Phase 1 study of intrathecal allogeneic B7-H3-targeted CAR γδ T cells for leptomeningeal metastasis from solid tumors

QH104 is an allogeneic B7 homolog 3 (B7-H3)-targeted CAR γδ T-cell therapy. A phase 1 study at the Cancer Hospital of the Chinese Academy of Medical Sciences (Beijing) evaluated intrathecal QH104 in patients with leptomeningeal metastasis (LM) from solid tumors. Three patients with LM from BH7-H3-positive lung adenocarcinoma (n=2) and triple-negative breast cancer (n=1) received QH104 at a fixed dose of 3 x 10⁷ cells per infusion via lumbar punction or an Ommaya reservoir. QH104 was generally well tolerated, with no grade 4 or 5 treatment-related adverse events (TRAEs). All TRAEs resolved with supportive care. All patients had stable disease on days 14 and 30 according to the RANO-LM criteria, with symptom improvement in two patients. 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 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. The authors conclude that this study provides preliminary proof of concept for intrathecal allogeneic B7-H3-CAR γδ T-cell therapy in LM.