Intrathecal Allogeneic B7-H3-targeted CAR γδ T Cells for Leptomeningeal Metastasis from Solid Tumors: Safety, Efficacy, and Immunological Dynamics in a Phase 1 Trial

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 1 study (NCT06592092), three patients with LM from B7-H3-positive solid tumors were enrolled, including two with lung adenocarcinoma and one 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 (TRAEs). One patient developed grade 3 immune effector cell-associated neurotoxicity syndrome. All TRAEs 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 two patients. Cerebrospinal fluid (CSF) cytology converted to and remained negative through day 30 in one patient with positive baseline cytology. B7-H3-CAR γδ T cells persisted in CSF for at least one week and were accompanied by increased interferon gamma (IFN-γ) levels. Single-cell sequencing suggested IFN-γ-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 IFN-γ-associated immune remodeling in CSF.