Browsing by Subject "Receptors, Chimeric Antigen"

Filter results by typing the first few letters
Now showing 1 - 2 of 2
  • Thumbnail Image
    ItemOpen Access
    B7-H3-redirected chimeric antigen receptor T cells target glioblastoma and neurospheres.
    (EBioMedicine, 2019-09) Nehama, Dean; Di Ianni, Natalia; Musio, Silvia; Du, Hongwei; Patané, Monica; Pollo, Bianca; Finocchiaro, Gaetano; Park, James JH; Dunn, Denise E; Edwards, Drake S; Damrauer, Jeffrey S; Hudson, Hannah; Floyd, Scott R; Ferrone, Soldano; Savoldo, Barbara; Pellegatta, Serena; Dotti, Gianpietro

    Background

    The dismal survival of glioblastoma (GBM) patients urgently calls for the development of new treatments. Chimeric antigen receptor T (CAR-T) cells are an attractive strategy, but preclinical and clinical studies in GBM have shown that heterogeneous expression of the antigens targeted so far causes tumor escape, highlighting the need for the identification of new targets. We explored if B7-H3 is a valuable target for CAR-T cells in GBM.

    Methods

    We compared mRNA expression of antigens in GBM using TCGA data, and validated B7-H3 expression by immunohistochemistry. We then tested the antitumor activity of B7-H3-redirected CAR-T cells against GBM cell lines and patient-derived GBM neurospheres in vitro and in xenograft murine models.

    Findings

    B7-H3 mRNA and protein are overexpressed in GBM relative to normal brain in all GBM subtypes. Of the 46 specimens analyzed by immunohistochemistry, 76% showed high B7-H3 expression, 22% had detectable, but low B7-H3 expression and 2% were negative, as was normal brain. All 20 patient-derived neurospheres showed ubiquitous B7-H3 expression. B7-H3-redirected CAR-T cells effectively targeted GBM cell lines and neurospheres in vitro and in vivo. No significant differences were found between CD28 and 4-1BB co-stimulation, although CD28-co-stimulated CAR-T cells released more inflammatory cytokines.

    Interpretation

    We demonstrated that B7-H3 is highly expressed in GBM specimens and neurospheres that contain putative cancer stem cells, and that B7-H3-redirected CAR-T cells can effectively control tumor growth. Therefore, B7-H3 represents a promising target in GBM. FUND: Alex's Lemonade Stand Foundation; Il Fondo di Gio Onlus; National Cancer Institute; Burroughs Wellcome Fund.
  • Thumbnail Image
    ItemOpen Access
    GD2-CAR T cell therapy for H3K27M-mutated diffuse midline gliomas.
    (Nature, 2022-03) Majzner, Robbie G; Ramakrishna, Sneha; Yeom, Kristen W; Patel, Shabnum; Chinnasamy, Harshini; Schultz, Liora M; Richards, Rebecca M; Jiang, Li; Barsan, Valentin; Mancusi, Rebecca; Geraghty, Anna C; Good, Zinaida; Mochizuki, Aaron Y; Gillespie, Shawn M; Toland, Angus Martin Shaw; Mahdi, Jasia; Reschke, Agnes; Nie, Esther H; Chau, Isabelle J; Rotiroti, Maria Caterina; Mount, Christopher W; Baggott, Christina; Mavroukakis, Sharon; Egeler, Emily; Moon, Jennifer; Erickson, Courtney; Green, Sean; Kunicki, Michael; Fujimoto, Michelle; Ehlinger, Zach; Reynolds, Warren; Kurra, Sreevidya; Warren, Katherine E; Prabhu, Snehit; Vogel, Hannes; Rasmussen, Lindsey; Cornell, Timothy T; Partap, Sonia; Fisher, Paul G; Campen, Cynthia J; Filbin, Mariella G; Grant, Gerald; Sahaf, Bita; Davis, Kara L; Feldman, Steven A; Mackall, Crystal L; Monje, Michelle
    Diffuse intrinsic pontine glioma (DIPG) and other H3K27M-mutated diffuse midline gliomas (DMGs) are universally lethal paediatric tumours of the central nervous system1. We have previously shown that the disialoganglioside GD2 is highly expressed on H3K27M-mutated glioma cells and have demonstrated promising preclinical efficacy of GD2-directed chimeric antigen receptor (CAR) T cells2, providing the rationale for a first-in-human phase I clinical trial (NCT04196413). Because CAR T cell-induced brainstem inflammation can result in obstructive hydrocephalus, increased intracranial pressure and dangerous tissue shifts, neurocritical care precautions were incorporated. Here we present the clinical experience from the first four patients with H3K27M-mutated DIPG or spinal cord DMG treated with GD2-CAR T cells at dose level 1 (1 × 106 GD2-CAR T cells per kg administered intravenously). Patients who exhibited clinical benefit were eligible for subsequent GD2-CAR T cell infusions administered intracerebroventricularly3. Toxicity was largely related to the location of the tumour and was reversible with intensive supportive care. On-target, off-tumour toxicity was not observed. Three of four patients exhibited clinical and radiographic improvement. Pro-inflammatory cytokine levels were increased in the plasma and cerebrospinal fluid. Transcriptomic analyses of 65,598 single cells from CAR T cell products and cerebrospinal fluid elucidate heterogeneity in response between participants and administration routes. These early results underscore the promise of this therapeutic approach for patients with H3K27M-mutated DIPG or spinal cord DMG.