Background The CAR T cell therapies have failed to produce long-term remission in glioma patients. One of the key challenges in the development of an effective CAR-T therapy is the absence of target antigens that are tumor-specific and have homogenous expression. To safely target glioblastoma-associated antigens (GAAs) in the tumor without attacking normal tissue expressing the same GAAs outside of the brain, we adopted a novel synthetic Notch (synNotch) receptor system and established a “prime and kill” sequential two-receptor CAR circuit. We used glioblastoma- (GBM) specific neoantigen EGFRvIII as a priming signal for synNotch receptor and have reported robust antitumor response in the mice bearing intracerebral PDX tumor with heterogenous EGFRvIII expression. However, less than 20% of adult GBM cases express EGFRvIII. Furthermore, EGFRvIII expression can diminish over time even after its detection in the primary GBM, and the EGFRvIII-synNotch primed CAR T cells may deplete EGFRvIII-expressing GBM cells via their cytotoxic effects, thereby losing the priming signal. To overcome these inherent challenges of the EGFRvIII-priming strategy, we used CNS (Central Nervous System) tissue-specific antigens as the priming signal to drive localized expression of the CAR against EphA2 and IL-13Rα2 and bypassed the need for tumor-specific antigen.
Methods We have found BCAN (also known as Brevican) as the most promising priming antigen based on the specific and robust priming among several CNS-specific cell surface proteins that we evaluated. We created a synNotch-CAR circuit in which BCAN primes the T cells to induce expression of a CAR that recognizes IL-13Rα2 and EphA2.
Results When mice bearing intracerebral GBM6 PDX received a single intravenous (IV) infusion of T cells engineered with the α-BCAN synNotch α-EphA2/IL-13Rα2 CAR (B-SYNC) circuit, all mice (10/10) demonstrated complete regression of the tumor. Furthermore, these B-SYNC T cells were significantly more efficacious than constitutively expressed EphA2/IL-13Rα2 CAR T cells. The enhanced in vivo efficacy and superior persistence of B-SYNC T cells were associated with its tissue-resident and memory stem-cell-like phenotype.
Conclusions Taken together, the B-SYNC approach represents a robustly efficacious and conceptually novel T cell therapy with the CNS tissue-specific CAR activation. This also enhances the translational significance of synNotch-CAR T cells by widely extending the eligibility to EGFRvIII-negative glioma patients. We are currently developing a phase I study to evaluate the safety as well as the homing and priming status (i.e. expression of CAR) of the IV-infused B-SYNC T cells in patients with GBM.
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.