BSLM-03 BRANCHED-CHAIN KETO ACIDS PROMOTE AN IMMUNE-SUPPRESSIVE AND NEURODEGENERATIVE MICROENVIRONMENT IN LEPTOMENINGEAL DISEASE

Abstract

Leptomeningeal disease (LMD) occurs when tumors seed into the leptomeningeal space and cerebrospinal fluid (CSF), leading to severe neurological deterioration and poor survival outcomes. We utilized comprehensive multi-omic analyses of CSF from patients with melanoma, breast cancer and lymphoma LMD to demonstrate an immunosuppressive cellular microenvironment dominated by inactive, dysfunctional T cells and alternatively activated macrophages. These findings were confirmed in mouse models of LMD. We identified dysregulations in proteins and lipids indicating neurodegenerative processes and reactive gliosis. Strikingly, we found a significant accumulation of toxic branched-chain keto acids (BCKA) in the CSF of patients with LMD. Functionally, BCKA disrupted the viability and function of T lymphocytes, chimeric antigen receptor (CAR) T cells, neurons, and meningeal cells. These findings support the severe neurological decline, deficiency in the anti-tumor immune environment, and lack of response to immune therapies observed in patients clinically. Sodium phenylbutyrate is an FDA-approved BCKA-lowering therapy with exceptional safety profile and CNS penetration. We show that sodium phenylbutyrate improved neurological function and survival outcomes in murine models of breast cancer, lymphoma and melanoma LMD. In lymphoma LMD models, sodium phenylbutyrate also improved the efficacy of CAR T cell therapy. This work provides the preclinical rationale for repurposing BCKA-lowering therapies such as sodium phenylbutyrate for patients with LMD.