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A Distinct CAR-T Cell Phenotype Mediates Therapeutic Response at Limited Doses

ABSTRACT: Chimeric antigen receptor (CAR) T cells are typically administered at high doses to ensure enduring therapeutic responses. However, achieving high cell numbers to meet end-product specifications is often challenging, posing substantial medical and socioeconomic barriers. Lower doses may be administered, but response rates are rather low, and the molecular and cellular mechanisms underlying therapeutic efficacy at limited doses remain unknown. To address this gap, we conducted deep phenotyping of anti-CD19 CAR-T cell products and their starting leukapheresis materials from a phase I/II clinical dose-escalation trial targeting B-cell malignancies. Patients responding to CAR-T cells despite low doses exhibited a dose-dependent enrichment of CAR-T cells with functional effector or effector memory-like states. The absolute number of these cells emerged as a robust biomarker of therapeutic response across varying dose levels. Notably, the manufacturing of CAR-T cells capable of mediating therapeutic responses at low doses was determined by T cell levels and T cell-supportive myeloid cells present in the starting material. Conversely, regulatory myeloid cell states contributed to the production of dysfunctional CAR-T cells and subsequent therapy failure. Our study provides critical insights into the phenotype, mechanisms, and biomarkers of CAR-T cells that drive therapeutic responses at low doses, with significant medical and socioeconomic implications.

ORGANISM(S): Homo sapiens

PROVIDER: GSE314571 | GEO | 2026/06/22

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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A Distinct CAR-T Cell Phenotype Mediates Therapeutic Response at Limited Doses

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