Fate Therapeutics has announced promising initial clinical and preclinical data for FT825 / ONO-8250, an induced pluripotent stem cell (iPSC)-derived chimeric antigen receptor (CAR) T-cell product candidate targeting human epidermal growth factor receptor 2 (HER2). The data, presented at the 2024 Society for Immunotherapy of Cancer (SITC) Annual Meeting, suggest a favorable safety profile and cancer-selective targeting of HER2-expressing solid tumors.
Phase 1 Clinical Trial: Safety and Early Signs of Activity
The ongoing Phase 1 study (NCT06241456) is evaluating the safety, pharmacokinetics, and activity of FT825 / ONO-8250 in patients with advanced solid tumors. The initial low-dose cohort (100 million cells) included three heavily pre-treated patients who had previously received multiple lines of therapy, including HER2-targeted agents. As of the data cutoff date (October 25, 2024), FT825 / ONO-8250 was well-tolerated, with no dose-limiting toxicities (DLTs) or events of cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), or graft-versus-host disease (GvHD).
Notably, peak CAR T-cell expansion was observed in all three patients on Day 8 following treatment. Phenotyping of FT825 / ONO-8250 cells from peripheral blood indicated an activated state, with high levels of Granzyme B expression and maintenance of CAR expression, and low levels of PD-1 and TIM3 expression, suggesting a lack of exhaustion.
Preclinical Data: Cancer-Selective HER2 Targeting
Preclinical studies highlighted the cancer-selective recognition profile of FT825 / ONO-8250's novel HER2 antigen-binding domain (H2CasMab-2). This domain preferentially targets HER2 expressed on tumor cells, including locally misfolded HER2 and p95 truncation variants, while limiting cytolytic targeting of HER2+ normal cells. This selectivity is designed to overcome the on-target, off-tumor toxicities associated with existing HER2-directed therapies like trastuzumab (Herceptin) and trastuzumab deruxtecan (Enhertu), which can cause significant adverse effects due to widespread HER2 expression in normal epithelial tissue.
The preclinical data also demonstrated that FT825 / ONO-8250 exhibits potent antibody-mediated cellular cytotoxicity (ADCC) through its high-affinity non-cleavable CD16 (hnCD16) Fc receptor. This synergizes with trastuzumab to enhance the clearance of HER2+ tumor cells and with cetuximab to enable multi-antigen targeting of HER2 and epidermal growth factor receptor (EGFR) expressed on cancer cells.
Implications for Solid Tumor Therapy
"FT825 / ONO-8250 integrates seven novel synthetic controls of CAR T-cell function designed to overcome multiple mechanisms that impede the safe and effective treatment of solid tumors," said Scott Wolchko, President and Chief Executive Officer of Fate Therapeutics. The favorable safety profile and cancer-selective targeting observed in the initial Phase 1 data and preclinical studies suggest that FT825 / ONO-8250 has the potential to address the unmet medical need for effective and well-tolerated HER2-targeted therapies in patients with advanced solid tumors. The ongoing Phase 1 study is continuing to enroll patients at higher dose levels and in combination with EGFR-targeted monoclonal antibody therapy.
