GD2 CAR T cells against human glioblastoma

Abstract

Glioblastoma is the most malignant primary brain tumor and is still in need of effective medical treatment. We isolated patient-derived glioblastoma cells showing high GD2 antigen expression representing a potential target for CAR T strategy. Data highlighted a robust GD2 CAR antitumor potential in 2D and 3D glioblastoma models associated with a significant and CAR T-restricted increase of selected cytokines. Interestingly, immunosuppressant TGF β1, expressed in all co-cultures, did not influence antitumor activity. The orthotopic NOD/SCID models using primary glioblastoma cells reproduced human histopathological features. Considering still-conflicting data on the delivery route for targeting brain tumors, we compared intracerebral versus intravenous CAR T injections. We report that the intracerebral route significantly increased the length of survival time in a dose-dependent manner, without any side effects. Collectively, the proposed anti-GD2 CAR can counteract human glioblastoma potentially opening a new therapeutic option for a still incurable cancer.

GD2-targeting CAR-T cells enhanced by transgenic IL-15 expression are an effective and clinically feasible therapy for glioblastoma

“…Our results differ from a recent study employing an orthotopic GBM model of xenografts and a second-generation CAR construct based on a novel IgM-derived and human GD2-specific scFv lacking cross-reactivity with murine GD2. The resulting GD2-CAR-T cells had significant antitumor activity only after intracerebral administration 23 . In contrast, in our study, the GD2-CAR-T cells were active against orthotopic glioblastoma xenografts after intravenous administration, perhaps because of the design of our CAR 44 or of our optimized manufacturing process 27 .…”

“…In addition, murine GD2-specific CAR-T cells cleared a GD2-expressing murine glioma cell line in a syngeneic, immunocompetent mouse model, but only when used in combination with radiotherapy 22 . In a recent preclinical report of GD2-CAR-T cell therapy in an intracranial model of human GBM, intratumoral administration was effective whereas intravenous administration was ineffective 23 . In addition, this study used a GD2-CAR derived from a monoclonal antibody with no cross-reactivity with mouse GD2, thus preventing the investigators from assessing off-tumor, on-target neurotoxicity.…”

Friends with Benefits: Chemokines, Glioblastoma-Associated Microglia/Macrophages, and Tumor Microenvironment

“…It is the first to explore autologous setting vs. GD2 as a target. GD2 has been identified as a possible target for CAR-T treatment for brain cancer by several research groups [ 239 , 240 , 241 , 242 ].…”

A Mathematical Model for On-Target Off-Tumor Effect of CAR-T Cells on Gliomas

“…Gliomas now have over 50 clinical trials using CAR-T cells registered on clinicaltrials.gov, making them the most common solid malignancy treated with CAR-T cell therapy (Barros et al, 2022). The most common CAR-T cell targets are disialoganglioside GD2, epidermal growth factor receptor (EGFR), HER2, IL-3Rα2, and B7H3 (Elsallab et al, 2020;Prapa et al, 2021). Moreover, another challenge with CAR-T cell therapy is the heterogeneous antigen expression on tumor cells, which can be circumvented by multi-target therapy.…”

“…Moreover, another challenge with CAR-T cell therapy is the heterogeneous antigen expression on tumor cells, which can be circumvented by multi-target therapy. In a very recent success of a first-in-human trial using GD2-CAR-T cells by sequential intravenous (IV) and intracerebroventricular (ICV) delivery, safety and early signs of clinical activity were observed (NCT04196413) (Prapa et al, 2021;Majzner et al, 2022). Toxicity was observed at the tumor location and the off-tumor effect was not observed, but several neurological symptoms were observed related to an inflammation in the central nervous system, called tumor inflammation-associated neurotoxicity.…”