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. Such "decoy" receptor engages CD155 binding to TIGIT, but tilts inhibitory TIGIT/CD155 interactions toward activation via downstream synNotch signaling. Usurping activities of TIGIT and CD73 promotes the function of adoptively transferred NK cells into intracranial patient-derived models of glioblastoma and enhances their natural cytolytic functions against this tumor to result in complete tumor eradication. In addition, targeting both receptors, in turn, reprograms the glioblastoma microenvironment via the recruitment of T cells and the downregulation of M2 macrophages. This study demonstrates that TIGIT/CD155 and CD73 are targetable receptor partners in glioblastoma. Our data show that synNotch-engineered pluripotent stem cell-derived NK cells are not only effective mediators of anti-glioblastoma responses within the setting of CD73 and TIGIT/CD155 co-targeting, but represent a powerful allogeneic treatment option for this tumor.

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. However, understanding the metabolic processes that drive alterations in immunological signaling on NK cells remains both difficult and vastly underexplored. We discuss the varied and complex drivers of NK cell metabolism in homeostasis and the tumor microenvironment (TME), challenges associated with their targetability, and unexplored therapeutic opportunities.

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. Out of these techniques, the ASD approach, where compounds are converted into amorphous form and embedded in the hydrophilic matrix, have been successfully used in many marketed preparations. The recent advancement of this ASD approach is the design of ternary solid dispersions (TSD), where an additional component is added to further improve their performance in terms of solubility, stability, and processability. This review discusses the classification, mechanism of performance improvement, preparation techniques, and characterizations for TSD.

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 (Tg)], crystallinity, and melting point depression, along with theoretical calculations such as solubility parameter, of five different drugs [i.e. curcumin (CUR), indomethacin (IND), flutamide (FLU), dipyridamole (DIP), and griseofulvin (GRI)] in the absence and presence of four different polymers in various drug-polymer ratios were determined and analyzed. Physical states of the drug in the solid dispersions (SDs) and their stability were characterized by X-ray diffraction and modulated differential scanning calorimetry. Infrared (IR) and Raman were used in selected systems (i.e. CUR, DIP, and GRI systems) to explore the role of drug-polymer interactions in the amorphization of SDs. The crystallization tendencies of pure drugs were categorized as low (CUR, IND), moderate (FLU), and high (DIP, GRI). In the presence of selected polymers, the crystallization tendency of the drugs changed, though a high polymer concentration was required for high crystallization-tendency drugs [i.e. DIP and GRI (>50% w/w)]. Polymers showing a greater effect on the crystallization tendency of drugs were found to have higher drug-polymer miscibility and stronger molecular interactions. Drug-polymer systems selected from the investigation of physical mixtures formed stable amorphous solid dispersions (ASD). Furthermore, the rank order of the crystallization tendency of drug-polymer systems correlated well with those on miscibility and molecular interactions. Those rank orders also correlated well with the stability of prepared/reported SDs. Hence, the developed approach has significant potential to be a rational screening method for the development of amorphous SDs.