Intracavity generation of glioma stem cell–specific CAR macrophages primes locoregional immunity for postoperative glioblastoma therapy

Abstract

Glioblastoma multiforme (GBM) remains incurable despite aggressive implementation of multimodal treatments after surgical debulking. Almost all patients with GBM relapse within a narrow margin around the initial resected lesion due to postsurgery residual glioma stem cells (GSCs). Tracking and eradicating postsurgery residual GSCs is critical for preventing postoperative relapse of this devastating disease, yet effective strategies remain elusive. Here, we report a cavity-injectable nanoporter-hydrogel superstructure that creates GSC-specific chimeric antigen receptor (CAR) macrophages/microglia (MΦs) surrounding the cavity to prevent GBM relapse. Specifically, we demonstrate that the CAR gene–laden nanoporter in the hydrogel can introduce GSC-targeted CAR genes into MΦ nuclei after intracavity delivery to generate CAR-MΦs in mouse models of GBM. These CAR-MΦs were able to seek and engulf GSCs and clear residual GSCs by stimulating an adaptive antitumor immune response in the tumor microenvironment and prevented postoperative glioma relapse by inducing long-term antitumor immunity in mice. In an orthotopic patient–derived glioblastoma humanized mouse model, the combined treatment with nanoporter-hydrogel superstructure and CD47 antibody increased the frequency of positive immune responding cells and suppressed the negative immune regulating cells, conferring a robust tumoricidal immunity surrounding the postsurgical cavity and inhibiting postoperative glioblastoma relapse. Therefore, our work establishes a locoregional treatment strategy for priming cancer stem cell–specific tumoricidal immunity with broad application in patients suffering from recurrent malignancies.

CAR-Macrophages and CAR-T Cells Synergistically Kill Tumor Cells In Vitro

“…Multiantigen logic gates or drug-sensitive modules can also be designed to engineer CAR-M to improve its safety. Additionally, considering the laborious and costly process of ex vivo autologous CAR-M cell production, in vivo programming of the macrophage into CAR-M using nonviral delivery of CAR-encoding DNA or mRNA is a promising strategy [ 28 , 29 ]. Lastly, combining CAR-M therapy with other therapeutics will be of great benefit to patients, especially those with high tumor burden.…”

Development of functional nanomedicines for tumor associated macrophages-focused cancer immunotherapy

“…In addition to those three main strategies, a novel TAMs-focused immunotherapy approach, CAR-macrophage (CAR-M) therapy, has been reported recently. Chen et al developed an injectable hydrogel co-loaded with macrophage-targeted genetic engineering nanoparticles (pCAR-NPs) and CD47 antibody for immunotherapy of GBM to prevent postoperative recurrence of GBM 190 . On one hand, pCAR-NPs performed in situ gene editing of local macrophages in postoperative GBM lumen, to form CAR-M that could target the removal of glioma stem cells (GSCs).…”

Targeting tumor-associated macrophages for the immunotherapy of glioblastoma: Navigating the clinical and translational landscape

“…In addition, chimeric antigen receptors macrophages (CAR-M) were shown as an efficient immunotherapy for GBM. Chen et al reported a method to engineer GSCs-CAR-M in the postsurgical cavity (122). The pentaspan transmembrane glycoprotein CD133, a marker for GSCs, was related to tumor progression, metastasis, and recurrence (154).…”

“…Chen et al. reported a method to engineer GSCs-CAR-M in the postsurgical cavity ( 122 ). The pentaspan transmembrane glycoprotein CD133, a marker for GSCs, was related to tumor progression, metastasis, and recurrence ( 154 ).…”