A Phase I, Open-label, Single-arm, Dose-escalation and Expansion Study of Dual-targeting VEGFR1 and PD-L1 CAR-T Cells in Patients With Pleural, Peritoneal, or Leptomeningeal Metastases From Solid Tumors
This is a Phase I, open-label, single-arm, dose-escalation and expansion study designed to evaluate the safety, tolerability, and preliminary antitumor activity of dual-targeting VEGFR1/PD-L1 chimeric antigen receptor (CAR) T-cells in patients with solid tumors presenting with pleural, peritoneal, or leptomeningeal metastases. Despite advances in systemic therapies, patients with serosal cavity and leptomeningeal dissemination face extremely poor prognoses and limited treatment options due to the unique immunosuppressive tumor microenvironment and the physical barrier of these anatomical sites. Preclinical evidence suggests that simultaneous blockade of VEGFR1-mediated angiogenesis and PD-L1-mediated immune checkpoint signaling via a bispecific CAR-T construct may synergistically overcome local immunosuppression and enhance tumor eradication in these sanctuary sites. The study consists of two phases: a dose-escalation phase utilizing a standard 3+3 design and backfilling design to determine the maximum tolerated dose (MTD) or recommended phase II dose (RP2D) of locoregionally administered CAR-T cells, followed by a dose-expansion phase to further assess safety and preliminary efficacy at the RP2D. Eligible patients will receive a single infusion of VEGFR1/PD-L1 dual-CAR T-cells via intrapleural, intraperitoneal, or intrathecal routes, depending on the primary site of metastasis. The primary endpoints are the incidence of dose-limiting toxicities (DLTs) and treatment-emergent adverse events (TEAEs) graded by CTCAE v5.0. Secondary endpoints include objective response rate (ORR) , progression-free survival (PFS), overall survival (OS), and assessment of CAR-T cell persistence and cytokine profiles in peripheral blood and local effusion fluids.
⁃ Male or female participants aged 18 to 75 years. Participants older than 75 years may be enrolled at the investigator's discretion based on overall health status.
• Females of childbearing potential must have a negative serum or urine pregnancy test. Females who have undergone surgical sterilization or have been postmenopausal for at least 2 years are considered not of childbearing potential.
• Histologically or cytologically confirmed advanced solid tumors with evidence of serosal cavity metastasis (pleural/peritoneal) and/or leptomeningeal metastasis, who have failed standard-of-care therapies.For leptomeningeal metastasis: patients must have received at least 3 intrathecal chemotherapy infusions with persistent positive CSF cytology and neurological symptoms, OR have re-positivity of CSF cytology after prior clearance.
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2.
• Life expectancy \> 3 months.
• Adequate organ and bone marrow function:
⁃ Absolute neutrophil count ≥ 1.5 × 10⁹/L Platelets ≥ 90 × 10⁹/L Absolute lymphocyte count ≥ 1.0 × 10⁸/L Hemoglobin ≥ 9.0 g/dL ALT/AST ≤ 2.5 × ULN (≤ 5 × ULN for patients with liver metastases) Total bilirubin ≤ 1.5 × ULN Creatinine \< 1.5 × ULN AND creatinine clearance ≥ 50 mL/min (Cockcroft-Gault formula). Creatinine clearance assessment is required only when creatinine ≥ 1.5 × ULN.
• Cardiac ejection fraction ≥ 50%. Patients with minimal or moderate pericardial effusion may be enrolled at the investigator's discretion.
• No other severe concurrent diseases (e.g., active autoimmune diseases, immunodeficiency).
• Chemotherapy must be discontinued for at least 3 weeks prior to CAR-T cell infusion.
⁃ Sexually active participants of childbearing potential must agree to use highly effective contraceptive methods from screening through 1 year after CAR-T cell infusion.
⁃ Voluntary participation with written informed consent obtained prior to any study-specific procedures.
⁃ Recovery from prior antitumor therapy to ≤ Grade 1 (CTCAE v5.0), except for alopecia, hormone-replacement-controlled hypothyroidism, Grade 2 peripheral neuropathy, vitiligo, well-controlled diabetes, or other chronic toxicities deemed by the investigator to be stable and not interfering with study conduct.