Arming Anti-EGFRvIII CAR-T With TGFβ Trap Improves Antitumor Efficacy in Glioma Mouse Models

Abstract

Glioblastoma (GBM) is an aggressive malignancy with poor prognosis. New therapeutic strategies for GBM are urgently needed. Although clinical studies have demonstrated the feasibility and safety of chimeric antigen receptor (CAR) T cell therapy for GBM, its efficacy has not been that impressive. The major limitation for anti-tumor efficacy of CARTs is the immunosuppressive milieu of the GBM tumor microenvironment (TME). TGFβ, a substantial component in GBM, compromises the immune response and contributes to immune evasion and tumor progression. To overcome this limitation and improve the efficacy of CART cells for GBM, we optimized an EGFRvIII-specific CAR construct with TGFRII ectodomain as a TGFβ-trap and generated TGFβ-resistant CARTs for GBM therapy. We demonstrated that this TGFβ-trapped architecture enhanced anti-tumor efficacy of EGFRvIII-specific CART and prolonged the survival of mice bearing GBM. In addition, the GBM-infiltrated microglia, typically considered tumorigenic, showed increased expression of M1 polarization markers after treatment with the TGFβ-trap CARTs group, indicating that these microglia were polarized toward a pro-inflammatory and anti-tumorigenic phenotype. Overall, these results indicated that arming CART cells with a TGFβ-trap diminishes the immunosuppressive effect and is a potential strategy to improve CART efficacy for GBM therapy.

Multifaceted Role of the Transforming Growth Factor β on Effector T Cells and the Implication for CAR-T Cell Therapy

“…TGF-β was found to repress T-cell activation of human T lymphocytes in the presence of strong T cell stimuli (anti-CD3/CD28 beads). This was correlated with a decrease in IFN-γ and IL-2 secretion and a lower proportion of CD8+ cells expressing GZMB and FASL [49]. Previous work indicates that blockade of endogenous TGF-β signaling in T cells using a dominant-negative TGF-βRII improves anti-tumor responses and tumor control in mice [50,51].…”

“…The investigators showed evidence that such modification can enhance anti-tumor efficacy against Glioma U87 cells and murine GL261 in tumor-bearing animals coinciding with prolonged CAR-T survival. The CAR-T cells were also found to modulate the TME since the TGF-β-trap CAR-T's condition was associated with increased M1 polarization of the infiltrated microglia [49].…”

The Role of Cytokines and Chemokines in Shaping the Immune Microenvironment of Glioblastoma: Implications for Immunotherapy

“…CAR-T cells with switch-signalling receptors offer a novel way to convert T cell inhibitory signals, such as those provided by PD1 [ 227 ] to activation signals such as CD28, and a similar process could potentially be used to reverse the inhibitory capacity of glioblastoma-abundant cytokines such as TGF-β, an idea which has been reviewed recently [ 228 ]. An early preclinical study of CAR-T cells with a decoy receptor for TGF-β (a non-signalling ectodomain of the TGF receptor II) prolonged the life of U87 glioblastoma bearing mice and polarized GAM towards an M1 phenotype [ 229 ].…”

Challenges and Perspectives of Standard Therapy and Drug Development in High-Grade Gliomas

“…Additionally, combining immunotherapy such as CAR T cell therapy with other therapeutic approaches could confer greater efficacy. In a recent study, the addition of TGFβ-trap into EGFRvIII -specific CAR T cell further prolonged the survival of mice [ 205 ]. The authors also observed the elevated expression of M1 polarization markers of GBM-infiltrated microglia, which may be responsible for disrupting the immunosuppressive tumor microenvironment.…”