Abstract 3549: Engineering an artificial antigen presenting system: A novel immunotherapeutic strategy for lung cancer

Abstract Lung cancer continues to be the major cause of cancer-related deaths worldwide, indicating the urgent need for innovative and effective treatment strategies. Immune checkpoint inhibitors (ICIs) have demonstrated great promise as a new therapy, offering new hope for patients with advanced lung cancer. However, resistance to ICIs is frequently observed in cancer patients, with many failing to achieve durable responses. One of the very important factors contributing to ICI resistance is the dysfunction of antigen-presenting cells (APCs), especially dendritic cells (DCs), which are key initiators of the anti-tumor immunity. In lung cancer patients, DCs are compromised with a low capability of generating cytotoxic T cells, which are indispensable for the effectiveness of ICIs. To overcome this challenge, we have designed an artificial antigen-presenting system (aAPS), a new bioengineered platform that enables the direct stimulation of anti-tumor T cell responses independent of host APCs. The platform comprises specifically engineered nanostructures presenting membrane-bound IL-2, co-stimulatory molecules (4-1BBL and CD40L), and major histocompatibility complex (MHC)-bound antigens. aAPS thus efficiently performs direct antigen presentation to lymphocytes, leading to a robust and specific adaptive immune response. By mimicking these three necessary signals—cytokine stimulation, co-stimulatory activation, and MHC-antigen presentation—aAPS can elicit and amplify T cell activation independently of dysfunctional host APCs. The membrane-bound IL-2 on aAPS is extensively oriented toward highly targeted T-cell engagement, improving immune cell activation and lowering the systemic toxicity usually linked with the administration of free cytokines. Our preliminary studies have shown that aAPS potently induces an antigen-specific T cell response, which is superior to the effects seen in conventional dendritic cell-based approach. The efficacy profile of aAPS has been quite promising in preclinical murine lung cancer models, showing a huge reduction in tumor growth, enhancement of tumor-infiltrating lymphocytes, and augmentation of the efficacy of ICIs. Such data indicate that aAPS may overcome one of the major immune suppressive barriers to ICI therapy in lung cancer, paving the way for potentially potent new tools to enhance anti-tumor immunity and improve patient outcomes. Further studies will confirm these results and move aAPS toward clinical application in advanced lung cancer by transforming the bioengineering strategies to reduce technical barriers, enabling high-yield and high-purity production of this innovative therapy. Citation Format: Sindhu Yalavarthi, 1 Li Wang, 1 Yusif-Abdul Rashid, 1 Kiki Parker, 2 I'yanah Gunter, 1 Ethan Li, 3 Emily Cao, 3 Jianjun Wei, 1 Zhenquan Jia, 4 Kounosuke Watabe, 5 Kerui Wu. Engineering an artificial antigen presenting system: A novel immunotherapeutic strategy for lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3549.