Abstract B032: STING agonist-loaded nanoparticles in ALK-driven lung cancer inhibit tumor growth through local and systemic immune microenvironment remodeling

Abstract Anaplastic lymphoma kinase-positive non-small cell lung cancer (ALK+ NSCLC) comprises 5-6% of all lung cancers with a median survival rate of 6.8 years. The primary treatment is tyrosine kinase inhibitors (TKI) which have a 30-80% response but acquired resistance is inevitable. Therefore, it is imperative to identify alternative additional effective treatment options. Until recently, the immune environment in ALK+ NSCLC has been minimally investigated as a possible area therapeutic intervention. Recent studies have shown that ALK+ NSCLC tumors have a high frequency of immunosuppressive myeloid-derived cells and a low frequency of T cells. To overcome these immunologic challenges, a treatment option is STING agonists. STING agonists initiate a systemic immune response through Interferon signaling, resulting in repolarization of macrophages populations and increase a cytotoxic T cell chemokine gradient. We present the utilization of a STING agonist and Manganese-loaded lipid-based nanoparticle to increase trafficking to the tumor, uptake by immune cells, and a systemic anti-tumor response. Immune-competent mice were inoculated subcutaneously with 5 x 105 EA1 cells, an ALK+ NSCLC cell line derived from TP53 wildtype mice that had a de novo chromosomal rearrangement of EML4 and ALK. The following mice groups were treated: (1) Control, (2) Anti-PD-1, (3) c-di-AMP (CDA) STING agonist + manganese (Mn), (4) CDA + Mn + Anti-PD-1, (5) CDA + Mn nanoparticle (CMP), (6) CMP + Anti-PD-1, or (7) CMP + Anti-PD-1 + Alectinib. Mice were treated with STING agonist or Anti-PD-1 for a total of 3 doses every 7 days and Alectinib was administered daily by oral gavage. All treatments were started when tumors were palpable and stopped at the same time point. Tumor growth, survival, cytokine secretion, mouse weight, immunohistochemistry, and flow cytometric analysis of tumor-draining lymph nodes and tumors were measured. Mice treated with CMP significantly inhibited tumor growth compared with soluble treatment and untreated control groups. In particular, CMP + Anti-PD-1 showed similar tumor growth to Alectinib at lower doses than clinically administered. Furthermre, CMP + Anti-PD-1 + Alectinib further inhibited tumor growth. These combination therapies significantly increased systemic inflammatory and CD8 T cell chemotaxis cytokines in the peripheral blood and CMP + Anti-PD-1 repolarized macrophages resulting in a higher M1:M2 ratio in the tumor. In conclusion, we show that STING agonists are able to elicit a systemic inflammatory immune response in an ALK+ NSCLC immune-competent mouse model that is not observed in an untreated setting. CMP combination therapies inhibited tumor growth at or below a sub-clinically relevant dose of first-line therapy Alectinib and repolarized macrophages in an immunosuppressive macrophage-dominant indication. While survival differences were insignificant among groups, immune environment observations indicate optimization of dose and regimen can improve treatment response and potentially confer long-term survival. Citation Format: Marisa E. Aikins, Abdullah Saeed, Xingwu Zhou, Andrew Yu, Tejas Thiyagarajan, Sydney Malawer, Madeline Bough, James J. Moon, Sofia E. Merajver, Kiran Lagisetty. STING agonist-loaded nanoparticles in ALK-driven lung cancer inhibit tumor growth through local and systemic immune microenvironment remodeling [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Fusion-Positive Cancer: From Discovery to Therapy; 2026 Jan 13-15; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(1_Suppl):Abstract nr B032.