Fate Therapeutics has announced initial clinical and preclinical data for FT825 / ONO-8250, an iPSC-derived CAR T-cell therapy targeting HER2, at the 2024 Society for Immunotherapy of Cancer (SITC) Annual Meeting. The Phase 1 study in advanced solid tumors showed a favorable safety profile in the initial low-dose cohort, while preclinical data demonstrated cancer-selective HER2 targeting.
Novel HER2-Targeting Approach
FT825 / ONO-8250 incorporates a novel H2CasMab-2 binding domain designed to preferentially target HER2 expressed on tumor cells, potentially mitigating off-target toxicities associated with traditional HER2-directed therapies like trastuzumab (Herceptin) and trastuzumab deruxtecan (Enhertu). This is particularly important as widespread HER2 expression in normal epithelial tissue can lead to significant side effects.
The cancer-selective recognition profile of FT825 / ONO-8250's HER2 antigen-binding domain was highlighted in preclinical studies. The therapy demonstrated potent HER2-specific, anti-tumor activity in both in vitro and in vivo settings with limited cytolytic targeting of HER2+ normal cells. This selectivity is attributed to the H2CasMab-2 antibody, which preferentially recognizes locally misfolded HER2 and p95 truncation variants of HER2, as compared to trastuzumab.
Phase 1 Clinical Trial Observations
The ongoing Phase 1 study (NCT06241456) is evaluating the safety, pharmacokinetics, and activity of FT825 / ONO-8250 as a monotherapy and in combination with monoclonal antibody (mAb) therapy in patients with advanced solid tumors. The initial low-dose cohort involved three heavily pre-treated patients who had previously undergone at least five prior lines of therapy, including HER2-targeted treatments. These patients received FT825 / ONO-8250 at a dose level of 100 million cells as a monotherapy after conditioning chemotherapy.
As of the data cutoff date of October 25, 2024, FT825 / ONO-8250 was well-tolerated, with no dose-limiting toxicities (DLTs) and no events of any grade of cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), or graft-versus-host disease (GvHD) observed. Peak CAR T-cell expansion was observed at Day 8 following treatment in all three patients. Phenotyping of FT825 / ONO-8250 sourced from the patients’ peripheral blood on Day 8 indicated an activated state, with high levels of Granzyme B expression and maintenance of CAR expression, and no evidence of exhaustion, as indicated by low levels of PD-1 and TIM3 expression.
Additional Preclinical Findings
Further preclinical data revealed that FT825 / ONO-8250 exhibits potent antibody-mediated cellular cytotoxicity (ADCC) through its high-affinity non-cleavable CD16 (hnCD16) Fc receptor. This mechanism 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.
Collaboration and Future Directions
Fate Therapeutics and Ono Pharmaceutical Co., Ltd. are jointly responsible for the development and commercialization of FT825 / ONO-8250 in the U.S. and Europe, while Ono maintains exclusive rights in the rest of the world. The companies are also collaborating on preclinical development of another solid tumor program targeting an undisclosed tumor-associated antigen. Enrollment is currently ongoing at the second dose level of 300 million cells as monotherapy and at the first dose level of 100 million cells in combination with epidermal growth factor receptor (EGFR)-targeted mAb therapy.
