Abstract CT030: Mesothelin-targeted CAR-T therapy FC004 for platinum-resistant ovarian cancer: A phase I trial

Abstract Background: Platinum-resistant is a highly aggressive gynecological malignancy with limited treatment options. Mesothelin (MSLN), overexpressed in ovarian cancer cells, is a promising target for chimeric antigen receptor (CAR) T-cell therapy. Recent evidence shows that MSLN-CAR T cells can recognize and attack cancer cells, offering a potential new treatment for platinum-resistant ovarian cancer. We report results from a phase I study of FC004, an MSLN-CAR T-cell therapy, in patients with platinum-resistant ovarian cancer. Methods: Eligible patients were aged 18-75 years, with histologically confirmed epithelial ovarian cancer and platinum-resistant disease that had failed standard therapies. MSLN expression was ≥ 2 or tumor positivity ≥ 40%. Patients were pre-treated with albumin-bound paclitaxel, cyclophosphamide, and fludarabine, then received a single infusion of FC004. A 3+3 dose-escalation design was used to determine the recommended phase II dose (RP2D), starting with 2×106 cells/kg. The primary endpoint were safety, the maximum tolerated dose (MTD) and RP2D. Key secondary endpoints included disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and pharmacokinetic profile. Results: As of January 2025, two patients were enrolled and received FC004 at the dose of 2×106 cells/kg. Patient #1, a 55-year-old female, received 1.09×108 CAR-T cells. CAR-T cell concentration peaked on day 7 post-infusion. One month after treatment, the patient achieved stable disease (SD) with no dose-limiting toxicities (DLTs), cytokine release syndrome (CRS), or immune effector cell-associated neurotoxicity syndrome (ICANS). Patient #2, a 51-year-old female, received 9.4×107 CAR-T cells. On the day of infusion, she experienced fever, followed by pulmonary infection and grade 3 CRS. CAR-T cell concentration peaked on day 7 and gradually decreased. On day 27, the percentage of CAR+ cells among CD3+ cells was 0.5%. Notably, CA125 levels decreased from 964 U/ml to 227 U/ml on day 11. The patient passed away one month later, likely due to complications from the infection. Conclusions: Preliminary results suggest that FC004 CAR-T cell therapy may have limited efficacy in treating platinum-resistant ovarian cancer. One patient achieved SD, while the other experienced significant toxicities, including severe CRS and pulmonary infection. The infection may have been exacerbated by prior high-dose steroids use, but a relationship with FC004 cannot be ruled out. Despite these adverse events, the decrease in CA125 levels in the latter patient suggests some biological activity. These findings highlight the need for careful patient selection and further optimization of the treatment protocol to improve safety and efficacy. Citation Format: Lin Zhou, Haixi Liang, Zhiwen Xie, Yin Wang, Qiaqia Li, Wenjuan Ma, Tong Xiang, Chunyan Lan. Sun Yat-sen. Mesothelin-targeted CAR-T therapy FC004 for platinum-resistant ovarian cancer: A phase I trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT030.