Sequential CD146 and GPC3 CAR-T Cell Therapy in Advanced Ovarian Cancer

Advanced ovarian cancer remains challenging to treat, especially in the relapsed or refractory setting. CD146 (also known as MUC18 or MCAM) is a cell adhesion molecule involved in tumor angiogenesis and metastasis; it is frequently overexpressed in ovarian cancer and has been associated with aggressive disease and poor prognosis. GPC3 (glypican-3) is an oncofetal antigen expressed in a subset of ovarian carcinomas (particularly clear cell histology) and has been identified as a potential immunotherapy target in ovarian cancer. By targeting both CD146 and GPC3, this dual CAR-T approach aims to address tumor heterogeneity and improve anti-tumor efficacy. Essen Biotech's CAR-T pipeline emphasizes multi-target strategies (including CD146) and innovative dual-CAR designs to overcome the solid tumor microenvironment, providing the rationale for sequentially administering two distinct CAR-T cell products in this study. In the Phase 1 portion (dose escalation), patients will be enrolled in sequential cohorts to receive escalating doses of CD146 CAR-T cells followed by GPC3 CAR-T cells. A standard 3+3 dose escalation design may be used to identify the maximum tolerated dose (MTD) and any dose-limiting toxicities. Lymphodepleting conditioning with cyclophosphamide and fludarabine will be given prior to CAR-T infusion to enhance T-cell engraftment. Arm A consists of an infusion of CD146-targeted CAR-T cells at the assigned dose; after a short interval (e.g. 1-7 days), Arm B consists of an infusion of GPC3-targeted CAR-T cells. Patients are closely monitored during and after each infusion for acute toxicities, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). The DLT observation period is typically the first 28 days following the sequential CAR-T infusions. If DLTs occur, dose levels may be adjusted accordingly. Once the Phase 1 portion establishes a recommended Phase 2 dose, the trial will expand into the Phase 2 portion. In the Phase 2 expansion, additional patients will be treated at the established dose to further evaluate efficacy outcomes. Tumor response will be assessed by imaging (e.g. RECIST 1.1 criteria) at regular intervals. The primary endpoints in Phase 2 include Objective Response Rate (the proportion of patients achieving a complete or partial response). Secondary efficacy endpoints include Progression-Free Survival (time from CAR-T infusion to disease progression or death) and Overall Survival (time from CAR-T infusion to death from any cause). Patients will also be evaluated for duration of response and immunological correlative endpoints (such as CAR-T cell persistence in blood), as applicable. All participants will be followed for up to 36 months post-treatment for long-term safety surveillance and survival status. This trial design will provide critical initial data on the feasibility, safety profile, and potential anti-tumor activity of a sequential dual-CAR T-cell therapy in ovarian cancer patients who have exhausted standard therapies.