Targeting cancer leptomeningeal metastasis with allogeneic chimeric antigen receptor γδ T-cell therapy.

Abstract

2533 Background: Leptomeningeal metastasis (LM) occurs in 1–10% of patients with advanced solid tumors during disease progression. LM significantly worsens prognosis due to the rapid onset and progression of symptoms associated with elevated intracranial pressure. Currently, no therapies specifically targeting LM have been approved. Here, we report our clinical observations from two patients treated with intrathecal infusion of allogeneic B7H3-targeted CAR-γδT cells(QH104). Methods: This is an open-label, single-arm clinical study designed to evaluate the safety and efficacy of QH104 in patients with LM originating from B7H3-positive solid tumors(NCT06592092). Eligibility criteria included a diagnosis of LM from any B7H3-positive solid malignancy. QH104 was administered as a single dose of 3×10^7 cells via lumbar puncture or Ommaya reservoir infusion. Treatment-emergent adverse events were graded using CTCAE v5.0 and ASTCT criteria. Efficacy was assessed using the RANO-LM criteria. Results: As of January 2025, two female lung adenocarcinoma patients were enrolled. They had previously received treatments targeting LM, including intrathecal chemotherapy and oral EGFR tyrosine kinase inhibitors. No adverse events higher than grade3 were reported. One patient experienced a transient episode of absence seizures on Day 1 after cell infusion, which was considered treatment-related. At the Day 30 assessment post-infusion, both patients had stable disease, with a reduction or complete elimination of tumor cells in the CSF and improvement in clinical symptoms associated with LM. CSF component analysis demonstrated the persistence of CAR-γδ T cells for one week post-infusion. CSF cytokine analysis revealed increased levels of interleukin-5, -6, -9, -13, and -22, TNF-α and IFN-γ post-infusion compared to baseline. No significant increases in CAR-γδ T cells or cytokines were detected in peripheral blood. Conclusions: Our initial clinical experience with the first two patients with leptomeningeal metastasis (LM) provides preliminary evidence supporting the safety and efficacy of B7H3-targeted CAR-γδT cell immunotherapy in this patient group. A longer follow-up period and a larger patient cohort are necessary for a comprehensive evaluation of therapeutic efficacy and response durability. Clinical trial information: NCT06592092 . Patients' baseline character, administration routes and treatment evaluation. Diagnosis Sex Age Genetic mutation B7H3Score B7H3+ CAR -γδT cells infused Administration route Treatment response at Day 30 Patient 01 Lung adenocarcinoma with LM F 53 EGFR 21 exon L858R mutation 70 3×10 7 Lumbar puncture Stable disease(CSF cytology: remain positiveCNS imaging: StableSymptoms assessment score:6 to 4) Patient 02 Lung adenocarcinoma with LM F 58 EGFR 21 exon L858R mutation 40 3×10 7 Ommaya reservoir Stable disease(CSF cytology: turned negativeCNS imaging: StableSymptoms assessment score:4 to 2)