Os06.3.a 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 Leptomeningeal disease (LMD) is a devastating complication of breast cancer (BC) where it occurs in approximately 5% of patients and has a poor prognosis. The CSF of patients with LMD have an innate, but not adaptive, immune 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. Mechanistic studies are in progress. Therefore, 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. MATERIAL AND METHODS This is a phase I single-arm, non-randomized dose escalation multicenter study (NCT05809752) to establish 1) the safety of IT cDC1s, 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, Ommaya reservoir & other treatments to treat LMD ≤ 2 weeks/5 ½ lives were excluded. IT cDC1 IT were administered weekly x 12 weeks at one of 4 dose levels (1 x 106 - 5 x 107) until PD, DLT or withdrawal during those 12 weeks. Endpoints were 1) the safety and MTD, and 2) association between clinical and immune profiles in the CSF. We used a BOIN design to find MTD. Response was measured using RANO-LM. DLTs were defined as ≥ gr. 3 not due to LMD & didn’t respond to medical intervention/CSF removal ≤ 96 hrs. Final pre & post cDC1 treatment cyto-, chemokine profiles and cellular/tumor profiles (scRNA-seq) were determined. RESULTS As of 03/15/25, the first 6 patients received 1 x 106 - 2 x 107 DCs weekly x 12 and there were no DLTs. Headaches were common and grade 3 in two (33%) patients. Performance status remained stable or improved in five (83%) patients. Two (33%) had progressive disease of LMD within thirteen weeks. At follow-up, one patient died from leukoencephalopathy induced by radiotherapy. The median OS was 48.0 weeks 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 suggest that this approach activates CD4+ Th1 adaptive immune responses that drives adaptive antitumor activity which is otherwise lacking in LMD(NCT05809752). Mechanistic studies are in progress.