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CD99 Is a Novel Immunotherapy Target in Diffuse Midline Glioma: Fratricide-Resistant CAR T Cells Enable Durable Tumor Control

ABSTRACT: Diffuse midline glioma (DMG) is a highly infiltrative brain tumor of the pons and other midline structures with a dismal prognosis. Chimeric antigen receptor (CAR) T cell therapy has shown promise for DMG; however, to date, clinical responses have generally been transient, underscoring the need for strategies that achieve more durable therapeutic benefit. Here, we identify CD99 as a highly and consistently expressed surface antigen in both H3K27M-mutant and histone wild-type DMG, supporting its potential as a pan-DMG therapeutic target. We engineered a second-generation CD99-directed CAR incorporating a single-chain variable fragment targeting a membrane-proximal epitope and a 4-1BB co-stimulatory domain, which demonstrated potent antitumor activity in DMG models. Locoregional delivery resulted in complete tumor regression in orthotopic xenografts. However, endogenous CD99 expression on T cells triggered severe fratricide, limiting expansion and persistence. To overcome this barrier, we generated fratricide-resistant CD99 CAR T cells via CRISPR/Cas9 deletion of CD99, which markedly improved T cell viability and durability, resulting in sustained tumor clearance in aggressive DMG models. Together, these findings establish CD99 as a promising immunotherapeutic target and show that underscoring the target-dependent need for genetic fratricide prevention.

ORGANISM(S): Homo sapiens

PROVIDER: GSE336326 | GEO | 2026/06/30

REPOSITORIES: GEO

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Project description:Diffuse intrinsic pontine glioma (DIPG) and other H3K27M-mutated diffuse midline gliomas (DMGs) are universally lethal central nervous system (CNS) tumors that occur most commonly in children and young adults1. Average life expectancy is ten months from diagnosis, and 5-year survival is less than 1%2. Palliative radiotherapy is the only established treatment3, and neither cytotoxic nor targeted pharmacological approaches have demonstrated anti-tumor responses or improved prognosis to date3,4. We previously discovered that the disialoganglioside GD2 is highly and uniformly expressed on H3K27M+ DMG cells and demonstrated that intravenously (IV) administered GD2.4-1BB.z chimeric antigen receptor (CAR) T-cells eradicated established DMGs in patient-derived orthotopic murine models5, thereby providing the rationale for a first-in-human/first-in-child Phase 1 clinical trial (NCT04196413). Because CAR T-cell-induced inflammation and edema of the brainstem can result in obstructive hydrocephalus, increased intracranial pressure, and dangerous tissue shifts, a number of neurocritical care precautions were incorporated in the clinical trial design and management plan. Here we present the clinical experience from the first four patients with H3K27M+ DMG treated with GD2-CAR T-cells at dose level 1 (DL1; 1e6 GD2-CAR T-cells/kg administered IV). Patients who exhibited clinical benefit were eligible for subsequent administrations of GD2-CAR T-cells. Given preclinical evidence for increased CAR T-cell potency6, and the potential for diminished immunogenicity with locoregional administration, second doses were administered intracerebroventricularly (ICV) through an Ommaya catheter to three patients. As predicted from preclinical models, toxicity was largely related to the neuroanatomical location of the tumors and was reversible with intensive supportive care. Although GD2 is expressed at low levels in normal neural tissue, no evidence of on-target, off-tumor toxicity was observed. Three of four patients exhibited clinical and radiographic improvement, underscoring the promise of this approach for H3K27M+ DMG therapy. Correlative studies of serum and CSF revealed marked proinflammatory cytokine production following GD2 CAR T cell administration and single cell transcriptomic analysis of 65,598 single cells from CAR T cell products and patient CSF has begun to reveal differences that correlate with the heterogeneity between subjects and routes of administration.

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CD99 Is a Novel Immunotherapy Target in Diffuse Midline Glioma: Fratricide-Resistant CAR T Cells Enable Durable Tumor Control

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