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• W4308377687 abstract "<h3>Background</h3> Solid tumors remain a challenging frontier for adoptive cellular therapies (ACT). Armoring T-cells with cytokines, such as interleukin 12 (IL-12), to remodel the tumor microenvironment (TME) has demonstrated preclinical efficacy against solid tumors. However, the clinical utility of IL-12 is limited by systemic toxicities, requiring tight control of expression. Herein, we show that T-cells armored with a small molecule-controlled membrane bound IL-12 (mbIL-12) drives regulation of pharmacodynamic markers and solid tumor efficacy in xenograft and syngeneic solid tumor models. <h3>Methods</h3> We regulated mbIL-12 expression using Obsidian’s cytoDRIVE® technology. In this system, a drug responsive domain (DRD) is fused to a protein of interest. In the “off-state” the fusion protein is rapidly degraded by the proteasome. Adding a small molecule ligand stabilizes the complex, enabling expression (the “on-state”). Here, we use a DRD derived from carbonic anhydrase 2 and the FDA-approved inhibitor acetazolamide (ACZ) as a stabilizing ligand. Unlike most other regulation systems, cytoDRiVE® is both fully human, reducing immunogenicity, and induced pharmacologically, allowing on-demand control. Adding oligomerization domains increases the local density of DRDs to form modulation-hubs that further increase the regulation of mbIL-12. Cytokine levels were determined using flow cytometry and Meso Scale Discovery assays. Human mbIL-12 modulation hubs and CD19-CARs were transduced in peripheral blood T-cells and evaluated <i>in vivo</i> against subcutaneous Raji xenografts that form solid tumors in NSG mice after inoculation in Matrigel. Mouse constructs were evaluated in CD8 gp100 (PMEL) TCR transgenic cells against subcutaneous B16-F10 melanoma in C57BL6 mice. <h3>Results</h3> In the xenograft setting, ACZ dosing resulted in 35-fold regulation of IL-12 in the plasma and showed remarkable ACZ-dependent anti-tumor efficacy against large, solid Raji tumors at a 10x lower cell dose than unarmored CAR-Ts. In the immunocompetent PMEL/B16 model, IL-12 modulation-hub PMEL cells slowed tumor growth over unarmored PMEL cells and showed improved tolerability over secreted IL-12. Animals receiving IL-12 modulation-hub cells showed ACZ-dependent regulation of IL-12 and IFNγ in the plasma with levels 100-fold and 20-fold less, respectively, than with constitutive secreted IL-12 cells. This regulation led to functional impacts at the cellular level, including an increase in circulating antigen presenting cells. <h3>Conclusions</h3> The cytoDRiVE® platform enables enhanced regulation of IL-12 armored T-cells in multiple preclinical solid tumor models, potentiating an improved therapeutic window for IL12 in ACT. <h3>Ethics Approval</h3> All animals studies were IACUC approved." @default.
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• W4308377687 date "2022-11-01" @default.
• W4308377687 modified "2023-09-25" @default.
• W4308377687 title "278 Pharmacologically-controlled expression of membrane-bound IL-12 results in T-cell therapy with enhanced potency in preclinical solid tumor models" @default.
• W4308377687 doi "https://doi.org/10.1136/jitc-2022-sitc2022.0278" @default.
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