Intrathecal Allogeneic B7-H3–Targeted CAR γδ T Cells for Leptomeningeal Metastasis from Solid Tumors: Safety, Efficacy, and Immunologic Dynamics in a Phase I Trial

Abstract Purpose: To evaluate intrathecal QH104, an allogeneic B7 homolog 3 (B7-H3)–targeted chimeric antigen receptor (CAR) γδ T-cell therapy, in patients with leptomeningeal metastasis (LM). Patients and Methods: In this phase I study (NCT06592092), 3 patients with LM from B7-H3–positive solid tumors were enrolled, including 2 with lung adenocarcinoma and 1 with triple-negative breast cancer. QH104 was administered at a fixed dose of 3 × 107 cells per infusion via lumbar puncture or an Ommaya reservoir. The primary objective was to evaluate clinical response. Secondary objectives included safety, overall survival, quality of life, and pharmacokinetic/pharmacodynamic profiling. Results: QH104 was generally well tolerated, with no grade ≥ 4 treatment-related adverse events (TRAE). One patient developed grade 3 immune effector cell–associated neurotoxicity syndrome. All TRAE resolved with supportive care. All patients had stable disease on days 14 and 30 according to the Response Assessment in Neuro-Oncology Leptomeningeal Metastases criteria, with symptom improvement in 2 patients. Cerebrospinal fluid (CSF) cytology converted to and remained negative through day 30 in 1 patient with positive baseline cytology. B7-H3–CAR γδ T cells persisted in CSF for at least 1 week and were accompanied by increased interferon (IFN) γ levels. Single-cell sequencing suggested IFNγ-associated immune remodeling in CSF, including expansion of an inflammatory macrophage state and subsequent lymphocyte recruitment. Conclusions: This study provides preliminary proof of concept for intrathecal allogeneic B7-H3–CAR γδ T-cell therapy in LM, with early evidence of safety, clinical activity, local persistence, and IFNγ-associated immune remodeling in CSF.