Christopher Jewell

• Massachusetts Institute of Technology

Regulatory T cells (Tregs) with multifaceted functions suppress anti-tumor immunity by signaling surrounding cells. Here we report Tregs use the surface lymphotoxin (LT)α1β2 to preferentially stimulate LT beta receptor (LTβR) nonclassical NFκB signaling on both tumor cells and lymphatic endothelial cells (LECs) to accelerate tumor growth and metast...

Descartes-08 is an mRNA-engineered chimeric antigen receptor (CAR) T-cell therapy targeting B-cell maturation antigen (BCMA). We hypothesized that replacing the traditional integrating vectors characteristic of CAR T with mRNA would improve the safety profile of CAR-T by reducing risk of cytokine release syndrome (CRS), immune effector cell-associa...

Chimeric antigen receptor–T cell (CAR-T) therapy has transformed the management of refractory hematological malignancies. Now that targeting pathogenic cells of interest with antigen-directed cytotoxic T lymphocytes is possible, the field is expanding the reach of CAR-T therapy beyond oncology. Recently, breakthrough progress has been made in the a...

Regulatory T cells (Tregs) are suppressors of anti-tumor immunity that exert multifaceted functions by signaling surrounding cells. We revealed Tregs use their high-level surface lymphotoxin (LT)α1β2 to preferentially stimulate LTβ receptor (LTβR) nonclassical NFκB signaling on both tumor and lymphatic endothelial cells (LECs) to accelerate tumor g...

Whereas CD4 ⁺ T cells conventionally mediate antitumor immunity by providing help to CD8 ⁺ T cells, recent clinical studies have implied an important role for cytotoxic CD4 ⁺ T cells in cancer immunity. Using an orthotopic melanoma model, we provide a detailed account of antitumoral CD4 ⁺ T cell responses and their regulation by major histocompatib...

Fleas transmit Yersinia pestis directly within the dermis of mammals to cause bubonic plague. Syringe-mediated inoculation is widely used to recapitulate bubonic plague and study Y. pestis pathogenesis. However, intradermal needle inoculation is tedious, error prone, and poses a significant safety risk for laboratorians. Microneedle arrays (MNAs) a...

Stem-like CD8+ T cells are regulated by T cell factor 1 (TCF1) and are considered requisite for immune checkpoint blockade (ICB) response. However, recent findings indicate that reliance on TCF1+CD8+ T cells for ICB efficacy may differ across tumor contexts. We find that TCF1 is essential for optimal priming of tumor antigen-specific CD8+ T cells a...

Background: Chimeric antigen receptor (CAR) T cells are highly effective in treating haematological malignancies, but associated toxicities and the need for lymphodepletion limit their use in people with autoimmune disease. To explore the use of CAR T cells for the treatment of people with autoimmune disease, and to improve their safety, we engine...

Biomaterials allow for the precision control over the combination and release of cargo needed to engineer cell outcomes. These capabilities are particularly attractive as new candidate therapies to treat autoimmune diseases, conditions where dysfunctional immune cells create pathogenic tissue environments during attack of self-molecules termed self...

Autoimmune diseases such as Multiple sclerosis (MS) and diabetes affect more than 50 million people worldwide. We have previously demonstrated that intra-lymph node injection of polymer microparticles (MPs) loaded with myelin antigen (MOG) and a tolerogenic immune cue (rapamycin) protect mice from experimental autoimmune encephalomyelitis (EAE), a...

Multiple sclerosis (MS) is an inflammatory disorder that occurs when autoreactive lymphocytes mistakenly attack myelin, resulting in motor deficits and cognitive deterioration. Current drugs are non-curative and require life-long treatment that make compliance challenging, and existing therapeutics can leave patients vulnerable to opportunistic inf...

Microneedle arrays (MNAs) are patches displaying hundreds of micron-scale needles that can penetrate skin. As a result, these arrays efficiently and painlessly access this immune cell-rich niche, motivating significant clinical interest in MNA-based vaccines. Our lab has developed immune polyelectrolyte multilayers (iPEMs), nanostructures built ent...

Immunotherapies are an evolving treatment paradigm for addressing cancer, autoimmunity, and infection. While exciting, most of the existing therapies are limited by their specificity─unable to differentiate between healthy and diseased cells at an antigen-specific level. Biomaterials are a powerful tool that enable the development of next-generatio...

Scientific bias originates from both researchers and techniques. Evidence-based strategies to mitigate this bias include the assembly of diverse teams, development of rigorous experimental designs, and use of unbiased analytical techniques. Here, we highlight potential starting points to decrease bias in bioengineering research.

Antigen-specific tolerance is a key goal of experimental immunotherapies for autoimmune disease and allograft rejection. This outcome could selectively inhibit detrimental inflammatory immune responses without compromising functional protective immunity. A major challenge facing antigen-specific immunotherapies is ineffective control over immune si...

Multiple sclerosis (MS) is an autoimmune disease that develops when dysfunctional autoreactive lymphocytes attack the myelin sheath in the central nervous system. There are no cures for MS, and existing treatments are associated with unwanted side effects. One approach for treating MS is presenting distinct immune signals (i.e., self-antigen and im...

Disease‐modifying drugs and biologics used to treat autoimmune diseases, although promising, are non‐curative. As the field moves toward development of new approaches to treat autoimmune disease, antigen‐specific immunotherapies (ASITs) have emerged. Despite clinical approval of ASITs for allergies, clinical trials using soluble ASITs for autoimmun...

Autoimmunity and allergies affect a large number of people across the globe. Current approaches to these diseases target cell types and pathways that drive disease, but these approaches are not cures and cannot differentiate between healthy cells and disease‐causing cells. New immunotherapies that induce potent and selective antigen‐specific tolera...

During autoimmunity or organ transplant rejection, the immune system attacks host or transplanted tissue, causing debilitating inflammation for millions of patients. There is no cure for most of these diseases. Further, available therapies modulate inflammation through nonspecific pathways, reducing symptoms but also compromising patients’ ability...

Recent clinical studies show activating multiple innate immune pathways drives robust responses in infection and cancer. Biomaterials offer useful features to deliver multiple cargos, but add translational complexity and intrinsic immune signatures that complicate rational design. Here a modular adjuvant platform is created using self‐assembly to b...

Recently approved cancer immunotherapies - including CAR-T cells and cancer vaccination, - show great promise. However, these technologies are hindered by the complexity and cost of isolating and engineering patient cells ex vivo. Lymph nodes (LNs) are key tissues that integrate immune signals to coordinate adaptive immunity. Directly controlling t...

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. Nea...

Clinical cancer imaging focuses on tumor growth rather than metastatic phenotypes. The microtubule-depolymerizing drug, Vinorelbine, reduced the metastatic phenotypes of microtentacles, reattachment and tumor cell clustering more than tumor cell viability. Treating mice with Vinorelbine for only 24 h had no significant effect on primary tumor survi...

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 wh...

Autoimmune diseases—where the immune system mistakenly targets self-tissue—remain hindered by non-specific therapies. For example, even molecularly specific monoclonal antibodies fail to distinguish between healthy cells and self-reactive cells. An experimental therapeutic approach involves delivery of self-molecules targeted by autoimmunity, along...

Lymph nodes (LNs), where immune responses are initiated, are organized into distinctive compartments by fibroblastic reticular cells (FRCs). FRCs imprint immune responses by supporting LN architecture, recruiting immune cells, coordinating immune cell crosstalk, and presenting antigens. Recent high-resolution transcriptional and histological analys...

Outcomes during immunotherapy are impacted not only by the specific therapeutic signals and pharmacodynamics, but also by the biophysical forms in which signals are delivered. This integration is determinative in autoimmunity because the disease is caused by immune dysregulation and inflammation. Unfortunately, the links between nanomaterial design...

Autoimmune diseases like multiple sclerosis (MS), type 1 diabetes, and lupus occur when the immune system attacks host tissue. Immunotherapies that promote selective tolerance without suppressing normal immune function are of tremendous interest. Here, nanotechnology was used for rational assembly of peptides and modulatory immune cues into immune...

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...

Mammosphere assays are widely used in vitro to identify prospective cancer-initiating stem cells that can propagate clonally to form spheres in free-floating conditions. However, the traditional mammosphere assay inevitably introduces cell aggregation that interferes with the measurement of true mammosphere forming efficiency. We developed a method...

Candida albicans is a commensal organism and opportunistic pathogen that can form biofilms that colonize surfaces such as implants, catheters, and dentures. Compared to planktonic C. albicans cells, cells in biofilms exhibit increased resistance to treatment. Histatin 5 (Hst-5) is an antimicrobial peptide that is natively secreted by human salivary...

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),...

Autoimmune diseases, transplantation, allergies and other inflammatory diseases impact a large number of individuals. These diseases are driven by dysfunctional immune responses (i.e., autoimmune disease, allergies), or normal immune responses that occur in unwanted contexts (i.e., transplant rejection, anti-drug antibodies). While tremendous progr...

In situ metabolic labelling and targeted modulation of dendritic cells has been achieved using a hydrogel system in combination with covalent capture of antigens and adjuvants, facilitating improved tumour-specific immune response.

The technical challenges of imaging non-adherent tumor cells pose a critical barrier to understanding tumor cell responses to the non-adherent microenvironments of metastasis, like the bloodstream or lymphatics. In this study, we optimized a microfluidic device (TetherChip) engineered to prevent cell adhesion with an optically-clear, thermal-crossl...

Uniform nanoparticle vaccines Precise loading of diverse peptides for vaccination is enabled by a strategy for peptide–TLR7/8 conjugate self-assembly of uniform nanoparticles. The approach is compatible with the development of personalized strategies, such as cancer vaccines targeting patient-specific neoepitopes.

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 powerf...

Lymph nodes (LNs) are at the cross roads of immunity and tolerance. These tissues are compartmentalized into specialized niche areas by lymph node stromal cells (LN SCs). LN SCs shape the LN microenvironment and guide immunological cells into different zones through establishment of a CCL19 and CCL21 gradient. Following local immunological cues, LN...

Bacteriophages, or phages, are viruses that specifically infect bacteria and coopt the cellular machinery to create more phage proteins, eventually resulting in the release of new phage particles. Phages are heavily utilized in bioengineering for applications ranging from tissue engineering scaffolds to immune signal delivery. Of specific interest...

Vaccines and immunotherapies have changed the face of health care. Biomaterials offer the ability to improve upon these medical technologies through increased control of the types and concentrations of immune signals delivered. Further, these carriers enable targeting, stability, and delivery of poorly soluble cargos. Inorganic nanomaterials posses...

A key challenge facing immunotherapy is poor infiltration of T cells into tumors, along with suppression of cells reaching these sites. However, macrophages make up a majority of immune cell infiltrates into tumors, creating natural targets for immunotherapies able to direct macrophages away from tumor-supportive functions and toward anti-tumor phe...

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 tech...

We describe the synthesis of CpG oligodeoxynucleotide-coated Prussian blue nanoparticles (CpG-PBNPs) that function as a nanoimmunotherapy for neuroblastoma, a common childhood cancer. These CpG-PBNPs increase the antigenicity and adjuvanticity of treated tumors, ultimately driving robust antitumor immunity through a multi-pronged mechanism. CpG-PBN...

Autoimmune disorders, such as multiple sclerosis and type 1 diabetes, occur when immune cells fail to recognize “self” molecules. Recently, studies have revealed aberrant inflammatory signaling through pathogen sensing pathways, such as toll-like receptors (TLRs), during autoimmune disease. Therapeutic inhibition of these pathways might attenuate d...

Autoimmune diseases, rejection of transplanted organs and grafts, chronic inflammatory diseases, and immune‐mediated rejection of biologic drugs impact a large number of people across the globe. New understanding of immune function is revealing exciting opportunities to help tackle these challenges by harnessing—or correcting—the specificity of imm...

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 TL...

Vaccines and immunotherapies that elicit specific types of immune responses offer transformative potential to tackle disease. The mechanisms governing the processing of immune signals—events that determine the type of response generated—are incredibly complex. Understanding these processes would inform more rational vaccine design by linking carrie...

Vaccines and immunotherapies have provided enormous improvements for public health, but there are fundamental disconnects between where most studies are performed-in cell culture and animal models-and the ultimate application in humans. Engineering immune tissues and organs, such as bone marrow, thymus, lymph nodes and spleen, could be instrumental...

During metastasis, tumor cells dynamically change their cytoskeleton to traverse through a variety of non-adherent microenvironments, including the vasculature or lymphatics. Due to the challenges of imaging drift in non-adhered tumor cells, the dynamic cytoskeletal phenotypes are poorly understood. We present a new approach to analyze the dynamic...

Significance statement: The last several years have brought exciting work exploring biomaterials as delivery vehicles for immunotherapies, vaccines, and gene therapies. However, a gap remains between the striking finding that many biomaterials exhibit intrinsic immunogenic features, and the specific structural properties that drive these responses...

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 insi...

The continued challenges facing vaccines in infectious disease and cancer highlight a need for better control over the features of vaccines and the responses they generate. Biomaterials offer unique advantages to achieve this goal through features such as controlled release and co-delivery of antigens and adjuvants. However, many synthesis strategi...

Purpose of review: To evaluate role of the lymph node in immune regulation and tolerance in transplantation and recent advances in the delivery of antigen and immune modulatory signals to the lymph node. Recent findings: Lymph nodes are a primary site of immune cell priming, activation, and modulation, and changes within the lymph node microenvi...

Multiple sclerosis (MS) is an autoimmune disease where myelin is incorrectly recognized as foreign and attacked by the adaptive immune system. Dendritic cells (DCs) direct adaptive immunity by presenting antigens to T cells, therefore serving as a target for autoimmune therapies. N-Phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxamide (PHCCC),...

In article number 1700290, Christopher M. Jewell and co-workers use quantum dots (yellow) to track and control the display density of self-molecules mistakenly attacked during autoimmune diseases. This precise display changes self-molecule processing by antigen-presenting cells (purple), reprogramming the disease-driving inflammatory T cells (red)...

Autoimmune disease occurs when the immune system incorrectly targets the body's own tissue. Inflammatory CD4(+) T cell phenotypes, such as TH1 and TH17, are key drivers of this attack. Recent studies demonstrate treatment with rapamycin-a key inhibitor of the mTOR pathway-can skew T cell development, moving T cell responses away from inflammatory p...

Myelin, a matrix that insulates the axons of neurons, is attacked by the immune system in multiple sclerosis (MS), leading to neurodegeneration. MS treatments are currently limited because they are non-curative and broadly-acting immunosuppressants that can leave patients immunocompromised. Recent reports show co-delivery of myelin peptides (MOG) a...

Recent studies demonstrate, they frequent, low-dose administration of rapamycin (Rapa) during vaccination can help maintain the plasticity of antigen-specific CD8+ T cells, polarizing the phenotypes of these cells toward central memory T cells (TCM). However, these effects required multiple, systemic doses of Rapa. Here we hypothesized that local,...

Multiple sclerosis (MS) is an autoimmune disease in which myelin insulating neurons is attacked. New research in humans shows excess inflammation through toll like receptors (TLR) contribute to disease. In animals, co-administration of self-antigens and regulatory cues leads to more specific tolerance. Polymers and other biomaterials can enable thi...

The immune system is an awe-inspiring control structure that maintains a delicate and constantly changing balance between pro-immune functions that fight infection and cancer, regulatory or suppressive functions involved in immune tolerance, and homeostatic resting states. These activities are determined by integrating signals in space and time; th...

Treatments for autoimmunity—diseases where the immune system mistakenly attacks self-molecules—are not curative and leave patients immunocompromised. New studies aimed at more specific treatments reveal that development of inflammation or tolerance is influenced by the form in which self-antigens are presented. Using a mouse model of multiple scler...

Recent research in the vaccine and immunotherapy fields has revealed that biomaterials have the ability to activate immune pathways, even in the absence of other immune-stimulating signals. Intriguingly, new studies reveal these responses are influenced by the physicochemical properties of the material. Nearly all of this work has been done in the...

An important goal for improving vaccine and immunotherapy technologies is the ability to provide further control over the specific phenotypes of T cells arising from these agents. Along these lines, frequent administration of rapamycin (Rapa), a small molecule inhibitor of the mammalian target of rapamycin (mTOR), exhibits a striking ability to pol...

Engineering cell surfaces with natural or synthetic materials is a unique and powerful strategy for biomedical applications. Cells exhibit more sophisticated migration, control, and functional capabilities compared to nanoparticles, scaffolds, viruses, and other engineered materials or agents commonly used in the biomedical field. Over the past dec...

Polymeric carriers are ubiquitously studied in vaccine and drug delivery to control the encapsulation, kinetics, and targeting of cargo. Recent research reveals many polymers can cause immunostimulatory and inflammatory responses, even in the absence of other immune signals. However, the extent to which this intrinsic immunogenicity evolves during...

Autoimmune diseases occur when the immune system incorrectly recognize self-molecules as foreign; in the case of multiple sclerosis (MS), myelin is attacked. Intriguingly, new studies reveal toll-like receptors (TLR), pathways usually involved in generating immune response again pathogens, play a significant role in driving autoimmune disease in bo...

Microneedles (MNs) are micron-scale polymeric or metallic structures that offer distinct advantages for vaccines by efficiently targeting skin-resident immune cells, eliminating injection-associated pain, and improving patient compliance. These advantages, along with recent studies showing therapeutic benefits achieved using traditional intradermal...

Many experimental therapies for autoimmune diseases, such as multiple sclerosis (MS), aim to bias T cells toward tolerogenic phenotypes without broad suppression. However, the link between local signal integration in lymph nodes (LNs) and the specificity of systemic tolerance is not well understood. We used intra-LN injection of polymer particles t...

Recent studies demonstrate that excess signaling through inflammatory pathways (e.g., toll-like receptors, TLRs) contributes to the pathogenesis of human autoimmune diseases, including lupus, diabetes, and multiple sclerosis (MS). We hypothesized that co-delivery of a regulatory ligand of TLR9, GpG oligonucleotide, along with myelin – the “self” mo...

Biomaterial vaccines offer new capabilities that can be exploited for both infectious disease and cancer. We recently developed a novel vaccine platform based on self-assembly of immune signals into immune polyelectrolyte multilayers (iPEMs). These iPEM vaccines are electrostatically assembled from peptide antigens and nucleic acid-based toll-like...

Free-floating tumor cells located in the peripheral circulation of cancer patients, known as circulating tumor cells (CTCs), play an important role in cancer and have become key targets for studying metastasis. The presence of CTCs in the bloodstream or lymphatics correlates with decreased cancer patient survival and provides a minimally invasive m...

While biomaterials provide a platform to control the delivery of vaccines, the recently-discovered intrinsic inflammatory characteristics of many polymeric carriers can also complicate rational design because the carrier itself can alter the response to other vaccine components. To address this challenge, we recently developed immune-polyelectrolyt...

Biomaterial vaccines offer cargo protection, targeting, and co-delivery of signals to immune organs such as lymph nodes (LNs), tissues that coordinate adaptive immunity. Understanding how individual vaccine components impact immune response has been difficult owing to the systemic nature of delivery. Direct intra-lymph node (i.LN.) injection offers...

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., cytoki...

Immunotherapies for cancer have progressed enormously over the past few decades, and hold great promise for the future. The successes of these therapies, with some patients showing durable and complete remission, demonstrate the power of harnessing the immune system to eradicate tumors. However, the effectiveness of current immunotherapies is limit...

Free-floating tumor cells located in the blood of cancer patients, known as circulating tumor cells (CTCs), have become key targets for studying metastasis. However, effective strategies to study the free-floating behavior of tumor cells in vitro have been a major barrier limiting the understanding of the functional properties of CTCs. Upon extrace...

Statement of significance: Degradable polymers are increasingly important in vaccination, but how the inherent immunogenicity of polymers changes during degradation is poorly understood. Using common rapidly-degradable vaccine carriers, we show that the activation of immune cells - even in the absence of other adjuvants - depends on polymer form (...

New vaccine adjuvants that direct immune cells toward specific fates could support more potent and selective options for diseases spanning infection to cancer. However, the empirical nature of vaccines and the complexity of many formulations has hindered design of well-defined and easily characterized vaccines. We hypothesized that nanostructured c...

Materials that allow modular, defined assembly of immune signals could support a new generation of rationally-designed vaccines that promote tunable immune responses. Toward this goal, we have developed the first polyelectrolyte multilayer (PEM) coatings built entirely from immune signals. These immune-PEMs (iPEMs) are self-assembled on gold nanopa...

Autoimmune disorders occur when the immune system abnormally recognizes and attacks self-molecules. Dendritic cells (DCs) play a powerful role in initiating adaptive immune response, and are therefore a recent target for autoimmune therapies. N-Phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxamide (PHCCC), a small molecule glutamate receptor e...

Nanoparticles, microparticles, and other biomaterials are advantageous in vaccination because these materials provide opportunities to modulate specific characteristics of immune responses. This idea of "tuning" immune responses has recently been used to combat infectious diseases and cancer, and to induce tolerance during organ transplants or auto...

A composition for delivery of a molecule into a cell is provided. The composition includes a protein transduction domain that is conjugated to the molecule which is incorporated into a multilayered film. Preferably, the protein transduction domain is a cationic protein transduction domain. More preferably, the cationic protein transduction domain i...

The present invention provides implantable medical devices coated with polyelectrolyte assemblies that are fabricated by layer-by-layer deposition of nucleic acid and polycation. Such devices facilitate the local delivery of a nucleic acid contained in the polyelectrolyte assembly into a cell or tissue at an implantation site. Also provided are met...

Generation of adaptive immune response relies on efficient drainage or trafficking of antigen to lymph nodes for processing and presentation of these foreign molecules to T and B lymphocytes. Lymph nodes have thus become critical targets for new vaccines and immunotherapies. A recent strategy for targeting these tissues is direct lymph node injecti...