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• W4308378124 abstract "<h3>Background</h3> Interleukin-12 (IL-12) is a powerful immunostimulatory cytokine that has been expressed ectopically in genetically engineered T cells to enhance their antitumor activity. However, the constitutive production of IL-12 by engineered T cells caused severe adverse effects in patients. Thus, to fully harness the immunostimulatory potential of IL-12 while avoiding systemic toxicity, we inserted <i>IL-12</i> gene into the <i>PDCD1</i> locus in T cell receptor (TCR)-engineered T cells using the CRISPR/Cas9-based genome editing tool, which allows for IL-12 secretion to be induced strictly in a T cell activation-dependent manner. <h3>Methods</h3> As a model TCR, we used a monoclonal TCR that is specific to the NY-ESO-1 (SLLMWITQV) peptide. The PD1-edited NY-ESO-1-specific TCR-T cells were generated by sequential lentiviral transduction and Cas9 RNP/AAV6-based knock-in into human primary T cells. The resulting TCR-T cells were co-cultured with an A375 cell line expressing NY-ESO-1 antigen to evaluate cytokine production, cytotoxicity, and proliferation <i>in vitro. In vivo</i> antitumor activity of the TCR-T cells was investigated in A375 xenograft models using NSG mice. <h3>Results</h3> The <i>PDCD1</i> locus was successfully edited in NY-ESO-1 TCR-T cells by replacing the endogenous PD-1 gene with a single-chain IL-12 transgene, without affecting the viability or expansion of the engineered T cells. Upon recognition of the target cells, the IL-12 transgene was expressed successfully, resulting in the strong phosphorylation of STAT-4 in the TCR-T cells. As compared to control TCR-T cells, these ΔPD-1-IL-12 NY-ESO-1 T cells displayed enhanced <i>in vitro</i> effector function, including increased secretion of IFNγ, TNF, and IL-10 as well as faster tumor cell lysis. In addition, ΔPD-1-IL-12 NY-ESO-1 T cells expanded more robustly after repeated challenges with PD-L1 overexpressing target cells. In xenograft models, ΔPD-1-IL12 NY-ESO-1 T cells potently eliminated established tumors and demonstrated increased tumor infiltration compared to control TCR-T cells. <h3>Conclusions</h3> Using the CRISPR/Cas9 system, we demonstrated that the upregulation of PD-1, an immune-suppressive event in T cells, could be reprogrammed to secrete immunostimulatory IL-12 in TCR-T cells. In both <i>in vitro</i> assays and <i>in vivo</i> mouse xenograft studies, these PD-1-edited TCR-T cells demonstrated enhanced cytotoxic activity. Our approach may offer a novel engineering option for adoptive T cell therapy against solid tumors." @default.
• W4308378124 created "2022-11-11" @default.
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• W4308378124 date "2022-11-01" @default.
• W4308378124 modified "2023-09-25" @default.
• W4308378124 title "235 CRISPR-mediated insertion of IL-12 into the<i>PDCD1</i>locus improves the antitumor activity of TCR-T cells against solid tumors" @default.
• W4308378124 doi "https://doi.org/10.1136/jitc-2022-sitc2022.0235" @default.
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