CELL INTELLIGENCE · 肿瘤细胞治疗研究

Inclusion Criteria:

* Expected survival time ≥3 months;
* Diagnosis: Histologically or cytologically confirmed epithelial ovarian carcinoma (including fallopian tube or primary peritoneal carcinoma considered as ovarian cancer) that is relapsed or refractory to standard therapies. Patients must have received and progressed on or after at least one line of platinum-based chemotherapy (or be platinum-resistant) and have no curative standard treatment options.
* Target Antigen Expression: Tumor must demonstrate positive expression of CD146 and GPC3 by immunohistochemistry (IHC) on a recent tumor tissue sample. Expression of both targets is required for eligibility (to ensure the presence of the CAR-T targets in the patient's cancer).
* Disease Status: Measurable disease as defined by RECIST 1.1 criteria (at least one measurable lesion on imaging).
* Age: Adults aged ≥18 years. (Patients must be legally adult and able to provide informed consent. Upper age limit may not be specified, but patients must meet other health criteria.)
* Performance Status: Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 (indicative of fully active or restricted in physically strenuous activity only).
* Organ Function: Adequate organ and bone marrow function, including: absolute neutrophil count (ANC) above a minimum threshold, platelet count above threshold, hemoglobin above threshold (transfusion allowed), serum AST/ALT and bilirubin ≤2× upper limit of normal (unless due to liver involvement by tumor), and adequate renal function (e.g. creatinine clearance ≥50 mL/min or per protocol criteria).
* Consent: Ability to understand and sign informed consent, and willing to comply with trial procedures and follow-up. Women of child-bearing potential must have a negative pregnancy test and agree to use effective contraception during the study and for a defined period after CAR-T cell infusion (due to unknown risks to a fetus).

Exclusion Criteria:

* Prior Therapy: Previous treatment with any CAR-T cell therapy or other gene-engineered T-cell therapy targeting CD146 or GPC3. (Patients who received prior immunotherapies such as checkpoint inhibitors are allowed if a washout period is met, but prior CAR-T could confound results or pose increased risk.)
* CNS Involvement: Active central nervous system (CNS) metastases or carcinomatous meningitis. (Patients with a history of CNS metastases that have been effectively treated and are radiographically stable off steroids may be eligible, per protocol specifics.)
* Comorbid Illness: Uncontrolled intercurrent illness including, but not limited to, active uncontrolled infection, clinically significant heart failure (e.g. NYHA Class III-IV), unstable angina or arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. (Patients with controlled chronic conditions may be eligible at the investigator's discretion.)
* Immunosuppression: Active hepatitis B or C infection with viremia, or known HIV infection with uncontrolled viral load. Patients requiring chronic systemic immunosuppressive therapy (e.g. for an autoimmune condition or organ transplant) are excluded, except for physiologic dose steroids.
* Pregnancy or Breastfeeding: Pregnant or breastfeeding women are excluded due to potential risks to the fetus or infant from the study treatment. Women of child-bearing potential who are unwilling or unable to use adequate contraception are not eligible.
* Other Malignancy: Presence of another active malignancy requiring treatment (with the exception of certain early-stage cancers or those in remission for a specified period, per protocol). This is to avoid confounding outcomes and ensure patient safety.
* Hypersensitivity: Known severe hypersensitivity to any component of the investigational CAR-T cell products or to the lymphodepletion chemotherapy drugs (cyclophosphamide, fludarabine).
* Other Exclusions: Any condition that, in the opinion of the investigator, would make the patient unsuitable for the study (such as life expectancy limited by comorbid illness, or significant laboratory abnormalities not covered above).

主要终点：Incidence and severity of dose-limiting toxicities (DLTs) following chemotherapy preparative regimen and infusion of GPC3/CD146 chimeric antigen receptor (CAR) T cells · Will be recorded and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 at three dose levels until the maximum tolerated dose (MTD) is determined. · 28 days
次要终点：Rate of successful manufacture and expansion of the CD146/GPC3 chimeric antigen receptor (CAR) T cells

• CD146 GPC3 CAR T cells, chemotherapy · EXPERIMENTAL · Patients will be administered fludarabine phosphate intravenously (IV) over a 30-minute period on days -4 to -2. Additionally, cyclophosphamide will be administered intravenously (IV) over 60 minutes on day -2. Subsequently, patients will receive CD146 GPC3 CAR T cells intravenously (IV) over a duration of 10-20 minutes on day 0. Patients who exhibit positive responses to the initial dose of GPC3 /CD146 CAR T cells, do not experience unacceptable side effects, and have a sufficient quantity of cells available may be eligible to receive 2 or 3 additional doses of GPC3/CD146 CAR T cells.

This is a multicenter, open-label Phase 1/2 clinical trial evaluating the safety and preliminary efficacy of sequentially administered CD146-targeted and GPC3-targeted CAR-T cell therapy in patients with advanced relapsed or refractory ovarian cancer. Eligible patients will undergo lymphodepleting chemotherapy with cyclophosphamide and fludarabine, followed by an infusion of autologous CD146-directed CAR-T cells (Arm A) and a subsequent infusion of autologous GPC3-directed CAR-T cells (Arm B). The Phase 1 portion will assess safety, tolerability, and dose-limiting toxicities (DLTs) to determine a recommended Phase 2 dose, while the Phase 2 portion will evaluate efficacy endpoints including objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Patients will be followed for up to 36 months after CAR-T infusion to monitor long-term outcomes and adverse events.