01
Drug delivery targeting central nervous system (CNS) is difficult to achieve both efficacy and safety. Since T cells have been engineered to infiltrate diverse tissues and reshape the microenvironment, T-cell-based CNS-specific delivery system can serve as a common platform to treat CNS disorders.
Firstly, the author conducted a comprehensive bioinformatic search to identify more reliable brain-specific antigens. Focusing on the extracellular molecules expressed predominantly in the CNS, they selected a list of 59 candidates which could be classified into three categories: ECM proteins, myelin sheath proteins and neuronal surface proteins. Then to construct brain-sensing cells, synNotch receptors were engineered to recognize candidate brain-specific antigens and induce the expression of therapeutic payloads upon binding. And seven out of the 59 antigens were selected to create various synNotch receptors and tested for antigen-specific activation. In vivo tests revealed that engineered T cells with αBCAN synNotch→CAR circuit could selectively kill GBM cells and persist in the brain providing long-term protection against tumor rechallenge. And the efficacy was also observed in the breast cancer brain metastases, with minimized off-target effects outside the brain.
Moreover, the engineered T cells were tested in the treatment on the neuroinflammation. The αBCAN SynNotch→IL-10 expression was designed to selectively produce the anti-inflammatory cytokine IL-10 in response to BCAN expression. These engineered T cells inhibited the CNS-autoreactive T cells and microglia in vitro and significantly alleviated the symptoms of experimental autoimmune encephalomyelitis (EAE). However, the T cells constitutively expressing IL-10 couldn’t protect the mice from disease progression, consistent with previous studies that systemic IL-10 delivery had limited efficacy in ameliorating MS-like conditions. And the brain-targeted T cells didn’t induce increased serum IL-10 levels and systemic immune suppression.
DOI: 10.1126/science.adl4237
02
Immune suppressor cells with locally targeted suppression can better reestablish homeostasis to bypass toxicities associated with systemic immunosuppression.
To explore the fundamental principles of local suppression and established a cell platform with conventional T cells that is stable, well characterized and facile to engineer, the author took a synthetic reconstitution approach of engineering conventional CD4+ T cells. First, they developed synNotch receptors-expressing T cells that produced various suppressive agents. And the most effective suppressive programs against CAR-T cell-mediated cytotoxicity were those that combined inhibitory cytokines (e.g. TGFβ1, IL-10) and IL-2 sinks (CD25).
In the tumor-bearing mice model, the dual-antigen type(HER2+ CD19+) and single-antigen type(HER2+) coexisted and the CAR T cells targeting HER+ were administrated. The synthetic suppressor T cells with αCD19-synNotch→TGFβ1+CD25 circuit could selectively suppress CAR T cell activity in the dual-antigen tumor site without affecting the single-antigen tumor cell killing. It suggested that synthetic suppressor T cells exhibited more effective local suppression in vivo, offering a strategy to minimize off-target toxicity in CAR T cell therapies and protect cross-reactive normal tissues.
Additionally, in a pancreatic islet transplant model, synthetic suppressor T cells protected eBC organoid transplants from immune rejection by anti–HLA-A2 CAR T cells. The suppressor T cells localized around the transplants, preventing CAR T cell activation and ensuring functional organoid survival. Importantly, TGFβ1 production was localized to the transplant site, with no detectable systemic increase.
DOI: 10.1126/science.adl4793
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Editor & Reviewer: Yanwen Zhu
