Remodeling the Immune Landscape in Breast Cancer Leptomeningeal Disease Using Dendritic Cell Therapy is an Effective Treatment and Protects Against Disease Recurrence. - Leptomeningeal Disease (LMD) occurs in 5% of advanced stage breast cancer (BC) patients, with an overall survival measured in weeks. While there is an unmet need for better treatment strategy, the knowledge about the biology of LMD in general is scarce. Novel approaches with a better understanding of this disease will benefit in developing a cure. Here we propose using polarized conventional Type I dendritic cell (cDC1) therapy (as a therapeutic and a vaccine) where cDC1s are primed with HER2 and HER3 to treat HER2+ BC and triple negative BC (TNBC) associated LMD. In murine models & clinical trials of systemic breast tumors we have found that class II HER2/HER3 peptide-pulsed Type I polarized cDC1s could partially restore anti-HER2 Th1 immune responses, which are CD4+ and CD8+ T cell dependent with pathologic CRs in BC patients. This represents a significant knowledge gap as we need to better understand novel therapies as proposed here. In replicated preliminary studies we found intrathecal (IT) delivery of HER2 and HER3 peptide-pulsed cDC1s significantly prolongs the survival in HER2+ and TNBC-LMD models with cures of 70% and 30%, respectively. The antitumor effect elicited by IT cDC1s is induced by a Th1 CD4+ T cell response. More importantly, most of these cured mice also resisted BC-LMD rechallenge, suggesting an immunological memory. Hence, the potential of this therapy as an effective treatment and prevention of LMD is intriguing. A first in person clinical trial of IT cDC1 therapy in LMD is currently accruing (IND27748; NCT05809752), highlighting the promising impact of our proposal. To understand the mechanisms of its treatment/prevention effects and evaluate combinatorial strategies we hypothesize IT delivery of cDC1s remodels the immunosuppressive environment in the cerebral spinal fluid (CSF) and target LMD by producing an IFN-g mediated proinflammatory Th1 response that is CD4+ T cell dependent, and orchestrating a multilayered immune responses which include antibody secretion by B cells, ADCC by NK cells, and flipping myeloid-induced immune suppression. In Aim 1 we will determine the cellular/cytokine mechanism(s) of responses to cDC1s using various genetic and pharmacological/antibody approaches to interrogate innate and adaptive immune responses. Common pathways between murine models and patients will be identified. In Aim 2 the mechanism(s) by which cDC1s induce long-term memory immune responses in LMD will be determined. In Aim 3, we will determine whether anti-LMD effect by cDC1 therapy could be enhanced by coupling with therapeutic IgG1 antibodies. Collectively, these findings will help develop clinically relevant strategies to treat LMD and optimize secondary prevention for potential disease occurrence.
