Abstract PD13-07: A transcriptomic analysis of a first in human phase I trial of intrathecal dendritic cells (cDC1s) in patients with leptomeningeal disease (LMD) shows development of an adaptive immune response and very long survival in LMD

Abstract Background: Leptomeningeal disease (LMD) is a devastating complication of breast cancer (BC) and occurs in ˜5% of patients and has a poor prognosis. The CSF of patients with LMD have an innate, but not adaptive, immuno cellular profile. We found in murine LMD models IT cDC1s were safe, induced a Th1 response, cured most HER2+ LMD, and prevented LMD recurrence. This provoked a Th1 response, was CD4+ > CD8+ T cell and B cell dependent. We hypothesized in BC LMD patients that a RP2D would be identified, and the CSF would be remodeled to have a Th1 adaptive immunological profile identified by transcriptomic analysis. Methods: This is a phase I dose escalation study (NCT05809752) that establishes 1) safety and 2) associations between clinical outcomes & translational CSF studies. Eligibility includes TNBC or HER+ LMD pts, prior pCSpRT/WBRT, ECOG PS ≤2, normal marrow and organ function and ommaya reservoir. IT cDC1 IT were administered weekly x 12 (1 x 106 – 5 x 107) until PD, DLT or withdrawal. Endpoints were 1) the safety/MTD, and 2) association between clinical and immune profiles in the CSF. DLTs were defined as ≥ gr. 3 not due to LMD. Final pre & post cDC1 treatment cyto-, chemokine profiles and cellular/tumor profiles (scRNA-seq) were determined. Results: As of 6/24/25, the first 6 patients in whom transcriptomics was possible, received 1 x 106 – 2 x 107 DCs weekly without DLTs. Headaches were common and grade 3 in two (33%) patients. Performance status remained stable or improved in five (83%) patients. Two (33%) had PD of LMD. At follow-up, one patient died from RT leukoencephalopathy. The median OS was 15 mos and five (83%) are alive. A focused clinical cytokine panel showed marked elevation of CSF Th1 cytokines: IFN-g (2. 5 - 5.2 x ULN), IL-6 (16.9 - 220 x ULN), IL-12 (3 -9.7 X ULN), TNF-a (14 - 34 X ULN); the Th2-related IL-4 was not elevated. Transcriptomic analyses of CSF showed a remodeled environment with marked increase in CD4+ T, CD8+ T and B cells with a reduction of tumor cells. Antibodies to HER2 or HER3 developed in four of five (80%) patients. Conclusion: Our results show IT cDC1s activates a CD4+ Th1 adaptive immune response which is otherwise lacking in LMD. Mechanistic studies are in progress. This treatment resulted in an average survival of 15 months, which is significantly longer than other clinical trials in LMD. A phase 2 combination study of IT cDC1s will open I January 2026 (NCT pending). Citation Format: P. Forsyth, V. Law, K. Ahmed, C. Piteo, B. Evernden, Y. Pina, S. Inna, N. Tran, P. Kalinski, B. Czerniecki. A transcriptomic analysis of a first in human phase I trial of intrathecal dendritic cells (cDC1s) in patients with leptomeningeal disease (LMD) shows development of an adaptive immune response and very long survival in LMD [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PD13-07.