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 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.
Forsyth et al. (Tue,) studied this question.