BSLM-04 Intrathecal Delivery of Peptide-Pulsed Type 1 Conventional Dendritic Cell Vaccine Is Highly Efficacious for the Treatment of Breast Cancer-Associated Leptomeningeal Disease in Preclinical Models

BACKGROUND Approximately 5% of advanced stage breast cancer (BC) will develop leptomeningeal disease (LMD), a rare form of metastasis in the meninges. The prognosis for LMD is dismal and current treatments are ineffective. Here, we found intrathecal (IT) delivery of MHC class II peptide-pulsed conventional Type 1 dendritic cells (cDC1s) could cure mice harbouring either HER2+ or triple negative breast cancer (TBNC) LMD. The data from our preclinical studies led to a Phase 1 clinical trial of cDC1s in HER2+ and TNBC LMD (NCT05809752; in progress). METHODS We created a “murine Ommaya” that mimics the clinically used Ommaya reservoir and allows for repeated IT injections of novel drugs at 3 – 7ml volume directly into the cerebral spinal fluid (CSF). A pipeline was developed for screening immunogenic MHC class II peptides from tumor-associated oncodrivers and using these targets we generated tumor-targeting cDC1 vaccine. We tested the efficacy of this therapy in murine BC-LMD by administering through the murine Ommaya. RESULTS We found cDC1 vaccine was highly effective against HER2+ LMD and TNBC-LMD; LMD mice that received IT cDC1s had reduced tumour burden and prolonged survival. Complete responses to treatment ranged between 30 - 70% in HER2+ LMD and TNBC-LMD and were CD4+ T cell and B cell dependent. Notably, some cured mice were protected against LMD reinoculation. Subsequent single cell RNA-sequencing analyses of pre- and post-treatment CSF revealed an adaptive change in the immune cellular landscape. We noted an elevation of Th1 proinflammatory cytokines such as IFN-g in the CSF. This was recapitulated in the CSF samples of patients enrolled in an on-going phase 1 trial, where early data showed IT cDC1 vaccine triggered a dramatic increase in the concentration of several proinflammatory Th1 cytokines. CONCLUSIONS IT cDC1 vaccine is effective against BC-LMD and prevents LMD recurrence. A future approach includes testing IT cDC1 platform in LMD from other cancers (e.g. melanoma etc.).