Early induction of cytokine release syndrome by rapidly generated CAR T cells in preclinical models.

Cytokine release syndrome (CRS) is a significant side-effect of conventional chimeric antigen receptor (CAR) T-cell therapy. To facilitate patient accessibility, short-term (st) CAR T cells, which are administered to patients only 24 h after vector exposure, are in focus of current investigations. Their impact on the incidence and severity of CRS has been poorly explored.

CAR Gene Delivery by T-cell Targeted Lentiviral Vectors is Enhanced by Rapamycin Induced Reduction of Antiviral Mechanisms.

Lentiviral vectors (LV) have become the dominant tool for stable gene transfer into lymphocytes including chimeric antigen receptor (CAR) gene delivery to T cells, a major breakthrough in cancer therapy. Yet, room for improvement remains, especially for the latest LV generations delivering genes selectively into T cell subtypes, a key requirement for in vivo CAR T cell generation. Toward improving gene transfer rates with these vectors, whole transcriptome analyses on human T lymphocytes are conducted after exposure to CAR-encoding conventional vectors (VSV-LV) and vectors targeted to CD8+ (CD8-LV) or CD4+ T cells (CD4-LV).

Dasatinib is a potent enhancer for CAR T cell generation by CD3-targeted lentiviral vectors.

CD3-targeted lentiviral vectors (CD3-LVs) mediate selective transduction of human T lymphocytes and while simultaneously activating the targeted cells. Previously, we have demonstrated that CD3-LV leads to downmodulation of the CD3:T cell receptor (TCR) complex. We therefore hypothesized that inhibition of CD3 phosphorylation by Src/Abl tyrosine kinase inhibitors such as dasatinib results in enhancement of gene delivery by T cell-targeted LVs.

Expansion of T memory stem cells with superior anti-tumor immunity by Urolithin A-induced mitophagy.

T memory stem cells (T) display increased self-renewal and prolonged survival capabilities, thus preventing T cell exhaustion and promoting effective anti-tumor T cell responses. T cells can be expanded by Urolithin A (UA), which is produced by the commensal gut microbiome from foods rich in ellagitannins and is known to improve mitochondrial health. Oral UA administration to tumor-bearing mice conferred strong anti-tumor CD8 T cell immunity, whereas ex vivo UA pre-treated T cells displayed improved anti-tumor function upon adoptive cell transfer.

Combining T-cell-specific activation and in vivo gene delivery through CD3-targeted lentiviral vectors.

Genetic modification of T lymphocytes is a key issue in research and therapy. Conventional lentiviral vectors (LVs) are neither selective for T cells nor do they modify resting or minimally stimulated cells, which is crucial for applications, such as efficient in vivo modification of T lymphocytes. Here, we introduce novel CD3-targeted LVs (CD3-LVs) capable of genetically modifying human T lymphocytes without prior activation.