Abstract 3229: Triggering anti-tumor immune response with a nanotherapeutic that targets TLR9 and STAT3 pathways

Abstract

Abstract Immune checkpoint inhibitors (ICIs) have provided long-lasting response but only in a small subset of cancer patients. To address this shortcoming, we developed a nanotherapeutic (AIRISE-02) that can manipulate both cancer cells and immunosuppressive tumor microenvironment (TME), leading to successful production of anti-tumor T cells that promote ICIs’ response. AIRISE-02 (Augmenting Immune Response and Inhibiting Suppressive Environment of tumors) is our patented polymer-coated mesoporous silica nanoparticle (Pdx-NPTM) that co-delivers immunostimulant CpG and siRNA against signal transducer and activator of transcription 3 (siSTAT3). CpG is a widely used adjuvant that activates antigen presenting cells (APCs) to process and present tumor antigens. STAT3 contributes to progression, metastasis, and immune escape of cancer cells. STAT3 also has roles in immunosuppressive TME, by inhibiting maturation and activation of APCs, suppressing M1 macrophage polarization, and mediating immunosuppressive function of myeloid-derived suppressor cells. AIRISE-02 can be given both intratumorally and systemically. In bilateral B16F10 melanoma and MC38 colon cancer models, three intratumoral injections of AIRISE-02 to one tumor inhibit both treated and untreated distal tumors. When combined with ICIs against PD-1 and CTLA-4, AIRISE-02 leads to long term cure in 63% of mice with B16F10 tumors and 43% of mice with MC38 colon tumors (while ICIs alone provides no cure in B16F10 and 17% cure in MC38 tumor mice). In the tumor rechallenge study at 6 months post-cure, B16F10 mice reject new B16F10 tumors, while allowing LLC-JSP lung tumors to grow, suggesting tumor-specific immune memory effect. Through antibody depletion studies, AIRISE-02’s activity is shown to be highly dependent on CD8+ T cells and IFN-ɣ, while slightly dependent on B cells and NK cells. Strikingly, depleting CD4+ T cells strongly boosts AIRISE-02’s activity, which is likely due to depleting regulatory T cells. Effectiveness of AIRISE-02 is owing to the ability of Pdx-NPTM to retain and protect oligonucleotide cargos in the tumors; e.g., 50% of injected siRNA dose remained at three days with Pdx-NP vs. 2% when given as free siRNA. In addition to STAT3, our platform technology can be tailored to other important therapeutic targets with the power of siRNA. Ongoing works to attack other hard-to-drug targets, such as KRAS, Myc, and AR will also be presented. Citation Format: Worapol Ngamcherdtrakul, Moataz Reda, Cole Baker, Noah Crumrine, Ruijie Wang, Alyssa Wallstrum, Natalie White, Jeremy Saito, Husam Zaidan, Justin Rehwaldt, Molly Nelson, Joe Gray, Wassana Yantasee. Triggering anti-tumor immune response with a nanotherapeutic that targets TLR9 and STAT3 pathways [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3229.