Paul Lin

Mesenchymal stem cells (MSCs) are currently being widely investigated both in the lab and in clinical trials for multiple disease states. The differentiation, trophic, and immunomodulatory characteristics of MSCs contribute to their therapeutic effects. Another often overlooked factor related to efficacy is the degree of engraftment. When reported, engraftment is generally low and transient in nature. MSC delivery methods should be tailored to the lesion being treated, which may be local or systemic, and customized to the mechanism of action of the MSCs, which can also be local or systemic. Engraftment efficiency is enhanced by using intra-arterial delivery instead of intravenous delivery, thus avoiding the “first-pass” accumulation of MSCs in the lung. Several methodologies to target MSCs to specific organs are being developed. These cell targeting methodologies focus on the modification of cell surface molecules through chemical, genetic, and coating techniques to promote selective adherence to particular organs or tissues. Future improvements in targeting and delivery methodologies to improve engraftment are expected to improve therapeutic results, extend the duration of efficacy, and reduce the effective (MSC) therapeutic dose.

Abstract There is a pressing need for allogeneic chimeric antigen receptor (CAR)-immune cell therapies that are safe, effective and affordable. We conducted a phase 1/2 trial of cord blood-derived natural killer (NK) cells expressing anti-CD19 chimeric antigen receptor and interleukin-15 (CAR19/IL-15) in 37 patients with CD19 + B cell malignancies. The primary objectives were safety and efficacy, defined as day 30 overall response (OR). Secondary objectives included day 100 response, progression-free survival, overall survival and CAR19/IL-15 NK cell persistence. No notable toxicities such as cytokine release syndrome, neurotoxicity or graft-versus-host disease were observed. The day 30 and day 100 OR rates were 48.6% for both. The 1-year overall survival and progression-free survival were 68% and 32%, respectively. Patients who achieved OR had higher levels and longer persistence of CAR-NK cells. Receiving CAR-NK cells from a cord blood unit (CBU) with nucleated red blood cells ≤ 8 × 10 7 and a collection-to-cryopreservation time ≤ 24 h was the most significant predictor for superior outcome. NK cells from these optimal CBUs were highly functional and enriched in effector-related genes. In contrast, NK cells from suboptimal CBUs had upregulation of inflammation, hypoxia and cellular stress programs. Finally, using multiple mouse models, we confirmed the superior antitumor activity of CAR/IL-15 NK cells from optimal CBUs in vivo. These findings uncover new features of CAR-NK cell biology and underscore the importance of donor selection for allogeneic cell therapies. ClinicalTrials.gov identifier: NCT03056339 .

Acellular, biologically derived matrices such as small intestinal submucosa have been extensively utilized to induce tissue regeneration and remodeling of connective tissue, vascular grafts, and urinary bladder; however, decellularized scaffolds have not been explored for their potential utility in hepatic tissue engineering. In the case of both extracorporeal hepatocyte-based devices and implantable hepatocyte-scaffold tissue-engineered constructs, maintenance of hepatocellular function is of prime importance. In this study, we specifically explored decellularized, porcine, liver-derived biomatrix (LBM) as a bioresorbable scaffold for primary hepatocytes. Primary rat hepatocytes were cultured on LBM and compared with well-characterized hepatocyte culture models--double-gel cultures that promote maintenance of liver-specific functions for many weeks, and adsorbed collagen monolayers that lead to the rapid decline of hepatocellular function and viability. Hepatocytes were maintained for up to 45 days on LBM and liver-specific functions such as albumin synthesis, urea production, and P-450 IA1 activity were found to be significantly improved over adsorbed collagen cultures. Our data indicate that LBM may be a favorable alternative to existing scaffolds for tissue engineering in that it is bioresorbable, can be easily manipulated, and supports long-term hepatocellular functions in vitro.

BACKGROUND AND STUDY AIMS: Subepithelial tumors of the stomach used to be considered as benign, but they do have malignant potential, especially when they originate from the muscularis propria layer. The aims of this study were to determine the feasibility of endoscopic submucosal dissection (ESD) for the removal of subepithelial tumors from the muscularis propria layer and to evaluate the efficacy and safety of ESD for this indication. PATIENTS AND METHODS: A total of 12 lesions in 11 patients were eligible for inclusion in the study during the period between December 2004 and February 2006. ESD using an insulated-tip knife was used to remove gastric subepithelial tumors from the muscularis propria where this was possible. Endoscopic mucosal resection using a suction and cap method ("EMR-c") was used to obtain a sufficiently large specimen for tissue diagnosis if complete resection by ESD was not possible. RESULTS: Nine tumors were resected completely by ESD (success rate 75 %). The mean tumor size as determined by endoscopic ultrasound as 20.7 mm (range 6 - 40 mm). The histological diagnosis was gastrointestinal stromal tumor for eight lesions and leiomyoma for four tumors. The mean operation time was 60.9 minutes (range 20 - 170 minutes), and the average blood loss was 30 ml. No patient developed perforation or massive hemorrhage requiring surgical treatment, and there were no other immediate postprocedure complications. CONCLUSIONS: ESD can be used for the resection of intraluminal gastric subepithelial tumors and could replace treatment by surgical resection in some cases. EMR-c is an alternative method that can be used to obtain sufficient tumor tissue for histological diagnosis if complete resection by ESD fails.