No abstract

Allogeneic natural killer (NK) cell transfer is a potential immunotherapy to eliminate and control cancer. A promising source are CD34 + hematopoietic progenitor cells (HPCs), since large numbers of cytotoxic NK cells can be generated. Effective boosting of NK cell function can be achieved by interleukin (IL)-15. However, its in vivo half-life is short and potent trans-presentation by IL-15 receptor α (IL-15Rα) is absent. Therefore, ImmunityBio developed IL-15 superagonist N-803, which combines IL-15 with an activating mutation, an IL-15Rα sushi domain for trans-presentation, and IgG1-Fc for increased half-life. Here, we investigated whether and how N-803 improves HPC-NK cell functionality in leukemia and ovarian cancer (OC) models in vitro and in vivo in OC-bearing immunodeficient mice. We used flow cytometry-based assays, enzyme-linked immunosorbent assay, microscopy-based serial killing assays, and bioluminescence imaging, for in vitro and in vivo experiments. N-803 increased HPC-NK cell proliferation and interferon (IFN)γ production. On leukemia cells, co-culture with HPC-NK cells and N-803 increased ICAM-1 expression. Furthermore, N-803 improved HPC-NK cell-mediated (serial) leukemia killing. Treating OC spheroids with HPC-NK cells and N-803 increased IFNγ-induced CXCL10 secretion, and target killing after prolonged exposure. In immunodeficient mice bearing human OC, N-803 supported HPC-NK cell persistence in combination with total human immunoglobulins to prevent Fc-mediated HPC-NK cell depletion. Moreover, this combination treatment decreased tumor growth. In conclusion,  N-803 is a promising IL-15-based compound that boosts HPC-NK cell expansion and functionality in vitro and in vivo. Adding N-803 to HPC-NK cell therapy could improve cancer immunotherapy.

Reconstruction of long ureteral defects often warrants the use of graft tissue and extensive surgical procedures to maintain the safe transport of urine from the kidneys to the urinary bladder. Complication risks, graft failure-related morbidity, and the lack of suitable tissue are major concerns. Tissue engineering might offer an alternative treatment approach in these cases, but ureteral tissue engineering is still an underreported topic in current literature. In this review, the most recent published data regarding ureteral tissue engineering are presented and evaluated, with a focus on cell sources, implantation strategies, and (bio)materials.

Identifying collagen produced de novo by cells in a background of purified collagenous biomaterials poses a major problem in for example the evaluation of tissue-engineered constructs and cell biological studies to tumor dissemination. We have developed a universal strategy to detect and localize newly deposited collagen based on its inherent association with dermatan sulfate. The method is applicable irrespective of host species and collagen source.

Cartilage consists of chondrocytes and a special extracellular matrix (ECM) having unique biochemical, biophysical, and biomechanical properties that play a critical role in the proliferation and differentiation of cells inherent to cartilage functions. Cartilage tissue engineering (CTE) requires recreating these microenvironmental physicochemical conditions to lead to chondrocyte differentiation from stem cells. ECM-derived hybrid scaffolds based on chondroitin sulfate, hyaluronic acid, collagen, and cartilage ECM analogs provide environments conducive to stem cell proliferation. In this review, we describe hybrid scaffolds based on these four cartilage ECM derivatives; we also categorize these scaffolds based on the methods used for their preparation. The use of hybrid scaffolds is increasing in CTE to address the complexity of cartilage tissue. Thus, a comprehensive review on the topic should be a useful guide for future research.Scaffolds fabricated from extracellular matrix (ECM) derivatives are composed of conducive structures for cell attachment, proliferation, and differentiation, but generally do not have proper mechanical properties and load-bearing capacity. In contrast, scaffolds based on synthetic biomaterials demonstrate appropriate mechanical strength, but the absence of desirable biological properties is one of their main disadvantages. To integrate mechanical strength and biological cues, these ECM derivatives can be conjugated with synthetic biomaterials. Hence, hybrid scaffolds comprising both advantages of synthetic polymers and ECM derivatives can be considered a robust vehicle for tissue engineering applications.