TIP-24. A first-in-human trial of intrathecal cDC1 therapy for breast cancer leptomeningeal disease induces adaptive immunity with transcriptomic evidence of immune awakening in the CSF

BACKGROUND Leptomeningeal disease (LMD) is a lethal complication of breast cancer (BC), occurring in ~5% of patients and characterized by poor prognosis. The cerebrospinal fluid (CSF) immune environment in LMD is predominantly innate, lacking adaptive immune responses. In murine LMD models, intrathecal (IT) administration of cDC1s was safe, elicited a CD4+ Th1-dominant response, eliminated HER2+ LMD, and prevented recurrence. These findings led us to hypothesize that in BC LMD patients, IT cDC1s could induce an adaptive Th1 immune shift in the CSF, as detected by transcriptomic analysis. METHODS We conducted a phase I, single-arm, dose-escalation trial (NCT05809752) in patients with triple-negative or HER2+ BC LMD. Participants received weekly IT cDC1s for up to 12 weeks across four dose levels (1 × 10⁶–5 × 10⁷ cells), using a BOIN design to determine the maximum tolerated dose (MTD). Primary endpoints were safety and MTD; secondary endpoints included clinical response (RANO-LM) and CSF immune profiling, including single-cell RNA sequencing (scRNA-seq). RESULTS (AS OF 03/15/25) Six patients received doses ranging from 1–2 × 10⁷ cells with no dose-limiting toxicities. Headaches were the most common adverse event (grade 3 in two patients). Five patients (83%) showed stable or improved performance status; median overall survival was 48 weeks. Cytokine analysis revealed elevated Th1 markers (IFN-γ, IL-6, IL-12, TNF-α) without increased IL-4. Transcriptomic analysis of CSF showed a remodeled immune landscape with expanded CD4+, CD8+, and B cell populations and reduced tumor cell burden. Anti-HER2/HER3 antibodies were detected in 80% of patients. CONCLUSION IT cDC1s are safe and induce robust Th1-polarized adaptive immune responses in BC LMD, as confirmed by transcriptomic and cytokine analyses. This approach offers a novel strategy to convert the immunologically cold CSF environment into one capable of mounting effective anti-tumor immunity.