IMMU-60. MYELOID POPULATIONS MODULATE GD2 CAR T CELL ACTIVITY IN DIFFUSE MIDLINE GLIOMA

H3K27M-mutated diffuse midline gliomas (DMGs) are universally lethal cancers in children and young adults. Our team previously demonstrated efficacy of GD2-targeting chimeric antigen receptor T cells (GD2-CAR T-cells) in preclinical models of DMG of the pons (also called diffuse intrinsic pontine gl...

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Published in:	Neuro-oncology (Charlottesville, Va.) Vol. 26; no. Supplement_8; p. viii166
Main Authors:	Ramakrishna, Sneha, Geraghty, Anna, Good, Zinaida, Desai, Moksha, Mancusi, Rebecca, Mahdi, Jasia, Song, Kun Wei, Ehlinger, Zachary, Chen, Yiyun, Hamilton, Mark, Rietberg, Skyler, Majzner, Robbie, Schultz, Liora, Richards, Becky, Kamens, Jennifer, Barsan, Vali, Campen, Cynthia, Partap, Sonia, Moon, Jennifer, Baggott, Christina, Kunick, Michael, Fujimoto, Michelle, Li, Amy, Jariwala, Sneha, Mavroukakis, Sharon, Egeler, Emily, Jacobs, Ashley, Erickson, Courtney, Prabhu, Snehit, Davis, Kara, Feldman, Steven, Sahaf, Bita, Mackall, Crystal, Monje, Michelle
Format:	Journal Article
Language:	English
Published:	11-11-2024
Online Access:	Get full text
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Summary:	H3K27M-mutated diffuse midline gliomas (DMGs) are universally lethal cancers in children and young adults. Our team previously demonstrated efficacy of GD2-targeting chimeric antigen receptor T cells (GD2-CAR T-cells) in preclinical models of DMG of the pons (also called diffuse intrinsic pontine glioma (DIPG) and DMG of the spinal cord, and opened a Phase I clinical trial (NCT04196413) treating patients with first intravenous (IV) followed by repeated infusions of intracerebroventricular (ICV) GD2-CAR T-cells. We employed high-dimensional analyses to define immune states contributing to CAR-T activity in patients. Single cell RNA-sequencing (scRNAseq) was conducted on 555,406 single cells from 115 cerebrospinal fluid (CSF) samples of 13 patients before and after CAR-T treatment. This is the largest CSF CAR-T dataset in central nervous system (CNS) tumors and provides insights into the immune biology surrounding CAR-T treatment for CNS malignancies. Patient CSF samples were dominated by T cell and myeloid populations. After CAR-T infusion, patient CSF exhibited an increased fraction of regulatory T cells and myeloid populations from baseline. Myeloid cells in early timepoints after ICV administration demonstrated a unique pro-inflammatory signature, while CSF samples from IV and late ICV timepoints exhibited a suppressive signature. To further explore the immune biology of these myeloid contributors, we developed a patient-derived xenograft model of DMG relapse following low-dose ICV GD2 CAR-T treatment. Using a pharmacological CSF1R-inhibitor, we demonstrate that depletion of microglia/myeloid cells at a specific window following CAR-T administration enhances durability of tumor control. Together, these data display the power of in-depth correlative analyses to identify distinct immune populations that drive durability of response. Key findings from these data will allow for optimization of CAR-T therapies for H3K27M+ DMG patients, providing hope to shift the paradigm of this fatal disease.
ISSN:	1522-8517 1523-5866
DOI:	10.1093/neuonc/noae165.0652