of IL-2, a lipid-coated nanogel, IL2-Pt@Nanogel, was innovated, amalgamating silk fibroin-loaded IL-2 with Pt-NHC. The nanogel aimed to enhance IL-2 pharmacokinetics and optimize tumor targeting. Concurrently, losartan was employed to alleviate desmoplasia within the tumor microenvironment.

Result: The chemoimmunotherapy nanogel, when coupled with losartan, showcased therapeutic potential in murine models of desmoplastic PDAC. Pt-NHC induced ER-localized reactive oxygen species (ROS) and DAMP release, reshaping the immunosuppressive microenvironment by repolarizing M2-type macrophages to M1 and diminishing the regulatory T-cell population. Co-delivery of IL-2 and Pt-NHC in the nanogel enhanced T-cell infiltration and activation, curbing tumor progression in primary and liver metastasized PDAC models. Importantly, the addition of losartan reduced collagen accumulation within tumors, resulting in heightened infiltration of effector T cells and more pronounced suppression of tumor growth in PDAC and metastasized liver.

Conclusion: This study introduces an innovative nanogel delivery system (IL2-Pt@Nanogel) for chemoimmunotherapy, effectively addressing the challenges associated with IL-2 therapy. Leveraging the enhanced permeability and retention (EPR) effect, the nanogel improves IL-2 stability and tumor delivery. Pt-NHC incorporation induces ICD, reshaping the tumor microenvironment, and in synergy with losartan, elicits robust anticancer immunity. This strategy holds promise for clinical translation as a secure and efficient treatment for immunosuppressive and desmoplastic cancers, such as PDAC, presenting a distinctive therapeutic avenue.

Citation Format: Hsuan Yu Mu, Yen-Nhi Ngoc Ta, Jing Rui Max Tham, Fu-Fei Hsu, Yu-Chieh Lin, Hsi-Chien Huang, Yun-Chieh Sung, Chih-I Huang, Ching-Ling Wu, Chao-Hung Chang, Sheng Yang, Tsung-Ying Lee, Jane Wang, Dan G. Duda, Yves Boucher, Jen-Huang Huang, Wee Han Ang, Yunching Chen. Enhancing cancer treatment Via a nanostructured chemoimmunotherapy gel facilitating interleukin-2 delivery and immunogenic cell death induction [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5737.