Armored Bicistronic CAR T Cells with Dominant-negative TGF-β Receptor II to Overcome Resistance in Glioblastoma.

in Molecular therapy : the journal of the American Society of Gene Therapy by Nannan Li, Jesse L Rodriguez, Yibo Yin, Meghan T Logun, Logan Zhang, Shengkun Yu, Kelly A Hicks, Jiasi Vicky Zhang, Laura Zhang, Chuncheng Xie, Jiabin Wang, Tianyu Wang, Jiayi Xu, Joseph A Fraietta, Zev A Binder, Zhiguo Lin, Donald M O'Rourke

TLDR

  • The study is trying to find a way to treat a type of brain tumor called glioblastoma (GBM). The study found that a special type of cell called CAR T cells can help fight GBM, but they don't work as well in solid tumors like GBM. The study thinks that one of the reasons is that the tumor's environment is suppressing the immune cells that could help fight the tumor. The study is trying to fix this by using a special protein called dnTGFβRII to help the CAR T cells work better in the GBM environment. The study found that the CART-EGFR-IL13Rα2-dnTGFβRII construct significantly augments T cell proliferation, enhances functional responses, and improves the fitness of bystander cells, particularly by decreasing the TGF-β concentration in a TGF-β-rich TME. The study also validated the safety and efficacy of the dnTGFβRII cooperating with CARs in targeting and eradicating GBM in a NSG mouse model.

Abstract

Chimeric antigen receptor (CAR) T cells have shown significant efficacy in hematological diseases. However, CAR T therapy has demonstrated limited efficacy in solid tumors, including glioblastoma (GBM). One of the most important reasons is the immunosuppressive tumor microenvironment (TME), which promotes tumor growth and suppresses immune cells to eliminate tumor cells. The human transforming growth factor-beta (TGF-β) plays a crucial role in forming the suppressive GBM TME and driving the suppression of the anti-GBM response. In order to mitigate TGF-β mediated suppressive activity, we combined a dominant-negative TGF-β receptor II (dnTGFβRII) with our previous bicistronic CART-EGFR-IL13Rα2 construct, currently being evaluated in a clinical trial, to generate CART-EGFR-IL13Rα2-dnTGFβRII, a tri-modular construct we are developing for clinical application. We hypothesized that this approach would more effectively subvert resistance mechanisms observed with GBM. Our data suggest that CART-EGFR-IL13Rα2-dnTGFβRII significantly augments T cell proliferation, enhances functional responses, and improves the fitness of bystander cells, particularly by decreasing the TGF-β concentration in a TGF-β-rich TME. Additionally, in vivo studies validated the safety and efficacy of the dnTGFβRII cooperating with CARs in targeting and eradicating GBM in a NSG mouse model.

Overview

  • The study aims to develop a tri-modular construct, CART-EGFR-IL13Rα2-dnTGFβRII, to overcome resistance mechanisms observed in glioblastoma (GBM) by targeting the transforming growth factor-beta (TGF-β) mediated suppressive activity. The study hypothesizes that this approach will enhance T cell proliferation, functional responses, and improve the fitness of bystander cells, particularly by decreasing the TGF-β concentration in a TGF-β-rich TME. The study uses a combination of in vitro and in vivo experiments to evaluate the safety and efficacy of the dnTGFβRII cooperating with CARs in targeting and eradicating GBM in a NSG mouse model.

Comparative Analysis & Findings

  • The study compares the outcomes observed under different experimental conditions or interventions, specifically the effects of CART-EGFR-IL13Rα2-dnTGFβRII versus CART-EGFR-IL13Rα2 alone. The results suggest that CART-EGFR-IL13Rα2-dnTGFβRII significantly augments T cell proliferation, enhances functional responses, and improves the fitness of bystander cells, particularly by decreasing the TGF-β concentration in a TGF-β-rich TME. The study also validates the safety and efficacy of the dnTGFβRII cooperating with CARs in targeting and eradicating GBM in a NSG mouse model.

Implications and Future Directions

  • The study's findings suggest that the CART-EGFR-IL13Rα2-dnTGFβRII construct could be a promising therapeutic approach for GBM. The study's results also highlight the importance of targeting the TGF-β mediated suppressive activity in GBM. Future research directions could include further preclinical studies to evaluate the efficacy of the CART-EGFR-IL13Rα2-dnTGFβRII construct in other GBM models, as well as clinical trials to evaluate the safety and efficacy of the construct in human patients with GBM.
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