BSLD-07 INTRATHECAL DENDRITIC CELL THERAPY DRIVES PROTECTIVE IMMUNE MEMORY IN BREAST CANCER LEPTOMENINGEAL DISEASE IN PRECLINICAL MODEL
Vincent Law, Colin Snynder, Zhihua Chen, Gary Koski, Brian Czerniecki, Peter ForsythAbstract
Background
Leptomeningeal disease (LMD) from breast cancer (BC) is a rare and fatal metastasis to the meninges, with a median survival of 2–6 months and no effective cure. Our ongoing first-in-human Phase 1 trial of intrathecal peptide-pulsed dendritic cell (IT cDC1) therapy (NCT05809752) has demonstrated encouraging clinical benefit, with median overall survival exceeding 19 months as of March 2026. Transcriptomic analysis of cerebrospinal fluid (CSF) from the first six patients revealed robust adaptive immune activation, including increased effector and central memory T cells and memory B cells, consistent with findings in murine BC LMD models. Clonal expansion of T cell receptors and B cell receptors was also observed in mice, suggesting a potential cancer-preventive immune mechanism.
Methods
BC LMD–cured and systemic BC–cured mice were generated using cDC1 therapy and subjected to LMD or systemic BC rechallenge. Survival was assessed, and tissue and CSF samples were collected for downstream analyses.
Results
In the HER2+ LMD rechallenge model, IT cDC1–cured mice showed significantly improved survival compared with untreated LMD controls (P < 0.0005), with 61% rejecting tumor engraftment. No survival difference was observed in systemic BC rechallenge; however, 40% of mice exhibited slowed tumor growth in the mammary fat pad. Notably, 90% of systemic BC–cured mice rejected LMD growth. Functional assays demonstrated IFN-γ responses in lymphocytes from cervical tumor-draining lymph nodes following HER2/HER3 peptide stimulation, indicating adaptive immune memory. Transcriptomic analysis revealed increased T and B cell populations and enhanced NKT cell signaling in LMD rechallenge CSF, suggesting a target for combination therapy.
Conclusions
IT cDC1 therapy induces adaptive immune memory that may protect against LMD recurrence. Ongoing studies aim to define underlying mechanisms and optimize combination strategies, including HER2/HER3-targeted and α-GalCer–loaded cDC1s. Phase 1 and Phase 2 clinical trials are underway.