Papers by Christopher Jewell
Biomaterials Science
Local signal integration in lymph nodes (LNs) controls the potency and selectivity of immune resp... more Local signal integration in lymph nodes (LNs) controls the potency and selectivity of immune responses. Here, intra-LN depots were used to direct communication within treated LNs, causing programmable and divergent systemic immunotherapy outcomes.
Frontiers in Immunology, 2022
Biomaterials hold great promise for vaccines and immunotherapy. One emerging biomaterials technol... more Biomaterials hold great promise for vaccines and immunotherapy. One emerging biomaterials technology is microneedle (MNs) delivery. MNs are arrays of micrometer-sized needles that are painless and efficiently deliver cargo to the specialized immunological niche of the skin. MNs typically do not require cold storage and eliminate medical sharps. Nearly all materials exhibit intrinsic properties that can bias immune responses toward either pro-immune or inhibitory effects. Thus, because MNs are fabricated from degradable polymers to enable cargo loading and release, understanding the immunological profiles of these matrices is essential to enable new MN vaccines and immunotherapies. Additionally, understanding the mechanical properties is important because MNs must penetrate the skin and conform to a variety of skin or tissue geometries. Here we fabricated MNs from important polymer classes – including extracellular matrix biopolymers, naturally-derived polymers, and synthetic polymer...
Cancers, 2022
Background: The development of chemoresistance to paclitaxel and carboplatin represents a major t... more Background: The development of chemoresistance to paclitaxel and carboplatin represents a major therapeutic challenge in ovarian cancer, a disease frequently characterized by malignant ascites and extrapelvic metastasis. Microtentacles (McTNs) are tubulin-based projections observed in detached breast cancer cells. In this study, we investigated whether ovarian cancers exhibit McTNs and characterized McTN biology. Methods: We used an established lipid-tethering mechanism to suspend and image individual cancer cells. We queried a panel of immortalized serous (OSC) and clear cell (OCCC) cell lines as well as freshly procured ascites and human ovarian surface epithelium (HOSE). We assessed by Western blot β-tubulin isotype, α-tubulin post-translational modifications and actin regulatory proteins in attached/detached states. We studied clustering in suspended conditions. Effects of treatment with microtubule depolymerizing and stabilizing drugs were described. Results: Among cell lines, ...
Veterinary Record, 2021
THIS is the first report by the Small Animal Veterinary Surveillance Network (SAVSNET) to collate... more THIS is the first report by the Small Animal Veterinary Surveillance Network (SAVSNET) to collate key companion animal health surveillance findings since the start of the SARS-CoV-2 pandemic. The report outlines the impact of SARS-CoV-2 on UK companion animal consultation volume, summarises syndromic surveillance events, comments on our current understanding of SARS-CoV-2 in companion animal species and looks globally to other notable companion animal disease events during these times. More detail on the impact of SARS-CoV-2 on UK companion animal practice is available on the SAVSNET website. 1
Discovery medicine, 2016
Autoimmune diseases occur when cells of the adaptive immune system incorrectly recognize and atta... more Autoimmune diseases occur when cells of the adaptive immune system incorrectly recognize and attack "self" tissues. Importantly, the proliferation and differentiation of these cells is triggered and controlled by interactions with antigen presenting cells (APCs), such as dendritic cells. Thus, modulating the signals transduced by APCs (e.g., cytokines, costimulatory surface proteins) has emerged as a promising strategy to promote tolerance for diseases such as multiple sclerosis, type 1 diabetes, and lupus. However, many approaches have been hindered by non-specific activity of immunosuppressive or immunoregulatory cues, following systemic administration of soluble factors via traditional injections routes (e.g., subcutaneous, intravenous). Biomaterials offer a unique opportunity to control the delivery of tolerogenic signals in vivo via properties such as controlled particle size, tunable release kinetics, and co-delivery of multiple classes of cargo. In this review, we h...
Frontiers in Bioengineering and Biotechnology, 2021
Therapies for autoimmune diseases such as multiple sclerosis and diabetes are not curative and ca... more Therapies for autoimmune diseases such as multiple sclerosis and diabetes are not curative and cause significant challenges for patients. These include frequent, continued treatments required throughout the lifetime of the patient, as well as increased vulnerability to infection due to the non-specific action of therapies. Biomaterials have enabled progress in antigen-specific immunotherapies as carriers and delivery vehicles for immunomodulatory cargo. However, most of this work is in the preclinical stage, where small dosing requirements allow for on-demand preparation of immunotherapies. For clinical translation of these potential immunotherapies, manufacturing, preservation, storage, and stability are critical parameters that require greater attention. Here, we tested the stabilizing effects of excipients on the lyophilization of polymeric microparticles (MPs) designed for autoimmune therapy; these MPs are loaded with peptide self-antigen and a small molecule immunomodulator. We...
Clinical Cancer Research, 2020
Ovarian carcinomas are categorized into five major histotypes, each characterized by distinct dif... more Ovarian carcinomas are categorized into five major histotypes, each characterized by distinct differences in grade at diagnosis, presentation with metastatic disease, and clinical responses to treatments. Microtentacles (McTNs), microtubule-based extensions of the plasma membrane, were initially described on cells of nongynecologic primaries with high metastatic potential but have not been extensively explored in ovarian carcinomas. In this study, we investigated whether ovarian cancer cells exhibit McTNs as well as the effect of microtubule-targeted drugs on ovarian cancer McTNs. We analyzed 3 immortalized ovarian surface epithelium cell lines (IOSE), 8 clear-cell (OCCC), 3 low-grade serous (LGS), and 6 high-grade serous (HGS) ovarian cancer cells for McTN phenotype, length, and number, using a novel tethering platform in which cells are suspended but stationary, allowing for analysis via confocal microscopy. Additionally, selected cell lines were also treated with microtubule-targ...
Frontiers in Immunology, 2021
Biomaterial delivery systems offer unique potential to improve cancer vaccines by offering target... more Biomaterial delivery systems offer unique potential to improve cancer vaccines by offering targeted delivery and modularity to address disease heterogeneity. Here, we develop a simple platform using a conserved human melanoma peptide antigen (Trp2) modified with cationic arginine residues that condenses an anionic toll-like receptor agonist (TLRa), CpG, into polyplex-like nanoparticles. We reasoned that these structures could offer several useful features for immunotherapy – such as tunable loading, co-delivery of immune cues, and cargo protection – while eliminating the need for synthetic polymers or other complicating delivery systems. We demonstrate that Trp2/CpG polyplexes can readily form over a range of Trp2:CpG ratios and improve antigen uptake by primary antigen presenting cells. We show antigen loading can be tuned by interchanging Trp2 peptides with defined charges and numbers of arginine residues. Notably, these polyplexes with greater antigen loading enhance the function...
Advanced Functional Materials, 2020
Biomaterial carriers offer modular features to control the delivery and presentation of vaccines ... more Biomaterial carriers offer modular features to control the delivery and presentation of vaccines and immunotherapies. This tunability is a distinct capability of biomaterials. Understanding how tunable material features impact immune responses is important to improve vaccine and immunotherapy design, as well as clinical translation. Here the modularity of biomaterial properties is discussed as a means of controlling encounters with immune signals across scales—tissue, cell, molecular, and time—and ultimately, to direct stimulation or regulation of immune function. These advances are highlighted using illustrations from recent literature across infectious disease, cancer, and autoimmunity. As the immune engineering field matures, informed design criteria could support more rational biomaterial carriers for vaccination and immunotherapy.
Nature Biotechnology, 2020
Personalized cancer vaccines (PCVs) targeting patient-specific neoantigens are a promising cancer... more Personalized cancer vaccines (PCVs) targeting patient-specific neoantigens are a promising cancer treatment modality; however, neoantigen physicochemical variability can present challenges to manufacturing PCVs in an optimal format for inducing anticancer T cells. Here, we developed a vaccine platform ("SNP-7/8a") based on charge-modified peptide-TLR-7/8a conjugates that are chemically programmed to self-assemble into nanoparticles of uniform size (~20 nm) irrespective of the peptide antigen composition. This approach provided precise loading of diverse peptide neoantigens linked to TLR-7/8a (adjuvant) in nanoparticles that increased uptake by and activation of antigen-presenting cells that promote T cell immunity. Vaccination of mice with SNP-7/8a using predicted neoantigens (n=179) from three tumor models induced CD8 T cells against ~50% of neoantigens with high predicted MHC-I binding affinity and led to enhanced tumor clearance. SNP-7/8a delivering in silico-designed mock neoantigens also induced CD8 T cells in non-human primates. Altogether, SNP-7/8a is a generalizable approach for co-delivering peptide antigens and adjuvants in nanoparticles for inducing anticancer T cell immunity.
Advanced Materials, 2019
The immune system has remarkable capabilities to combat disease with exquisite selectivity. This ... more The immune system has remarkable capabilities to combat disease with exquisite selectivity. This feature has enabled vaccines that provide protection for decades, and more recently, advances in immunotherapies that can cure some cancers. Greater control over how immune signals are presented, delivered, and processed will help drive even more powerful options that are also safe. Such advances will be underpinned by new tools that probe how immune signals are integrated by immune cells and tissues. Biomaterials are valuable resources to support this goal, offering robust, tunable properties. This review highlights the growing role of biomaterials as tools to dissect immune function in fundamental and translational contexts. These technologies can serve as tools to understand the immune system across molecular, cellular, and tissue length scales. A common theme is exploiting biomaterial features to rationally direct how specific immune cells or organs encounter a signal. This precision strategy, enabled by distinct material properties, allows isolation of immunological parameters or processes in a way that is challenging with conventional approaches. The utility of these capabilities is demonstrated through examples in vaccines for
Scientific Reports, 2019
previous research suggests that dog owners are slightly more physically active than those without... more previous research suggests that dog owners are slightly more physically active than those without dogs, but have only studied one household member, and it is unclear whether time spent dog walking replaces other physical activity (PA). A survey of 191 dog owning adults (DO), 455 non-dog owning adults (NDO), and 46 children, living in 385 households in West Cheshire UK, was conducted in July-August 2015. Objective (accelerometer) validation occurred on a subset (n = 28 adults). Survey PA outcomes were modelled using hierarchical logistic and linear multivariable regression modelling, accounting for clustering of participants in households. DO were far more likely than NDO to report walking for recreation (oR = 14.35, 95% CI = 5.77-35.79, P < 0.001), and amongst recreational walkers walked for longer per week (RR = 1.39, 95% CI = 1.27-5.91, P < 0.001). Other PA undertaken did not differ by dog ownership. The odds of DO meeting current physical activity guidelines of 150 mins per week were four times greater than for NDo (oR = 4.10, 95% CI = 2.05-8.19, P < 0.001). Children with dogs reported more minutes of walking (p = 0.01) and free-time (unstructured) activity (P < 0.01). Dog ownership is associated with more recreational walking and considerably greater odds of meeting PA guidelines. Policies regarding public spaces and housing should support dog ownership due to PA benefits.
British Journal of Nutrition, 1999
The effect of 16 d intake of 300 mg carotenoids/kg diet (β-carotene (βC), bixin (BX), lycopene (L... more The effect of 16 d intake of 300 mg carotenoids/kg diet (β-carotene (βC), bixin (BX), lycopene (LY), lutein (LU), canthaxanthin (CX) or astaxanthin (AX)) on xenobiotic metabolizing enzymes in the liver, lung, kidney and small intestine of male Wistar rats was assessed. A control group received the basal diet (AIN-76) without carotenoids and a positive control group for enzyme induction received 3-methylcholanthrene (3-MC) at 666 mg/kg diet. Cytochrome P450 activity was assessed using the substrates ethoxyresorufin for P450 1A1, methoxyresorufin for P450 1A2, pentoxyresorufin for P450 2B1/2 and benzyloxyresorufin for P450 types 1A1/2, 2B1/2 and 3A. Glutathione-S-transferase (EC2.5.1.18) and reduced glutathione status were assessed. Carotenoid uptake by the tissues was also determined. 3-MC and the carotenoids BX, CX and AX led to significant increases compared with control in liver, lung and kidney ethoxyresorufin-O-deethylation. Methoxyresorufin-O-demethylation activity was signific...
Advanced Therapeutics, 2019
Small alterations during early stages of innate immune response can drive large changes in how ad... more Small alterations during early stages of innate immune response can drive large changes in how adaptive immune cells develop and function during protective immunity or disease. Controlling these events creates exciting potential in the development of immune engineered vaccines and therapeutics. This progress report discusses recent biomaterial technologies exploiting innate immunity to dissect immune function and to design new vaccines and immunotherapies for infectious diseases, cancer, and autoimmunity. Across these examples, an important idea is the possibility to co-opt innate immune mechanisms to enhance immunity during infection and cancer. During inflammatory or autoimmune disease, some of these same innate immune mechanisms can be manipulated in different ways to control excess inflammation by promotion of immunological tolerance.
Biomaterials Science, 2018
Microdisks formulated using advanced manufacturing techniques provide tunable control over vaccin... more Microdisks formulated using advanced manufacturing techniques provide tunable control over vaccine cargo loading while maintaining a high degree of uniformity.
Nano Research, 2018
Many experimental cancer vaccines are exploring toll-like receptor agonists (TLRas) such as CpG, ... more Many experimental cancer vaccines are exploring toll-like receptor agonists (TLRas) such as CpG, a DNA motif that agonizes toll-like receptor 9 (TLR9), to trigger immune responses that are potent and molecularly-specific. The ability to tune the immune response is especially important in the immunosuppressive microenvironments of tumors. Because TLR9 is located intracellularly, CpG must be internalized by immune cells for functionality. Polyplexes can be selfassembled through electrostatics using DNA (anionic) condensed by a positively charged carrier. These structures improve cell delivery and have been widely explored for gene therapy. In contrast, here we use cationic poly (β-amino esters) (PBAEs) to assemble polyplexes from CpG as an adjuvant to target and improve immune stimulation in cells and mouse models. Polyplexes were formed over a range of PBAE:CpG ratios, resulting in a library of complexes with increasingly positive charge and stronger binding as PBAE:CpG ratio increased. Although higher PBAE:CpG ratios exhibited improved CpG uptake, lower ratios of PBAE:CpG-which condensed CpG more weakly, activated DCs and tumorspecific T cells more effectively. In a mouse melanoma model, polyplexes with lower binding affinities improved survival more effectively compared with higher binding affinities. These data demonstrate that altering the polyplex interaction strength impacts accessibility of CpG to TLRs in immune cells. Thus, physiochemical properties, particularly the interplay between charge, uptake, and affinity, play a key role in determining the nature and efficacy of the immune response generated. This insight identifies new design considerations that must be balanced for engineering effective immunotherapies and vaccines.
Trends in Immunology, 2018
Polymers, lipids, scaffolds, microneedles, and other biomaterials are rapidly emerging as technol... more Polymers, lipids, scaffolds, microneedles, and other biomaterials are rapidly emerging as technologies to improve the efficacy of vaccines against infectious disease and immunotherapies for cancer, autoimmunity, and transplantation. New studies are also providing insight into the interactions between these materials and the immune system. This insight can be exploited for more efficient design of vaccines and immunotherapies. Here, we describe recent advances made possible through the unique features of biomaterials, as well as the important questions for further study.
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Papers by Christopher Jewell