PVR Receptor-Based CAR-T Cells Combined with NK-92 Cells Exert Potent Activity Against Glioblastoma
Menée à l'aide de cellules souches de gliomes, d'organoïdes, de xénogreffes intracrâniennes ou sous-cutanées sur des modèles murins et d'échantillons tumoraux issus de patients atteints d'un glioblastome sans mutation de l'Isocitrate déshydrogénase, cette étude met en évidence l'activité antitumorale d'un traitement combinant cellules NK-92 et lymphocytes CAR-T ciblant le récepteur PVR
Background : Poliovirus receptor (PVR) interacts with three receptors: T-cell immunoglobulin immunoreceptor tyrosine-based inhibitory motif (TIGIT), CD96, DNAX accessory molecule-1 (DNAM), that are predominantly expressed on T cells and natural killer cells. Many solid tumors, including IDH-wildtype glioblastoma, have been reported to overexpress PVR, and this overexpression is associated with poor prognosis. However, there is no preclinical or clinical trials investigating the use of cell-based immunotherapies targeting PVR in IDH-wildtype glioblastoma. Methods : We analyzed PVR expression in transcriptome sequencing databases and specimens from IDH-wildtype glioblastoma patients. We developed PVR targeting chimeric antigen receptor (CAR)-T cells using lentivirus. The antitumor activity of CAR-T cells was demonstrated in patient-derived glioma stem cells (GSCs), intracranial and subcutaneous mouse xenograft models. Results : We verified PVR expression in primary GSCs, surgical specimens from IDH-wildtype glioblastoma patients and organoids. Accordingly, we developed PVR receptor-based second-generation CAR-T cells. The antitumor activity of CAR-T cells was demonstrated in GSCs and xenograft models. Tumor recurrence occurred in intracranial xenograft model because of antigen loss. The combinational therapy of TIGIT extracellular domain-based CAR-T cells and NK-92 cells markedly suppressed tumor recurrence and prolonged survival. Conclusions : PVR receptor-based CAR-T cells were capable of killing GSCs and suppressing tumor recurrence when combined with NK-92 cells.