journal contribution
posted on 2023-03-31, 00:25 authored by Laurie Menger, Anna Sledzinska, Katharina Bergerhoff, Frederick Arce Vargas, Julianne Smith, Laurent Poirot, Martin Pule, Javier Herrero, Karl S. Peggs, Sergio A. Quezada PD-1-TALEN activity screen in murine thymoma EL4 cells.PD-1 gene inactivation in pmel-1 CD8+T cells and functional analysis. PD-1-TALEN activity in TRL from MCA205. Effector/memory phenotype of TRL from MCA205.
Funding
http://dx.doi.org/10.13039/501100000289
CRUK, Leukemia and Lymphoma Research
Department of Health and CRUK
History
ARTICLE ABSTRACT
Despite the promising efficacy of adoptive cell therapies (ACT) in melanoma, complete response rates remain relatively low and outcomes in other cancers are less impressive. The immunosuppressive nature of the tumor microenvironment and the expression of immune-inhibitory ligands, such as PD-L1/CD274 by the tumor and stroma are considered key factors limiting efficacy. The addition of checkpoint inhibitors (CPI) to ACT protocols bypasses some mechanisms of immunosuppression, but associated toxicities remain a significant concern. To overcome PD-L1–mediated immunosuppression and reduce CPI-associated toxicities, we used TALEN technology to render tumor-reactive T cells resistant to PD-1 signaling. Here, we demonstrate that inactivation of the PD-1 gene in melanoma-reactive CD8+ T cells and in fibrosarcoma-reactive polyclonal T cells enhanced the persistence of PD-1 gene-modified T cells at the tumor site and increased tumor control. These results illustrate the feasibility and potency of approaches incorporating advanced gene-editing technologies into ACT protocols to silence immune checkpoints as a strategy to overcome locally active immune escape pathways. Cancer Res; 76(8); 2087–93. ©2016 AACR.
