Abstract 4826: Tyrosine kinase inhibitor combination therapies with AZD5851, dominant-negative TGFβRII armored anti-GPC3 CAR-T, for the treatment of hepatocellular carcinoma

Abstract Background: AZD5851 is a glypican-3 (GPC3)-targeting CAR-T armored with a TGFβRII dominant-negative receptor that protects the CAR-T from the immunosuppressive cytokine TGFβ. AZD5851 is currently being tested in a Phase I/II clinical trial (NCT06084884) for patients with advanced/recurrent hepatocellular carcinoma (HCC). The multi-target tyrosine kinase inhibitors (TKIs) sorafenib and lenvatinib are licensed for first line treatment of advanced/recurrent HCC. Sorafenib inhibits tumor cell proliferation and angiogenesis by blocking the Ras/Raf pathway, vascular endothelial growth factor receptors (VEGFR), and platelet-derived growth factor receptor (PDGFR). Lenvatinib mediates its antiangiogenic functions by targeting VEGFR, PDGFR, and fibroblast growth factor receptors (FGFR). Additionally, lenvatinib can reduce immunosuppression in the tumor microenvironment by decreasing infiltration of tumor-associated macrophages, myeloid-derived suppressor cells, and T regulatory cells. Due to these anti-tumor and immunomodulatory effects, we evaluated whether sorafenib or lenvatinib can enhance in vivo efficacy in combination with AZD5851, and if either TKI impacts CAR-T function. Results: Therapeutic concentrations of sorafenib and lenvatinib did not affect AZD5851 viability, antigen dependent proliferation, activation, effector cytokine secretion, and target cell killing after co-culture with GPC3+ target tumor cells in vitro. In the PLC/PRF/5 HCC xenograft model, efficacious doses of both TKIs did not impair CAR-T anti-tumor function. High efficacious dose of sorafenib in combination with AZD5851 only subtly enhanced anti-tumor efficacy, whereas coadministration of high dose lenvatinib significantly increased tumor control compared to AZD5851 alone. To further explore the combination of lenvatinib with AZD5851, pharmacokinetic modeling for lenvatinib was performed to determine doses that would achieve exposures in mice equivalent to those observed in human patients. Combination of AZD5851 with the clinically relevant dose of lenvatinib significantly enhanced the anti-tumor efficacy and survival compared to CAR-T or lenvatinib alone. Conclusions: The TKI lenvatinib enhances TGFβRII dominant-negative receptor armored GPC3 CAR-T (AZD5851) anti-tumor efficacy in vivo without affecting acute CAR-T viability, proliferation, activation, effector cytokine production, and cytotoxicity. Therefore, combining AZD5851 with lenvatinib may be a promising combination therapeutic regimen for patients with HCC. Citation Format: Nina J. Chu, Ashley A. Merlino, John Stone, Niresh Hariparsad, Scott Rata, Gordon Moody, Letizia Giardino. Tyrosine kinase inhibitor combination therapies with AZD5851, dominant-negative TGFβRII armored anti-GPC3 CAR-T, for the treatment of hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4826.