Abstract
Abstract Background: A growing body of evidence indicates that the blockade of PD-1 and other immunosuppressive receptors can increase the efficacy of adoptively transferred cells in immunotherapy for cancer. The expression of PD-1 can be suppressed by ex vivo treatment of transferred lymphocytes by self-deliverable RNAi (sd-rxRNA®) compounds. sd-rxRNAs are based on proprietary chemical modifications of siRNA compounds making them stable to nuclease degradation and capable of penetration into target cells without the use of transfection reagents or physical methods. Aim: To determine whether the reduction of PD-1 by ex vivo treatment of mesothelin-targeting CAR-T cells with sd-rxRNA will improve the efficacy of meso-CAR-T cells in a mouse model of ovarian cancer. Methods: Second-generation human CAR-T cells expressing P4 antibody fragments targeting mesothelin (meso-CAR-T) were treated ex vivo with PD-78, a self-deliverable siRNA silencing the PD-1 gene. The meso-CAR-T cells were then injected into tumors in a xenograft mouse model of human ovarian cancer (A1847 cell line expressing mesothelin and PD-L1) in NSG mice. The tumor volumes were monitored over the course of one month. After the animals were sacrificed, human CD45-containing cells extracted from the tumor were analyzed for PD-1 expression by flow cytometry. Results: We observed a statistically significant reduction in tumor growth in the group of mice injected with meso-CAR-T cells pretreated ex vivo with PD-78. The post-mortem tumor analysis by flow cytometry showed that the expression of PD-1 in meso-CAR-T cells was significantly suppressed for the full duration of the experiment (one month). Conclusion: Our results suggest that the silencing of immunosuppressive genes by ex vivo treatment with sd-rxRNA may improve efficacy of CAR-T cells in the treatment of solid tumors. A similar approach may be applied to other types of adoptive cell transfer. Citation Format: Alexey Wolfson, Alexey Eliseev, Taisia Shmushkovich, Monica Betancur-Boissel, Monica Betancur-Boissel, Nathalie Scholler. Enhancement of CAR-T cell activity via PD-1 knockdown by self-deliverable RNAi [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5650. doi:10.1158/1538-7445.AM2017-5650
Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
