synNotch-programmed iPSC-derived NK cells usurp TIGIT and CD73 activities for glioblastoma therapy.

Severe heterogeneity within glioblastoma has spurred the notion that disrupting the interplay between multiple elements on immunosuppression is at the core of meaningful anti-tumor responses. T cell immunoreceptor with Ig and ITIM domains (TIGIT) and its glioblastoma-associated antigen, CD155, form a highly immunosuppressive axis in glioblastoma and other solid tumors, yet targeting of TIGIT, a functionally heterogeneous receptor on tumor-infiltrating immune cells, has largely been ineffective as monotherapy, suggesting that disruption of its inhibitory network might be necessary for measurable responses. It is within this context that we show that the usurpation of the TIGIT - CD155 axis via engineered synNotch-mediated activation of induced pluripotent stem cell-derived natural killer (NK) cells promotes transcription factor-mediated activation of a downstream signaling cascade that results in the controlled, localized blockade of CD73 to disrupt purinergic activity otherwise resulting in the production and accumulation of immunosuppressive extracellular adenosine.

Metabolic adaptation of NK cell activity and behavior in tumors: challenges and therapeutic opportunities.

The adaptation of natural killer (NK) cells to conditions in the microenvironment of tumors is deeply affected by their metabolic activity, itself a result of nutrient availability and the metabolism of the cancer cells themselves. Elevated rates of glycolysis and lipid metabolism in cancers not only lead to the accumulation of immunosuppressive byproducts but also contribute to an environment of elevated concentrations of extracellular metabolites. This results in altered NK cell bioenergetics through changes in transcriptional and translational profiles, ultimately affecting their pharmacology and impairing NK cell responses.

Ternary solid dispersions: classification and formulation considerations.

The number of active pharmaceutical compounds from the biopharmaceutical classification system (BCS) belonging to Class II and IV have significantly increased in recent years. These compounds have high therapeutic potential but are difficult to formulate as oral dosage forms due to their poor aqueous solubility. The solubility and bioavailability of these poorly water-soluble compounds can be increased by various formulation approaches, such as amorphous solid dispersions (ASD), salt formation, complexations, etc.

Investigating crystallization tendency, miscibility, and molecular interactions of drug-polymer systems for the development of amorphous solid dispersions.

Crystallization tendencies, thermal analysis [i.e. glass transition temperature ()], crystallinity, and melting point depression, along with theoretical calculations such as solubility parameter, of five different drugs [i.