Abstract BACKGROUND: Glypican-3 (GPC3) is uniquely expressed and has been associated with the development of several pediatric solid embryonal tumors, making it a prime target for GPC3 CAR-T cell killing. TGF-β, a cytokine associated with immunosuppression, has also been shown to be highly expressed in the microenvironment of these tumors, potentially hindering CAR-T cell antitumor activity. In this study, we examined the therapeutic efficacy of AZD5851, an autologous CAR-T product that expresses a CAR specific for GPC3 and a dominant negative (dn)TGFβRII as an armoring strategy. METHODOLOGY: To assess the drug’s in vivo efficacy, 5 established patient-derived orthotopic xenograft (PDOX) models of pediatric medulloblastoma (ICb-2123MB, -1299MB, -S1129MB), atypical teratoid rhabdoid tumor (IC-L1115ATRT) and a high grade glioma (IC-2664HGG), with confirmed expression of GPC3 and TGF-β through immunohistochemical staining, were treated with untransduced T cells dosed at 12x106 cells/mouse, intravenously (IV) once or GPC3 CAR-T cells (dosed at 5x106 cells/mouse, IV once). 20 eight-week-old SCID mice per model received intra-cerebral (IC) or intra-cerebellar (ICb) tumor cell implantation and were divided into 2 treatment groups (n=10 per group): Untransduced T cells and GPC3 CAR-T cells. Animal survival times were analyzed using Gehan-Breslow-Wilcoxon analysis. RESULTS: GPC3 CAR-T cell treatment was well tolerated in mice with no loss of body weight or other toxicities. GPC3 CAR-T cell treatment significantly improved the median survival time in 2/5 models, including ICb-2123MB from 90.5 days in the untransduced T cell group to 162.5 days (P=0.02) and IC-L1115ATRT from 136 days to 174 days (P=0.02). CONCLUSION: Our data identifies single agent antitumor activity for GPC3 CAR-T cells for PDOX models of pediatric medulloblastoma and atypical teratoid rhabdoid tumor. The results support further clinical translational efforts involving the use of AZD5851 alone or in combination with other therapies for the treatment of these tumors. Citation Format: Milagros Suarez, Aalaa Abdallah, Xin Zhai, Zilu Huang, Yuchen Du, Nitin Wadhwani, Alicia Lenzen, Jee Young Kwon, Steven B. Neuhauser, Timothy Stearns, Jeffrey H. Chuang, Emily L. Jocoy, Carol J. Bult, Beverly Teicher, Malcolm A. Smith, Xiao Nan Li. AZD5851, a TGF-β-resistant GPC3 CAR-T cell product, prolongs animal survival times in patient derived orthotopic xenograft models of medulloblastoma and atypical teratoid rhabdoid tumor 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 1528.
Suárez et al. (Fri,) studied this question.
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