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Expansion of endogenous T cells in CSF of pediatric and young adult CNS tumor patients undergoing locoregional delivery of IL13R⍺2-targeting CAR T cells: an interim analysis

ABSTRACT: Outcomes for pediatric brain tumor patients remain poor, yet there is optimism that chimeric antigen receptor (CAR) T cell therapy can improve prognosis. Here, we present interim results from the first six patients treated on an ongoing phase I clinical trial (NCT04510051) of IL13BBζ-CAR T cells delivered weekly into the lateral cerebral ventricles. Our preliminary clinical findings suggest CAR T cell therapy is safe and well tolerated in both lymphodepleted and nonlymphodepleted patients, and may offer modest clinical benefit. In addition to our clinical findings, we carried out a series of correlative analyses leveraging single cell genomics and orthogonal methods to profile PBMCs, mononuclear cells in the cerebrospinal fluid (CSF) and post-treatment tumors. leveraging both single cell genomics and more traditional approaches. These studies identified important interactions between CAR T infusions and the endogenous immune system. Notably, we identified and characterized a population of expanding CAR- CD8+ T cells identified in the CSF. Furthermore, we found these and other immune changes observed in the CSF were not well captured by PBMCs. Conversely, we provide evidence of clonally expanded TCRs shared between CSF and post-treatment tumor. While these data are limited, our findings suggest T cell dynamics observed in the CSF are reflected in the tumor, but not in PBMCs. Taken together, these initial findings provide support for continued investigation into locoregionally-delivered IL13BBζ-CAR T cells for children and young adults with brain tumors, and provide important insights into endogenous immune response during therapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE261235 | GEO | 2025/03/14

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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Expansion of endogenous T cells in CSF of pediatric and young adult CNS tumor patients undergoing locoregional delivery of IL13R⍺2-targeting CAR T cells: an interim analysis

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