将肿瘤转变为治疗性药物工厂:跨肿瘤适应证的疗效

Although DNA can be used to drive expression of cancer therapeutics, clinical use is often restricted to intratumoral injection due to lack of specificity. Earli's cancer-activated expression platform permits broad systemic DNA delivery to a multitude of cancers by using conditionally active promoters to drive potent anti-tumor activity while minimizing systemic toxicity. This is achieved via orthogonal levers of specificity: (1) lipid nanoparticles (LNP) for extrahepatic delivery of nucleic acids following intravenous (IV) injection to maximize tumor DNA delivery, and (2) highly engineered synthetic cancer-activated promoters (CAP) that restrict expression to malignant cells. As a result, the therapeutic protein production is concentrated within the diseased tissues while avoiding broad systemic exposure and corresponding dose-limiting toxicities. Typically, IV-dosed LNPs are rapidly opsonized and cleared by the liver. Proprietary Earli LNPs were optimized for systemic delivery of DNA beyond the liver including solid tumors. Biodistribution and expression from different LNPs were assessed using a DNA with a CAG promoter driving luciferase in subcutaneous xenograft models. The lead LNP achieved more than a 6-fold higher tumor expression than the same DNA formulated in an LNP used in a commercial siRNA product. Importantly, tumor tropism confirmed a robust 88-fold difference in tumor-to-liver BLI ratio. Cancer-activated expression was initially tested in syngeneic subcutaneous models. An IV-dosed CAP-driven IL-12 DNA construct resulted in tumor regression in all treated animals, achieving a 100% cure rate at modest DNA levels. This response was accompanied by robust CD8⁺ T cell activation. IL-12 was detected in the tumor but remained undetectable in the serum, confirming selective expression driven by the CAP element. To demonstrate utility in clinically relevant models, the platform was tested in orthotopic models of lung cancer. In an aggressive lung metastases model, CAP-IL-12 significantly reduced lung tumor burden by over 7-fold compared to a non-expressing control construct, and significantly reduced metastatic nodules and lung weights. Immune-profiling revealed IL-12-driven immune activation, such as 2-fold increases in Ki67⁺ cells and a 4-fold increase in cytotoxic CD8⁺ T cells compared to control. Central and effector memory T cells were also elevated by 2-fold. Myeloid cells showed enhanced activation with a 3-fold increase in MHC II expression on dendritic cells, indicative of improved antigen presentation within the tumor microenvironment. Ongoing experiments are evaluating the efficacy of CAP-driven IL-12 delivered with newly developed LNPs in orthotopic bladder and liver models. Overall, our findings demonstrate Earli's cancer-activated expression platform across cancer indications, supporting its development for broad application across oncologic indications.