Abstract A052: Development of PD-L1 and STING-targeted nanoparticles for lung cancer treatment
Authors: Crumrine Noah , Reda Moataz , Kumar Pramod , Wang Ruijie , Watcharawittayakul Tongchatra , Gouw Victoria , Khalil Sylvia , Ngamcherdtrakul Worapol , Yantasee Wassana 
Published: February 2025

Metastatic non-small cell lung cancer (NSCLC) is a highly lethal cancer with limited effective treatment options. Although immune checkpoint inhibitors show some promise, they benefit only a minority of patients and often result in resistance. We have developed a novel nano-immunotherapy for NSCLC using our patented polymers-coated mesoporous silica nanoparticle, Pdx-NPTM, which co-delivers a STING (Stimulator of Interferon Genes) agonist and an anti-PDL1 antibody, forming our drug candidate STACI - STING Agonist and Checkpoint Inhibitor. STING is widely expressed across various cell types, including innate immune cells (e.g., dendritic cells, macrophages), T cells, and cancer cells. Activation of the STING pathway leads to the production of type I interferons and other cytokines, promoting an anti-cancer immune response. Leading synthetic cyclic dinucleotide (CDN)-based STING agonists, including ADU-S100 and MK-1454, have been in clinical trials. However, their use is limited to intratumoral injection to activate local immune responses in head and neck tumors and lymphoma, rather than systemic administration. Due to the short half-life of CDNs and their poor cellular uptake, their efficacy is only modest even when combined with anti-PD1 antibody. Our hypothesis is that co-delivering an anti-PDL1 and a STING agonist on our Pdx-NPTM nanoparticle platform will overcome the limitations of STING agonist delivery, reduce the required anti-PDL1 dose to improve safety, and promote a synergistic effect between anti-PDL1 and STING agonist through delivery to both cancer and immune cells. STING agonists are known to remodel tumor microenvironment, to be immunogenic, and to upregulate PDL1 expression on cancer and antigen-presenting cells, providing a strong rationale for combining it with an anti-PDL1 antibody, which serves as both a tumor homing agent and an immune checkpoint inhibitor when loaded on our Pdx-NPTM. The nanoparticles also protect CDNs from enzymatic degradation, extend their bio-availability, and promote cellular uptake and activity in cancer and immune cells. In mice, we observed the activation of 60% of DCs in lymph nodes 48 hours after a footpad injection of nanoparticles loaded with natural 3’3’-c-di-GMP or synthetic ADU-S100 (vs. 10% by saline). In mice carrying NSCLC tumors (LLC-JSP), Pdx-NPTM co-delivering anti-PD-L1 antibody, a STING agonist, and an ICD agent (volasertib) for 3 doses significantly prolonged median survival from 11 days (saline treated) to 24 days. No toxicity effect was observed. Work to further fine-tune the STACI formulation and establish safety and efficacy profiles in multiple tumor models is ongoing and will be presented. Our versatile Pdx-NP™ platform addresses the current need of cancer immunotherapy focusing on combination therapy - where complementary biological pathways are simultaneously targeted.

Citation Format: Noah Crumrine, Moataz Reda, Pramod Kumar, Ruijie Wang, Tongchatra Watcharawittayakul, Victoria Gouw, Sylvia Khalil, Worapol Ngamcherdtrakul, Wassana Yantasee. Development of PD-L1 and STING-targeted nanoparticles for lung cancer treatment [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr A052.