
==== Front
Neurooncol Adv
Neurooncol Adv
noa
Neuro-Oncology Advances
2632-2498
Oxford University Press US

10.1093/noajnl/vdae090.014
vdae090.014
Final Category: Basic Science Leptomeningeal Disease
AcademicSubjects/MED00300
AcademicSubjects/MED00310
BSLM-03 BRANCHED-CHAIN KETO ACIDS PROMOTE AN IMMUNE-SUPPRESSIVE AND NEURODEGENERATIVE MICROENVIRONMENT IN LEPTOMENINGEAL DISEASE
Khaled Mariam Moffitt Cancer Center, Tampa, FL, USA
Cairo University, Cairo, Egypt

Ren Yuan Moffitt Cancer Center, Tampa, FL, USA

Kundalia Ronak Moffitt Cancer Center, Tampa, FL, USA

Alhaddad Hasan Moffitt Cancer Center, Tampa, FL, USA

Chen Zhihua Moffitt Cancer Center, Tampa, FL, USA

Wallace Gerald Moffitt Cancer Center, Tampa, FL, USA

Evernden Brittany Moffitt Cancer Center, Tampa, FL, USA

Ospina Oscar Moffitt Cancer Center, Tampa, FL, USA

Hall MacLean Moffitt Cancer Center, Tampa, FL, USA

Liu Min Moffitt Cancer Center, Tampa, FL, USA

Darville Lancia Moffitt Cancer Center, Tampa, FL, USA

Izumi Victoria Moffitt Cancer Center, Tampa, FL, USA

Chen Y Ann Huntsman Cancer Institute, Salt Lake City, UT, USA

Pilon-Thomas Shari Moffitt Cancer Center, Tampa, FL, USA

Stewart Paul Moffitt Cancer Center, Tampa, FL, USA

Koomen John Moffitt Cancer Center, Tampa, FL, USA

Corallo Salvatore Moffitt Cancer Center, Tampa, FL, USA

Jain Michael Moffitt Cancer Center, Tampa, FL, USA

Robinson Timothy Yale University, New Haven, CT, USA

Locke Fredrick Moffitt Cancer Center, Tampa, FL, USA

Forsyth Peter Moffitt Cancer Center, Tampa, FL, USA

Smalley Inna Moffitt Cancer Center, Tampa, FL, USA

8 2024
02 8 2024
02 8 2024
6 Suppl 1 2024 SNO/ASCO CNS Metastases Conference i5i5
© The Author(s) 2024. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.
2024
https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

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.
==== Body
pmc
