BSLD-02 a First in Human Phase I Trial of Intrathecal Dendritic Cells Primed Against Her2/Her3 in Patients With Leptomeningeal Disease From Triple-Negative or Her2+ Breast Cancer Show Development of Adaptive Immune Responses

BACKGROUND The CSF of patients with LMD have an innate, but not adaptive, immune cellular profile. Murine LMD models showed IT cDC1s were safe, induced a Th1 response (CD4+ > CD8+ T cell and B cell dependent), cured most HER2+ LMD, and prevented LMD recurrence. We conducted a Phase I study of IT DCs and hypothesized the CSF would be remodeled to have a Th1 adaptive immunological profile. METHODS This is a Phase I single-arm, dose escalation study to establish 1) the safety and 2) associations between clinical outcomes & translational CSF studies. Eligibility includes TNBC or HER+ LMD pts, prior pCSpRT/WBRT, ECOG PS ≤2, and Ommaya reservoir. IT cDC1 IT were administered weekly x 12 at one of 4 dose levels (1 x 106 – 5 x 107) until PD/DLT. Endpoints were 1) safety, MTD RP2D, 2) association between clinical and immune profiles in the CSF. DLTs were defined as ≥ gr. 3 not due to LMD & didn’t respond to intervention. RESULTS As of 03/15/25, the first 6 patients received 1 x 106 – 2 x 107 DCs with no DLTs. Headaches were common and grade 3 in two (33%) patients. Two (33%) had PD of LMD within 13 weeks. One patient died from leukoencephalopathy. The median OS was 48.0 weeks and five (83%) are alive. CSF cytokines Th1 cytokines included IFN-g, IL-6, IL-12, TNF-a; Th2-related IL-4 was not elevated. Transcriptomics showed a 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 suggest this approach activates CD4+ Th1 adaptive immune responses that drives adaptive antitumor activity which is otherwise lacking in LMD (NCT05809752).