Engineering second-generation TCR-T cells by site-specific integration of TRAF-binding motifs into the locus.

Background: The incorporation of co-stimulatory signaling domains into second-generation chimeric antigen receptors (CARs) significantly enhances the proliferation and persistence of CAR-T cells in vivo, leading to successful clinical outcomes.

Methods: To achieve such functional enhancement in transgenic T-cell receptor-engineered T-cell (TCR-T) therapy, we designed a second-generation TCR-T cell in which CD3ζ genes modified to contain the intracellular domain (ICD) of the 4-1BB receptor were selectively inserted into the locus.

Results: This modification enabled the simultaneous recruitment of key adaptor molecules for signals 1 and 2 on TCR engagement.

Reprogramming of IL-12 secretion in the PDCD1 locus improves the anti-tumor activity of NY-ESO-1 TCR-T cells.

Introduction: Although the engineering of T cells to co-express immunostimulatory cytokines has been shown to enhance the therapeutic efficacy of adoptive T cell therapy, the uncontrolled systemic release of potent cytokines can lead to severe adverse effects. To address this, we site-specifically inserted the (IL-12) gene into the PDCD1 locus in T cells using clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9)-based genome editing to achieve T-cell activation-dependent expression of IL-12 while ablating the expression of inhibitory PD-1.

Methods: New York esophageal squamous cell carcinoma 1(NY-ESO-1)-specific TCR-T cells was investigated as a model system.

Anti-inflammatory clearance of amyloid-β by a chimeric Gas6 fusion protein.

Clearing amyloid-β (Aβ) through immunotherapy is one of the most promising therapeutic approaches to Alzheimer's disease (AD). Although several monoclonal antibodies against Aβ have been shown to substantially reduce Aβ burden in patients with AD, their effects on improving cognitive function remain marginal. In addition, a significant portion of patients treated with Aβ-targeting antibodies experience brain edema and microhemorrhage associated with antibody-mediated Fc receptor activation in the brain.