Sun Y, Dong Y, Sun R, et al. Chimeric Anti-GPC3 sFv-CD3 Epsilon Receptor-Modified T Cells with IL7 Co-Expression for the Treatment of Solid Tumors. Molecular Therapy — Oncolytics. 2022; 25: 160 (doi: 10.1016/j.omto.2022.04.003). Researchers report that chimeric antigen receptor (CAR) T cells targeting glypican-3 (GPC3) represent a potentially viable therapeutic pathway for solid tumors and, with modification, offer superior antitumor immunity compared with other CAR constructs. GPC3, a heparin sulfate proteoglycan, is overexpressed in hepatocellular carcinomas (HCCs) and several other solid tumors but is not typically present in healthy adult tissues. While GPC3-specific CAR cells using the 28-Zeta construct showed treatment promise in 13 patients with advanced HCCs, more than one-half developed severe cytokine release syndrome (CRS). To improve safety and efficacy, scientists modified T cells with anti-GPC3 single-chain fragment variables (sFv) linked to CD3e to create an achimeric environment that works more like the natural T cell receptor signaling pathway. The resulting sFv-ε T cells demonstrated robust antitumor properties and reduced CRS compared with other types of CAR T cells. Researchers further modified them with interleukin-7 co-expression in an effort to stimulate T cell survival and mobilize the endogenous immune system. Immunocompetent murine models showed that 7sFv-ε T cells were superior to sFv-ε T cells, based on higher persistence, greater antitumor efficacy, and better immunological memory — all while keeping production of cytokines linked to CRS in check.