On November 9, 2024 Fate Therapeutics, Inc. (NASDAQ: FATE), a clinical-stage biopharmaceutical company dedicated to bringing a first-in-class pipeline of induced pluripotent stem cell (iPSC)-derived cellular immunotherapies to patients with cancer and autoimmune disorders, reported initial clinical and new preclinical data for FT825 / ONO-8250, a multiplexed-engineered, chimeric antigen receptor (CAR) T-cell product candidate targeting human epidermal growth factor receptor 2 (HER2), at the 2024 Society of Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) 39th Annual Meeting being held in Houston, TX on November 6-10, 2024 (Press release, Fate Therapeutics, NOV 9, 2024, View Source [SID1234648059]). FT825 / ONO-8250 incorporates a novel H2CasMab-2 binding domain targeting HER2 that is designed to overcome on-target, off-tumor toxicity and to recognize variants associated with poor clinical outcomes and tumor escape. In an ongoing Phase 1 study in advanced solid tumors, three patients were treated with FT825 / ONO-8250 in the first low-dose cohort as monotherapy, and 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) were observed. The multi-center, Phase 1 study is currently being conducted under a strategic collaboration with Ono Pharmaceutical Co., Ltd. (Ono).
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"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. We are very pleased with initial Phase 1 clinical observations from the first low-dose cohort, which showed a favorable safety profile, product expansion, and maintenance of an activated CAR T-cell state," said Scott Wolchko, President and Chief Executive Officer of Fate Therapeutics. "In addition, new preclinical data for FT825 / ONO-8250 presented today at SITC (Free SITC Whitepaper) highlighted the cancer-selective recognition profile of its novel HER2 antigen binding domain, including its potential to target variants uniquely expressed on tumor cells. Under our collaboration with Ono, we are excited to further assess the potential of FT825 / ONO-8250 to benefit patients with hard-to-treat advanced solid tumors who currently have limited treatment options."
Initial Phase 1 Clinical Observations
The Phase 1 study is designed to assess the safety, pharmacokinetics, and activity of FT825 / ONO-8250 as monotherapy and in combination with monoclonal antibody (mAb) therapy in patients with advanced solid tumors (NCT06241456). Three heavily pre-treated patients, all of whom were previously treated with at least five prior lines of therapy including HER2-targeted therapy, were administered conditioning chemotherapy and FT825 / ONO-8250 at the first dose level of 100 million cells as monotherapy. In all three patients, peak CAR T-cell expansion was observed at Day 8 following treatment. In addition, phenotyping of FT825 / ONO-8250 sourced from the patients’ peripheral blood on Day 8 was indicative of an activated state (as evidenced by high levels of Granzyme B expression and maintenance of CAR expression) with no evidence of exhaustion (as evidenced by low levels of PD-1 and TIM3 expression). As of a data cutoff date of October 25, 2024, FT825 / ONO-8250 was well-tolerated with no DLTs and no events of any grade of CRS, ICANS, or GvHD. 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.
Preclinical Data
While HER2-directed therapies, such as trastuzumab (Herceptin) and trastuzumab deruxtecan (Enhertu), are effective in treating HER2-positive cancers, widespread HER2 expression in normal epithelial tissue can lead to significant off-tumor, on-target toxicities. At an oral presentation today at SITC (Free SITC Whitepaper) entitled "Preferential targeting of HER2-expressing cancer cells by FT825 / ONO-8250, an off-the-shelf iPSC-derived CAR-T cell incorporating novel synthetic mechanisms for enhanced solid tumor activity", scientists from the Company, Ono, Osaka University, and Tohoku University highlighted that FT825 / ONO-8250 demonstrated potent HER2-specific, anti-tumor activity in both in vitro and in vivo settings with limited cytolytic targeting of HER2+ normal cells. The on-tumor selectivity of FT825 / ONO-8250 was attributed to its incorporation of a novel HER2-targeted antigen binding domain, which was derived from a cancer-specific monoclonal antibody H2CasMab-2 (Kaneko et al., 2024), that was shown to differentially and preferentially recognize both locally misfolded HER2 and p95 truncation variants of HER2 as compared to trastuzumab. The scientists also presented preclinical data demonstrating that FT825 / ONO-8250 exhibits potent antibody-mediated cellular cytotoxicity (ADCC) through its high-affinity non-cleavable CD16 (hnCD16) Fc receptor, synergizing with trastuzumab to enhance 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.
Under the terms of its partnership with Ono for FT825 / ONO-8250, Fate and Ono are jointly responsible for development and commercialization in the U.S. and Europe, and Ono maintains exclusive development and commercialization rights in the rest of the world. The parties are also conducting preclinical development of an additional solid tumor program targeting an undisclosed tumor-associated antigen.