•“Orexi” CAR T cells in combination with an orthogonally targeted monoclonal antibody are more effective than traditional CAR T cells.•OrexiCAR T cells reversed immunosuppression of tumor ...microenvironment myeloid cells.
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Chimeric antigen receptor (CAR) T-cell therapy has shown success in the treatment of hematopoietic malignancies; however, relapse remains a significant issue. To overcome this, we engineered “Orexi” CAR T cells to locally secrete a high-affinity CD47 blocker, CV1, at the tumor and treated tumors in combination with an orthogonally targeted monoclonal antibody. Traditional CAR T cells plus the antibody had an additive effect in xenograft models, and this effect was potentiated by CAR T-cell local CV1 secretion. Furthermore, OrexiCAR-secreted CV1 reversed the immunosuppression of myelomonocytoid cells both in vitro and within the tumor microenvironment. Local secretion of the CD47 inhibitor bypasses the CD47 sink found on all cells in the body and may prevent systemic toxicities. This combination of CAR T-cell therapy, local CD47 blockade, and orthogonal antibody may be a combinatorial strategy to overcome the limitations of each monotherapy.
An immune-suppressive tumor microenvironment is a major barrier to the efficacy of antibody-based therapies. Dacek et al present a novel strategy to overcome this by enhancing the antibody-dependent killing of tumors through additional infusion of chimeric antigen receptor (CAR) T cells engineered to locally secrete a small anti-CD47 blocking agent that disrupts antiphagocytic signaling induced by tumor cell CD47 binding to macrophage signal-regulatory protein α. This increases macrophage-mediated antibody-dependent cellular phagocytosis or antibody-dependent cellular cytotoxicity and enables increased tumor cell lysis in a mouse model. Such strategies can now be tested in clinical trials.
Drug nanoaggregates are particles that can deleteriously cause false positive results during drug screening efforts, but alternatively, they may be used to improve pharmacokinetics when developed for ...drug delivery purposes. The structural features of molecules that drive nanoaggregate formation remain elusive, however, and the prediction of intracellular aggregation and rational design of nanoaggregate-based carriers are still challenging. We investigate nanoaggregate self-assembly mechanisms using small molecule fragments to identify the critical molecular forces that contribute to self-assembly. We find that aromatic groups and hydrogen bond acceptors/donors are essential for nanoaggregate formation, suggesting that both π-π stacking and hydrogen bonding are drivers of nanoaggregation. We apply structure-assembly-relationship analysis to the drug sorafenib and discover that nanoaggregate formation can be predicted entirely using drug fragment substructures. We also find that drug nanoaggregates are stabilized in an amorphous core-shell structure. These findings demonstrate that rational design can address intracellular aggregation and pharmacologic/delivery challenges in conventional and fragment-based drug development processes.
Choline geranate (also described as Choline And GEranic acid, or CAGE) has been developed as a novel biocompatible antiseptic material capable of penetrating skin and aiding the transdermal delivery ...of co-administered antibiotics. The antibacterial properties of CAGE were analyzed against 24 and 72 hour old biofilms of 11 clinically isolated ESKAPE pathogens (defined as Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumanii, Pseudomonas aeruginosa, and Enterobacter sp, respectively), including multidrug resistant (MDR) isolates. CAGE was observed to eradicate in vitro biofilms at concentrations as low as 3.56 mM (0.156% v:v) in as little as 2 hours, which represents both an improved potency and rate of biofilm eradication relative to that reported for most common standard-of-care topical antiseptics in current use. In vitro time-kill studies on 24 hour old Staphylococcus aureus biofilms indicate that CAGE exerts its antibacterial effect upon contact and a 0.1% v:v solution reduced biofilm viability by over three orders of magnitude (a 3log10 reduction) in 15 minutes. Furthermore, disruption of the protective layer of exopolymeric substances in mature biofilms of Staphylococcus aureus by CAGE (0.1% v:v) was observed in 120 minutes. Insight into the mechanism of action of CAGE was provided with molecular modeling studies alongside in vitro antibiofilm assays. The geranate ion and geranic acid components of CAGE are predicted to act in concert to integrate into bacterial membranes, affect membrane thinning and perturb membrane homeostasis. Taken together, our results show that CAGE demonstrates all properties required of an effective topical antiseptic and the data also provides insight into how its observed antibiofilm properties may manifest.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The recent emergence of engineered cellular therapies, such as Chimeric antigen receptor (CAR) CAR T and T cell receptor (TCR) engineered T cells, has shown great promise in the treatment of various ...cancers. These agents aggregate and expand exponentially at the tumor site, resulting in potent immune activation and tumor clearance. Moreover, the ability to elaborate these cells with therapeutic agents, such as antibodies, enzymes, and immunostimulatory molecules, presents an unprecedented opportunity to specifically modulate the tumor microenvironment through cell-mediated drug delivery. This unique pharmacology, combined with significant advances in synthetic biology and cell engineering, has established a new paradigm for cells as vectors for drug delivery. Targeted cellular micropharmacies (TCMs) are a revolutionary new class of living drugs, which we envision will play an important role in cancer medicine and beyond. Here, we review important advances and considerations underway in developing this promising advancement in biological therapeutics.
This study examines the role of living—learning (L/L) programs in facilitating first-generation students' perceived academic and social transition to college. Using a sample of 1,335 first-generation ...students from 33 4-year institutions who participated in the National Study of Living—Learning Programs during Spring 2004, the results of the study show that first-generation students in L/L programs reported a more successful academic and social transition to college than their first-generation counterparts living in a traditional residence hall setting. In addition, interactions with faculty members and using residence hall resources facilitated an easier academic transition for first-generation students in L/L programs, and supportive residence hall climates were related to an easier social transition. A preliminary interpretation of this study's results is that structured activities, such as faculty interaction and residence hall programming, are more influential for this population than informal peer groups.
Abstract The blood-brain barrier (BBB) is one of the greatest barriers for the effective treatment of brain tumors, including H3K27-altered diffuse midline glioma (DMG), a near universally fatal ...childhood brain cancer. The BBB typically requires drugs to be given at maximally tolerated doses that are limited by systemic toxicities, particularly in settings of combination therapy. We have developed a clinically compatible fucoidan nanoparticle (Fi-NP) that homes to P-selectin on tumor vasculature after low-dose radiation (RT) to breach the BBB through an active caveolin-1-dependent mechanism and deliver several classes of targeted therapies. In non-CNS cancer xenograft models and a transgenic mouse model of SHH-driven medulloblastoma with an intact BBB, this approach improved survival while eliminating on-target systemic toxicities. We have now applied this approach to both brainstem and non-brainstem RCAS-TVA mouse models of DMG with an intact BBB. Specifically, we have found that DMG tumor vasculature expresses P-selectin, and that a single low-dose 2 Gy fraction of ionizing radiation further enhances it in a time-dependent manner up to 24 hours post-treatment. Importantly, we have also found that this P-selectin targeted drug delivery approach facilitates DMG tumor localization of Fi-NP encapsulated EZH2 inhibitor tazemetostat (EPZ-6438) as well as larger macromolecules including the PROTAC BET degrader dBET6, two promising targeted therapies for DMG limited by extremely poor BBB-penetration, while sparing drug delivery to non-tumor healthy brain regions. Work to measure PK, biodistribution, survival benefit, and drug target inhibition is ongoing. Our findings will provide the foundation for this P-selectin targeted Fi-NP approach to be evaluated in clinical trials for children with this lethal cancer.
Science museums have become more inclusive and engaging to audiences, including the development of programming intended to reach wider audiences and provide more equitable access to science learning. ...However, how do educators and designers of these programs conceptualize equity? To explore this question, interviews with educators (n=6), student artifacts, and program documents were analyzed to identify the ways educators talked about equity in one out-of-school youth program created and implemented by a large, urban science museum. These discourses of equity fit into five categories: bridging in-school and out-of-school, community acceptance, infrastructure access, motivation/enjoyment and positive affective responses, and increase access for a select few.
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