Matrix-binding checkpoint immunotherapies enhance antitumor efficacy and reduce adverse events.

Immune checkpoint blockade exhibits considerable antitumor activity, but previous studies have reported instances of severe treatment-related adverse events. We sought to explore local immune checkpoint blockade, with an antibody (Ab) form that would be retained intra- or peritumorally, limiting systemic exposure. To accomplish this, we conjugated the checkpoint blockade Abs to an extracellular matrix (ECM)-super-affinity peptide derived from placenta growth factor-2 (PlGF-2123-144). We show enhanced tissue retention and lower Ab concentrations in blood plasma after PlGF-2123-144 conjugation, reducing systemic side effects such as the risk of autoimmune diabetes. Peritumoral injections of PlGF-2123-144-anti-CTLA4 (cytotoxic T lymphocyte antigen 4) and PlGF-2123-144-anti-PD-L1 (programmed death ligand 1) Abs delayed tumor growth and prolonged survival compared to the unmodified Abs in genetically engineered murine tumor models of melanoma and breast cancer. The PlGF-2123-144-Abs increased tumor-infiltrating activated CD8+ and CD4+ T cells, resulting in a delay of distant tumor growth as well. This simple and translatable approach of engineered ECM-binding Abs may present a viable and safer approach in checkpoint blockade.

Engineered acellular collagen scaffold for endogenous cell guidance, a novel approach in urethral regeneration.

UNLABELLED: The treatment of congenital malformations or injuries of the urethra using existing autologous tissues can be associated with post-operative complications. Using rat-tail collagen, we have engineered an acellular high-density collagen tube. These tubes were made of 2 layers and they could sustain greater burst pressures than the monolayered tubes. Although it remains a weak material this 2 layered tube could be sutured to the native urethra. In 20 male New Zealand white rabbits, 2cm long grafts were sutured in place after subtotal excision of the urethra. This long-term study was performed in Lausanne (Switzerland) and in Kuala Lumpur (Malaysia). No catheter was placed post-operatively. All rabbits survived the surgical implantation. The animals were evaluated at 1, 3, 6, and 9months by contrast voiding cysto-urethrography, histological examination and immunohistochemistry. Spontaneous re-population of urothelial and smooth muscle cells on all grafts was demonstrated. Cellular organization increased with time, however, 20% of both fistula and stenosis could be observed post-operatively. This off-the shelf scaffold with a promising urethral regeneration has a potential for clinical application. STATEMENT OF SIGNIFICANCE: In this study we have tissue engineered a novel cell free tubular collagen based scaffold and used it as a urethral graft in a rabbit model. The novelty of our technique is that the tube can be sutured. Testing showed better burst pressures and the grafts could then be successfully implanted after a urethral excision. This long term study demonstrated excellent biocompatibility of the 2cm graft and gradual regeneration with time, challenging the current literature. Finally, the main impact is that we describe an off-the-shelf and cost-effective product with comparable surgical outcome to the cellular grafts.

Tubular Compressed Collagen Scaffolds for Ureteral Tissue Engineering in a Flow Bioreactor System.

Ureteral replacement by tissue engineering might become necessary following tissue loss after excessive ureteral trauma, after retroperitoneal cancer, or even after failed reconstructive surgery. This need has driven innovation in the design of novel scaffolds and specific cell culture techniques for urinary tract reconstruction. In this study, compressed tubular collagen scaffolds were evaluated, addressing the physical and biological characterization of acellular and cellular collagen tubes in a new flow bioreactor system, imitating the physiological pressure, peristalsis, and flow conditions of the human ureter. Collagen tubes, containing primary human smooth muscle and urothelial cells, were evaluated regarding their change in gene and protein expression under dynamic culture conditions. A maximum intraluminal pressure of 22.43 ± 0.2 cm H2O was observed in acellular tubes, resulting in a mean wall shear stress of 4 dynes/cm(2) in the tubular constructs. Dynamic conditions directed the differentiation of both cell types into their mature forms. This was confirmed by their gene expression of smooth muscle alpha-actin, smoothelin, collagen type I and III, elastin, laminin type 1 and 5, cytokeratin 8, and uroplakin 2. In addition, smooth muscle cell alignment predominantly perpendicular to the flow direction was observed, comparable to the cell orientation in native ureteral tissue. These results revealed that coculturing human smooth muscle and urothelial cells in compressed collagen tubes under human ureteral flow-mimicking conditions could lead to cell-engineered biomaterials that might ultimately be translated into clinical applications.