CLTR-04 INTRATHECAL DENDRITIC CELL THERAPY IN A FIRST-IN-HUMAN TRIAL FOR BREAST CANCER LEPTOMENINGEAL DISEASE INDUCES ADAPTIVE IMMUNITY AND TRANSCRIPTOMIC IMMUNE AWAKENING IN THE CEREBRAL SPINAL FLUID
Vincent Law, Patrick Grogan, Yolanda Pina, Kamran Ahmed, Cecily Piteo, Brittany Evernden, Nam Tran, Pawel Kalinski, Gary Koski, Brian Czerniecki, Peter ForsythAbstract
Background
Leptomeningeal disease (LMD) is a lethal complication of breast cancer (BC), affecting ∼5% of patients and associated with poor prognosis. The cerebrospinal fluid (CSF) immune environment in LMD is predominantly innate, with limited adaptive immune involvement. In murine models, intrathecal (IT) delivery of conventional type 1 dendritic cells (cDC1s) was well tolerated, induced a CD4+ Th1-skewed response, eliminated disease, and prevented recurrence. We hypothesized that IT cDC1 therapy in patients with BC LMD would similarly induce a Th1 adaptive immune shift in the CSF.
Methods
We conducted a Phase I, single-arm, dose-escalation trial (NCT05809752) in patients with HER2-positive or triple-negative BC LMD. Patients received weekly IT cDC1s for up to 12 weeks across four dose levels (1 × 106 to 5 × 107 cells) using a Bayesian optimal interval 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.
Results (as of March 26, 2026)
Among 14 patients, grade 3 headache occurred in 57%. Dose-limiting toxicities (DLTs) occurred in 14% at the highest dose (5 × 107), prompting de-escalation to 1 × 107 cells, with no DLTs observed to date. Cytokine and transcriptomic analyses (n = 7) showed increased Th1-associated cytokines (IFN-γ, IL-6, IL-12, TNF-α) without IL-4 elevation. Single-cell RNA sequencing demonstrated expansion of CD4+, CD8+, γδ T cells, and B cells. Median survival was not determined as treatments in 2 patients were still in progress.
Conclusions
IT cDC1 therapy is safe and induces robust Th1-polarized adaptive immunity in BC LMD. This approach may convert the immunologically “cold” CSF into an active anti-tumor environment.