Abstract LB-B011: DN64- <i>CAR-V</i> : AN OFF-THE-SHELF CYTOCIDAL CHIMERIC (tARGETED) AMPHOTROPIC RNA VECTOR FOR SELECTIVELY MODIFYING THE TUMOR MICROENVIRONMENT IN IL-6 DRIVEN SARCOMAS (NCT04091295)

Abstract Background: Interleukin-6 (IL-6) is a key cytokine that mediates inflammation, tumor proliferation, immunosuppression and chemoresistance in bone and soft-tissue sarcomas. DNG64-CAR-V is an off-the-shelf cytocidal replication-incompetent chimeric/tumor targeted amphotropic RNA expression vector that inhibits hyperplasia and selectively targets cancer cells, neoangiogenesis and reactive cytokine-producing cancer associated fibroblasts (CAFs) within the tumor microenvironment (TME). Methods: Objectives: 1) Evaluate the cytocidal activity of DNG64-CAR-V in HT1080 human fibroblastic cell cultures in vitro, and 2) Report on the clinical effects of DNG64-CAR-V on circulating IL-6 levels and treatment outcome parameters in patients with IL-6 driven sarcomas. HT1080 cell cultures were transduced with DNG64-CAR-V and the number of cells were quantified at 3-5 days post transduction. Cytocidal activity was measured by the following formula: % cytocidal activity = [# cells (medium-treated cultures) - # cells (vector treated cultures)] divided by [# cells (medium-treated cultures)] x 100 Treatment Schedule: Patients with advanced sarcomas and high IL-6 blood levels (&amp;gt;26 pg/ml) were treated with DNG64-CAR-V 1.7 x 10e10 VC/dose i.v. 3x a week + metronomic low doses of an FDA approved chemotherapy + immunotherapy (DNG64-CAR-V+). One patient received DNG64-CAR-V + tocilizumab. Results: The mean cytocidal activity of DNG64-CAR-V was 89% in triplicate HT1080 cell cultures at 5 days post transduction. Three patients with advanced sarcomas with high serum levels of IL-6 experienced either a significant reduction (n=2) or no reduction (n=1) in IL-6 levels. One patient with a dramatic reduction to normal IL-6 levels had a sustained partial response &amp;gt;12 months, and two patients with a two-fold or no fall in IL-6 levels had stable disease &amp;gt;6 months. No treatment-related adverse events were reported. Conclusions: Taken together, the data indicates that (1) DNG64-CAR-V may exhibit significant cytocidal activity in cytokine producing CAFs in the TME, (2) DNG64-CAR-V with or without tocilizumab may reduce inflammation iwithn theTME and thereby convert an immune-suppressive to an immune-responsive lesion, (3) By selectively killing cancer cells, proliferative neovasculature and the extracellular matrix producing CAFs, DNG64-CAR-V may reduce stroma formation and alter the TME, hence, facilitating entry of chemo/immunotherapy drugs into the TME, and (4) The DNG64-CAR-V+ regimen may be a safe and effective therapy for patients with advanced IL-6 driven sarcomas. Citation Format: Piya Mann, Vaishali Kumar, Samantha Jeffrey, Neal S. Chawla, Sant P. Chawla, Rebecca A. Reed, Frederick L . Hall, Erlinda M. Gordon. DN64-CAR-V: AN OFF-THE-SHELF CYTOCIDAL CHIMERIC (tARGETED) AMPHOTROPIC RNA VECTOR FOR SELECTIVELY MODIFYING THE TUMOR MICROENVIRONMENT IN IL-6 DRIVEN SARCOMAS (NCT04091295) [abstract]. In: Proceedings of the AACR Immuno-Oncology Conference (AACR IO): Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2026 Feb 18-21; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2026;14(2 Suppl):Abstract nr LB-B011.