What question did this study set out to answer?

To investigate the role of phosphorylated IRF7 in enhancing the antitumor efficacy of GPC3-targeted CAR T cells.

April 5, 2026

Abstract 5203: Phosphorylated IRF7 enhances antitumor activity of GPC3-targeted CAR T cells in solid tumors

Key Points

To investigate the role of phosphorylated IRF7 in enhancing the antitumor efficacy of GPC3-targeted CAR T cells.
Conducted single cell RNA sequencing on tumor infiltrating CAR T cells to identify molecular profiles.
Assessed naive, central memory, and effector memory cell populations using flow cytometry.
Evaluated CAR T cell expansion and killing efficacy in tumor-challenge assays along with in vivo testing in mouse models.
IRF7.CAR and pIRF7.CAR T cells showed higher naive and central memory populations compared to 15.CAR T cells.
Significantly improved killing efficacy was noted in repeated tumor-challenge assays (p<0.001).
In vivo, pIRF7 GPC3+ cells demonstrated rapid tumor clearance in mouse models with xenografts.

Abstract

Abstract Glypican-3 (GPC3) is highly expressed in hepatocellular carcinoma (HCC) and hepatoblastoma (HBL), but not in healthy mature tissues; thus, represents a promising immunotherapeutic target. In a recent study, GPC3-CAR or IL15 co-expressing GPC3-CAR T cells (15. CAR) were safe in patients, IL15 co-expression significantly enhanced CAR T cell expansion and resulted in a disease control rate of 66% and antitumor response rate of 33%. To elucidate molecular programs associated with therapeutic response, single cell RNA sequencing of tumor infiltrating CAR T cells was performed and unique transcriptomic profile differences were identified associated with antitumor responses including downregulation of SWI/SNF and upregulation of FOS/JUN and Type I Interferon family members. Transcription factor motif enrichment analyses identified Interferon regulatory factor 7 (IRF7) as the dominant transcriptional driver of genes upregulated in responders. We hypothesized that IRF7 will boost the antitumor activity and this study examined the role of wild type and constitutively active IRF7 expression in GPC3-CAR T cells (IRF7. CAR and pIRF7. CAR, respectively). Compared with 15. CAR T cells, IRF7. CAR and pIRF7. CAR T cells showed significantly higher naïve (CD45RA+ CCR7+ CD62L+; CD4 p=0. 0348; in CD8 p=0. 0163;), Central memory (CM, CD45RO+ CCR7+ CD62L+; CD4 p= 0. 0382), LAG3+ (CD4 p=0. 0236, CD8 p=0. 0030) and significantly lower effector memory (TEM, CD45RA- CCR7- CD62L-; CD4 p= 0. 0221) cell population at baseline, post-manufacturing based on flow cytometry. IRF7. CAR and pIRF7. CAR T cells had higher expansion and significantly improved killing efficacy (p0. 001) in repeated tumor-challenge assays using the IncuCyte system. Finally, In vivo, pIRF7GPC3+ cells showed more rapid tumor clearance under both high (5x10⁶) - and low-dose (3x10⁶) conditions in NSG-MHC I/II double knockout mice bearing HCC and HBL xenografts. These findings demonstrate that pIRF7 enhances CAR T-cell function. Incorporation of pIRF7 into GPC3-targeted CARs represents a novel strategy to improve efficacy against solid tumors. Citation Format: Inci Cevher Zeytin, Che-Hsing Li, David de la Cerda, Leidy Diana Caraballo Galva, Andras Attila Heczey. Phosphorylated IRF7 enhances antitumor activity of GPC3-targeted CAR T cells in solid tumors abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (7 Suppl): Abstract nr 5203.

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