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Two peptide-derived low-molecular-weight gelators bearing different capping groups, 9-fluorenylmethyloxycarbonyl (Fmoc) and phenothiazine, were synthesized and their gel networks were characterized. The variation of the N-terminal capping group affects the viability of these hydrogels as a three-dimensional cell culture for multicellular tumor spheroids. These results indicate that the phenothiazine capping group is a more biocompatible alternative to the widely used Fmoc moiety. [ABSTRACT FROM AUTHOR]

Cellular therapies utilizing T cells expressing chimeric antigen receptors (CARs) have garnered significant interest due to their clinical success in hematological malignancies. Unfortunately, this success has not been replicated in solid tumors, with only a small fraction of patients achieving complete responses. A number of obstacles to effective CAR-T cell therapy in solid tumors have been identified including tumor antigen heterogeneity, poor T cell fitness and persistence, inefficient trafficking and inability to penetrate into the tumor, immune-related adverse events due to on-target/off-tumor toxicity, and the immunosuppressive tumor microenvironment. Many preclinical studies have focused on improvements to CAR design to try to overcome some of these hurdles. However, a growing body of work has also focused on the use of local and/or regional delivery of CAR-T cells as a means to overcome poor T cell trafficking and inefficient T cell penetration into tumors. Most trials that incorporate locoregional delivery of CAR-T cells have targeted tumors of the central nervous system - repurposing an Ommaya/Rickham reservoir for repeated delivery of cells directly to the tumor cavity or ventricles. Hepatic artery infusion is another technique used for locoregional delivery to hepatic tumors. Locoregional delivery theoretically permits increased numbers of CAR-T cells within the tumor while reducing the risk of immune-related systemic toxicity. Studies to date have been almost exclusively phase I. The growing body of evidence indicates that locoregional delivery of CAR-T cells is both safe and feasible. This review focuses specifically on the use of locoregional delivery of CAR-T cells in clinical trials. [Display omitted] [ABSTRACT FROM AUTHOR]

Despite the rapid development of drug delivery vehicles that react to a specific biological environment, the complexity of triggering drug release in a particular target area remains an enduring challenge. Here, the engineering of bioresponsive polymer-mesoporous silica nanoparticles (MSNs) with function akin to an AND logic gate is described. Polycaprolactone (esterase degradable) is immobilized into the core of MSNs while polyacrylic acid (PAA), which is pH responsive, covered the outside of the MSNs to create a PAA-PCL-MSNs construct. Fluorescence spectroscopy indicates that the construct releases the payload (doxorubicin, cancer drugs) in the presence of, and only in the presence of, both low pH AND esterase. Confocal microscopy and fluorescence lifetime microscopy (FLIM) demonstrate uptake of the intact construct and subsequent intracellular doxorubicin (DOX) delivery into the nucleus. Further in vitro IC50 studies demonstrate the AND logic gate delivery system results in more than an eightfold efficacy against neuroblastoma (SK-N-BE(2)) cells in comparison with normal fibroblasts (MRC-5). These results demonstrate the utility of MSN-polymer construct to create an AND gate capable of selectively delivering a drug payload. [ABSTRACT FROM AUTHOR]

Several anti-mesothelin (MSLN) chimeric antigen receptor (CAR) T cells are in phase 1/2 clinical trials to treat solid-organ malignancies. The effect of MSLN antigen density on MSLN CAR cytotoxicity against tumor cells has not been examined previously, nor are there data regarding the effect of agents that increase MSLN antigen density on anti-MSLN CAR T cell efficacy. MSLN antigen density was measured on a panel of pancreatic cancer and mesothelioma cell lines by flow cytometry. In parallel, the cytotoxicity and specificity of two anti-MSLN CAR T cells (m912 and SS1) were compared against these cell lines using a real-time impedance-based assay. The effect of two MSLN 'sheddase' inhibitors (lanabecestat and TMI-1) that increase MSLN surface expression was also tested in combination with CAR T cells. SS1 CAR T cells were more cytotoxic compared with m912 CAR T cells against cell lines that expressed fewer than ∼170 000 MSLN molecules/cell. A comparison of the m912 and amatuximab (humanized SS1) antibodies identified that amatuximab could detect and bind to lower levels of MSLN on pancreatic cancer and mesothelioma cell lines, suggesting that superior antibody/scFv affinity was the reason for the SS1 CAR's superior cytotoxicity. The cytotoxicity of m912 CAR T cells was improved in the presence of sheddase inhibitors, which increased MSLN antigen density. These data highlight the value of assessing CAR constructs against a panel of cells expressing varying degrees of target tumor antigen as occurs in human tumors. Furthermore, the problem of low antigen density may be overcome by concomitant administration of drugs that inhibit enzymatic shedding of MSLN. [Display omitted] [ABSTRACT FROM AUTHOR]