| Yvonne Y. Chen |
University of California Los Angeles |
Engineering Multi-pronged CAR-T Cells for Cancer Therapy
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The adoptive transfer of T cells expressing chimeric antigen receptors (CARs) has demonstrated robust efficacy in the treatment of advanced hematological malignancies. However, challenges such as antigen escape and immunosuppression limit the long-term efficacy of adoptive T-cell therapy, particularly for solid tumors. Here, I will discuss the development of next-generation T cells that can target multiple cancer antigens, modify the tumor microenvironment, and/or engage endogenous immunity to overcome tumor-defense mechanisms. This presentation will highlight the potential of synthetic biology in generating novel mammalian cell systems with multifunctional outputs for therapeutic applications.
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| Bali Pulendran |
Stanford University School of Medicine |
Systems Vaccinology |
Although the development of effective vaccines has saved countless lives from infectious diseases, the basic workings of the human immune system are complex and have required the development of animal models, such as inbred mice, to define mechanisms of immunity. However, past results are not necessarily a reliable guide to the future, and a notable limitation of animal models has been their failure to accurately model some human diseases and their inability to predict human immune responses in many cases. In the past decade there has been an explosion of new approaches and technologies to explore the human immune system with unprecedented precision. Insights into the human immune response to vaccination, cancers, and viral infections such as COVID-19 have come from high-throughput “omics” technologies that measure the behavior of genes, mRNA, proteins, metabolites, cells, and epigenetic modifications, coupled with computational approaches. I will discuss how these “Systems Vaccinology” approaches are advancing our mechanistic understanding of the human system and its response to vaccines and infections in diverse populations, including the elderly population, and facilitating the development of vaccines against HIV, malaria and other infectious diseases. |
| Gabe A. Kwong |
Georgia Institute of Technology |
Building Synthetic Immunity: Designing T Cells to Measure, Detect, and Treat Cancer |
The success of engineered T cells for cancer therapy is revealing new opportunities to design immune cells for broad cancer applications. In this presentation, I will first share our work on displaying protease-activatable receptors on T cells to create a measurement tool for mapping the cancer degradome across various cancer types and tissues. I will highlight how this activity-based atlas can be harnessed for the design of ultrasensitive biosensors with improved detection limits and specificity compared to conventional blood biomarkers. In the second half of the talk, I will share our strategies to overcome the challenges of solid tumor therapy with CAR T cells. These include the design of thermal gene switches to control the intratumoral production of immune potentiators, synthetic antigens to sensitize tumors to cell killing, and antigen-specific in vivo cell engineering. Taken together, our work illustrates how bioengineering can drive the development of improved tools for cancer detection and treatment. |
| Danielle Elise Soranno |
Indiana University |
Local and Sustained Delivery of Therapeutics to Treat Kidney Disease |
This talk will review the use of injectable hydrogels to deliver therapeutics to improve outcomes in experimental models of acute kidney injury (AKI) and chronic kidney disease (CKD). Hydrogels are water-swollen polymers that can be made from a variety of natural and synthetic polymers. Numerous chemistries can be utilized to formulate hydrogels that are injectable, enabling facile in situ delivery of therapeutics such as cytokines or cells. Cells delivered via injectable hydrogels survive injection better than cells injected in saline/media suspension. Hyaluronic acid (HA) can be chemically modified using guest-host interactions to formulate an injectable hydrogel. The chemistry can be modified such that the hydrogels degrade quickly or slowly in vivo. HA hydrogels have been used to deliver interleukin-10, anti-TGFβ, and mesenchymal stem cells in various models of kidney disease. Numerous studies have demonstrated that HA hydrogel therapy alone reduces inflammation and fibrosis. Transcutaneous measurements of glomerular filtration rate have demonstrated that delivery of the hydrogel under the kidney capsule does not impair measured kidney function. |
| Brian Alberto Aguado |
University of California San Diego |
Understanding Sex Chromosome and Sex Hormone Regulation of Cardiovascular Disease and Inflammation Using Biomaterials |
Cardiovascular disease is the leading cause of death in both men and women, yet our mechanistic knowledge of the sex-specific molecular and cellular mechanisms that guide cardiovascular disease progression, particularly in women, remain poorly characterized. Studies evaluating disease mechanisms rarely state the sex of cells used for in vitro studies or are performed primarily in male animal models, causing our gap in knowledge. My laboratory uses precision biomaterials as in vitro and in vivo tools to dissect mechanisms that contribute to sexual dimorphisms in cardiovascular diseases, specifically aortic valve stenosis and cardiac fibrosis. In my talk, I will discuss how we have used hydrogel biomaterials as engineered valve matrix mimics to explore sex dimorphisms in valvular interstitial cell phenotypes in vitro and describe sex-specific molecular mechanisms that may drive dimorphisms in aortic valve stenosis. We have also utilized biomaterial implants to determine effects of sex chromosomes and gonadal sex on immune cell populations before and after implantation. Our work seeks to leverage biomaterial technologies to understand sex dimorphisms in health and disease, with the long-term goal of achieving sex and gender equity in cardiovascular disease treatments and outcomes. |
| Suzanne L. Topalian |
Johns Hopkins University School of Medicine and Bloomberg-Kimmel Institute for Cancer Immunotherapy |
PD-1 Pathway Blockade: Using “Precision Immunology” To Unleash the Immune System Against Cancer |
The PD-1 pathway, including the receptor Programmed Cell Death 1 (PD-1) on immune cells and its ligands PD-L1 (B7-H1) and PD-L2 (B7-DC) on tumor and myeloid cells, mediates immunosuppression in the tumor microenvironment. Drugs that “release the brakes” on anti-tumor immunity by blocking PD-1 or PD-L1 have shown substantial and durable activity against multiple cancers, validating them as a “common denominator” for cancer therapy. Since September 2014, the US FDA has approved several different PD-(L)1 monoclonal antibodies to treat advanced or high-risk cancers, spanning more than 20 different tumor types. These drugs, initially tested and approved in the advanced unresectable disease setting, are now being applied against earlier stages of cancer in the adjuvant and neoadjuvant settings, to prevent post-surgical relapse from micrometastatic disease. Research to identify biomarkers predicting response to anti-PD-(L)1 therapy has revealed 3 markers garnering FDA approval: PD-L1 protein expression in pre-treatment biopsies, tumor MSI-high/dMMR status, and high tumor mutational burden. More complex biomarkers integrating multidimensional data are expected to provide greater sensitivity and predictive power compared to the unidimensional markers currently in use. The continued development of biomarkers in a “precision immunology” approach will further refine the risk:benefit profile for PD-1/PD-L1 antagonists, increase our understanding of the mechanistic underpinnings of this pathway, and guide the development of more effective combination treatment regimens. |
| Honggang Cui |
The Johns Hopkins University |
Prodrug Hydrogelators as Immune Modulators for Localized Chemoimmunotherapy |
Immunotherapy has revolutionized cancer treatment by harnessing the body’s own immune system to combat tumors. However, despite its success, response rates remain modest, and systemic administration often leads to immune-related adverse effects. To overcome these limitations, we have developed a self-assembling prodrug hydrogelator platform for localized delivery of immunotherapies, designed to improve efficacy while minimizing systemic toxicity. This carrier-free, injectable hydrogel system forms an in situ depot at the tumor site, enabling sustained release of chemotherapeutic agents—such as camptothecin or paclitaxel—alongside immunomodulatory agents including immune checkpoint inhibitors (e.g., anti–PD-1), STING agonists, and CD47 blockers. Our findings position prodrug hydrogelators as a versatile and translationally promising platform for combination immunotherapy, offering a rational and modular design strategy for the local delivery of synergistic therapeutic agents to enhance cancer treatment outcomes. |
| Ying Mei |
Clemson University |
Hypoimmunogenic hPSC-Derived Cardiac Organoids Evade Host Immune Rejection and Promote Cardiac Functional Recovery |
Myocardial infarction (MI) is a major cause of death worldwide and bears an immense economic burden. As adult human heart tissue has limited regenerative capacity, human pluripotent stem cells (hPSCs) have shown promise as a cell source for deriving functional cardiomyocytes (hPSC-CMs) for heart repair. However, current approaches face significant challenges, including moderate cell survival and engraftment, as well as immune rejection risks necessitating human leukocyte antigen (HLA) matching and immunosuppressive treatments. To address these limitations, we have developed hypoimmunogenic hPSCs through genetic deletion of the beta-2 microglobulin (B2M) gene and knock-in of the HLA-E fusion molecule (B2M-/- HLA-E+ hPSCs). B2M knockout eliminates HLA class I-mediated T cell killing, while HLA-E expression mitigates NK cell-mediated lysis. The B2M-/- HLA-E+ hPSCs retain the capacity to differentiate into hPSC-CMs, cardiac fibroblasts (hPSC-cFbs), endothelial cells (hPSC-ECs), and pericytes (hPSC-PCs). Our data showed that B2M-/- HLA-E+ hPSC-derived cardiac cells evade NK- and T cell-mediated lysis in vitro. Furthermore, cardiac organoids fabricated from B2M-/- HLA-E+ hPSC-derived cardiac cells show comparable transcriptome, structure and function to wild-type counterparts. Importantly, B2M-/- HLA-E+ hPSC cardiac organoids demonstrate robust engraftment and significantly enhance cardiac function in a rat myocardial ischemia/reperfusion injury model, performing comparably to their wild-type counterparts. These findings underscore the potential of hypoimmunogenic hPSC-derived cardiac organoids as a clinically relevant approach for allogenic cardiac regenerative therapy, eliminating the need for immunosuppression while promoting effective cardiac recovery. |
| Aaron P. Esser-Kahn |
University of Chicago |
Discovery of New Trained Immunity Molecules and Pathways |
Trained immunity involves epigenetic and metabolic reprogramming in response to specific stimuli, enhancing cytokine and immune responses for broad protection against diseases. It also has potential to improve the effectiveness of vaccines and immunotherapies. Current studies rely on complex molecules like β-glucan and the BCG vaccine, which complicate gene analysis due to their mixed effects.
To advance research, we screened 2,000 drugs and drug-like compounds and identified over two dozen small molecules that induce trained immunity without initial immune activation. Notably, glucocorticoids, traditionally considered immunosuppressive, were found to trigger this response. We further characterized seven top candidates in vivo, significantly expanding the pool of compounds for studying and applying innate immune training in clinical settings. |
| Babar Bashir |
Thomas Jefferson University |
Immunological and Preliminary Clinical Responses to Ad5.F35-hGUCY2C-PADRE Vaccine in GI Cancers |
Guanylyl cyclase-C (GCC) is a mucosally-restricted self antigen that is compartmentalized and over expressed in GI cancers, thus a suitable immunotherapy candidate. Our group developed a vaccine (Ad5.F35-hGUCY2C-PADRE) that aims to train native T-cells to identify cancer cells expressing GCC and killing them, while sparing normal colonic mucosa (compartmentalization). Here we report first results of Ad5.F35-hGUCY2C-PADRE vaccine’s immunologic and preliminary clinical responses. |
| Benjamin Youngblood |
St. Jude Children’s Research Hospital |
Reverse Translation of Patient-Identified Epigenetic Regulators Limiting Durable Tumor Immunotherapy |
T cell-based immunotherapies have emerged as one of the most promising frontiers in the fight against cancer and chronic infections. However, it has become clear that prolonged exposure of T cells to their cognate antigen drives them toward a terminally differentiated state, limiting their therapeutic efficacy. The commitment of T cells to this “exhausted” fate is currently a major barrier in the advancement of T cell immunotherapy efforts. We have recently demonstrated that the progressive decline in a T cell’s developmental potential is coupled to the acquisition of discrete epigenetic programs. Here I will describe our effort to block these programs using gene-editing approaches, and how disruption of ‘epigenetic differentiation checkpoints’ preserves the T cell’s developmental plasticity and enhances anti-tumor responses settings of PD-1 blockade and adoptive T cell therapy. From these studies we have identified a trans-species set of epigenetic programs that reinforce the developmental state of T cell exhaustion that subsequently limit the therapeutic potential of T cells. We are now translating these discoveries into novel clinical strategies and diagnostic biomarkers to rationally guide the development of current and future T cell-based therapies. |
| Laura Suggs |
University of Texas at Austin |
Apoptic Cell-Inspired Immunoengineering |
Macrophages play a critical role in the initiation, maintenance, and resolution of inflammation following disease or injury because of their diverse and highly plastic phenotypic responses. One important physical cue that robustly drives an anti-inflammatory macrophage response and the resolution of inflammation is apoptotic cell recognition and engulfment. This anti-inflammatory response is mediated by several receptors on the macrophage, and a number of proteins, lipids and metabolites derived from engulfed apoptotic cells, apoptotic bodies and other vesicles. We have developed a nanoparticle that mimics features of apoptotic bodies based on three key steps in the process through which apoptotic cells or apoptotic bodies modulate inflammation, that is: “find me,” “eat me,” and “tolerate me.” Our work here seeks to tease out soluble and membrane-bound components that can be derived from dead cells that are therapeutically important. |
| Ana Maria Porras |
University of Florida |
Genomic and Functional Profiling of Microbiome Enzymes that Remodel Intestinal Extracellular Matrix |
The intestinal mucosa is maintained by a delicate balance between extracellular matrix (ECM) remodeling and microbial activity. Disruption of this balance is central to the pathogenesis of chronic inflammatory disorders such as inflammatory bowel disease (IBD), where microbial dysbiosis coincides with aberrant ECM turnover. While the microbiota is increasingly recognized as an active participant in shaping immune responses, the mechanisms through which commensal species alter host tissue structure and modulate inflammation remain poorly defined.
We focused on the Bacteroides genus, a dominant component of the gut microbiome with species frequently associated with IBD and colorectal cancer. Through comparative genomic analyses of 14 Bacteroides species, we identified a rich repertoire of enzymes with the potential to degrade ECM components, including glycoside hydrolases, glycosaminoglycan-targeting polysaccharide lyases, and multiple classes of proteases. Predicted substrates included hyaluronan, chondroitin sulfate, heparan sulfate, collagen, and decorin—molecules whose breakdown products are known to amplify inflammatory signaling and leukocyte recruitment.
To functionally validate these predictions, we exposed purified ECM substrates to bacterial supernatants. B. ovatus and B. thetaiotaomicron preferentially degraded glycosaminoglycans, while multiple B. fragilis strains degraded fibrillar and basement membrane collagens as well as elastin. Protease inhibitor assays implicated secreted cysteine, serine, and metalloproteases in this activity. Early evidence from mouse colitis models indicates that ECM-degrading activity from Bacteroides isolates correlates with accelerated inflammation.
Together, our results highlight a previously underappreciated axis of host–microbe interaction: commensal-derived enzymes that remodel the ECM, potentially shaping mucosal immunity. By linking comparative genomics, in vitro assays, and preliminary in vivo/clinical data, this work uncovers candidate microbial pathways that may accelerate tissue damage in IBD and related disorders. |
| John T. Wilson |
Vanderbilt University |
Engineering Nanotechnologies for Immuno-Oncology |
Cancer immunotherapy is revolutionizing the treatment of an ever-expanding diversity of cancer types, yielding impressive complete and durable responses in a subset of patients. However, most patients do not respond to currently approved immune checkpoint inhibitors. Our group is working to solve this emergent grand challenge in immuno-oncology through the development of molecularly engineered technologies that increase immune recognition of tumors. This talk will focus on our recent work in the design of polymer and protein-based drug delivery platforms for activation of antitumor innate immunity and how we are leveraging these materials to increase tumor immunogenicity and responses to immunotherapy. |
| Laura A. Vella |
University of Pennsylvania/Children's Hospital of Philadelphia |
Decoding the HIV Reservoir |
Persistence of the HIV reservoir is a major barrier to cure. Many cure-directed clinical trials use novel interventions to reactivate the reservoir for immune targeting and reservoir reduction. Improving the targeting and elimination of HIV reservoir requires a cell-by-cell understanding of where reservoir is and how reservoir persists after cure interventions. However, current strategies to identify the multi-modal biology of cells with integrated provirus cannot fully resolve the intact proviral reservoir: they cannot detect provirus in closed chromatin and cannot discern intact from defective provirus. We adapted histone removal and long-read sequencing approaches in a new single cell pipeline termed SCRIPT-seq (Single Cell detection of Retroviral Integration and PhenoTyping). This approach maintains cellular surface protein, transcriptional identity, and HIV transcriptional detection while opening closed chromatin to increase the detection of integrated provirus as well as the proviral integration site. Applied to clinical samples, SCRIPT-seq will directly inform both the targets and impact of strategies for cure. |
| Dmitry Gabrilovich |
AstraZeneca |
Immune Suppressive Myeloid Cells: From Biology to Therapeutic Targeting |
Myeloid cells represent a major component of the tumor microenvironment (TME) and are critically involved in the regulation of tumor progression and metastasis. In recent years, the overarching concept has emerged that the biology of myeloid cells is largely defined by a limited number of functional states that transcend the narrowly defined cell populations. These functional states are primarily cantered around classical and pathological states of activation, with the latter state being commonly defined as myeloid-derived suppressor cells (MDSC). These states of activation are currently well defined with clear association with tumor progression. We will discuss several major mechanisms regulating the function of these cells and potential targets for therapeutic intervention. This includes ferroptosis – programmed cell death triggered in cells with impaired redox regulation whereby excessive availability/activity of redox-active iron primarily due to defect in glutathione peroxidase 4/glutathione (GPX4/GSH) system. Ferroptosis does not commonly occur in myeloid cells in bone marrow or spleen of tumor-free or tumor-bearing mice. However, the active ROS/RNS-generating machinery of polymorphonuclear MDSC (PMN-MDSC) in tumors shattered redox balance and stimulated a ferroptotic death of these cells. Ferroptotic PMN-MDSC demonstrated potent immune suppressive activity. We will discuss the mechanism and clinical implications of ferroptosis of myeloid cells in cancer. Among other therapeutic opportunities we will discuss the effect of inhibition of DNA damage repair protein the Ataxia telangiectasia and Rad3-related (ATR) on myeloid cell function and on the effect of check pint inhibitors. We specifically discuss the role of IFNI in this process and its effect on immune response in cancer. |
| Katey Rayner |
University of Ottawa Heart Institute |
Exploring Novel Inflammatory Mediators and Vascular Disease |
Chronic inflammation is a central player in a vast majority of age-related chronic diseases. Sterile inflammation, or that which is found in the absence of infection, underpins the progression of diseases of the heart, liver and brain, and contributes to co-morbidities such as obesity and autoimmune diseases. Our work to date has identified a key pro-inflammatory cell death pathway, termed necroptosis, that is uniquely active in advanced human plaques, and correlates with risk of plaque rupture. In preclinical studies, blocking members of this pathway (RIPK1, RIPK3, MLKL) using small molecules, RNA-based drugs and/or genetic deletion leads to reduced disease. Importantly, and highly relevant to the current proposal, we also used this pathway to develop a novel radiotracer for diagnostic imaging that can help identify advanced atherosclerotic plaques. My presentation will focus on the molecular underpinnings of metabolically-driven inflammatory diseases and identify specific pathways that can be targeted therapeutically and diagnostically to reduce tissue injury and disease. |
| Ronald J. Vagnozzi |
University of Colorado Anschutz Medical Campus |
Optimizing Macrophage Fate and Function for Cardiac Repair |
Pathological inflammation and fibrosis occur in the vast majority of cardiovascular diseases and significantly contribute to heart failure burden. However, therapeutics that directly target the immuno-fibrosis axis are lacking. Our lab strives to discover new mechanisms that resolve chronic inflammation and fibrosis, to harness beneficial immune responses in non-regenerative organs like the heart. We use genetic lineage tracing and gene manipulation to interrogate the proximal signals through which cardiac macrophage subsets drive tissue healing and regulate fibroblasts. Currently we are examining CX3CR1 signaling in cardiac macrophages as well as the role of damage sensing cascades in driving pro-inflammatory versus pro-resolving immune responses by cardiac fibroblasts. We are also part of a multidisciplinary collaborative effort exploring epigenetic regulation of macrophage gene expression in heart failure and cardiac remodeling. This initiative has uncovered specialized context-dependent regulation of macrophage transcriptional networks through the epigenetic reader protein BRD4. Our ongoing work seeks to uncover nodal axes of signaling that can be harnessed to accelerate pro-remodeling and tissue rejuvenating features of cardiac tissue macrophages in the setting of cardiac disease. |
| Krithika Lingappan |
University of Pennsylvania |
Harnessing Macrophages for Therapy in the Developing Lung |
Macrophages are master regulators of inflammation, angiogenesis, and tissue repair. In many disease contexts, however, they are depleted or maladaptive, limiting their capacity to promote regeneration. The talk will describe the central orchestrating role of macrophages in neonatal lung injury and regeneration and the possibility of using engineered macrophages ras a versatile cellular therapy for inflammatory and developmental lung diseases, with immediate application to bronchopulmonary dysplasia (BPD) as a clinically relevant model. BPD remains the most common and morbid complication of extreme prematurity, characterized by arrested alveolar and vascular development driven in part by persistent pulmonary inflammation. |
| Tram T. Dang |
Nanyang Technological University, Singapore |
Proteases as Immuno-Modulators for Biomaterials and Drug Delivery Systems |
The interaction between immune system and material surface are governed by complex, dynamic interplay between cellular and biochemical signals with material surface characteristics. We comprehensively profiled the role of proteases as a material-specific biomolecular signature of material-induced host immune response. The basic understanding and non-invasive characterization of protease activity in the immunological interaction between polymeric biomaterials and immune systems lays foundation for our development of immune-mediated therapeutic delivery systems. Specifically, we leveraged the role of proteases as immunological cures to design and demonstrate quantitatively robust inflammation-responsive drug delivery systems in vivo and their efficacy in rodent models of chronic diseases. |
| Brendan Harley |
University of Illinois at Urbana-Champaign |
Composite Biomaterials To Shape Regenerative Trajectories |
Defects in craniofacial bones of the skull occur congenitally, after high-energy impacts, and during the course of treatment for stroke and cancer. They can be devastating, affect a broad segment of the US population, are large and irregularly shaped, and heal poorly. Autologous bone or alloplastic implants are the clinical gold-standards for repair. However, limited quantities and the need for time-intensive intraoperative fitting of autologous bone, the non-regenerative nature of alloplastic implants, and surgical challenges that stem from irregular defect margins and the quality of the surrounding bone lead to poor healing and high complication rates. Regenerative implants would be transformative for craniofacial reconstruction. While the osteogenic properties of a biomaterial are important, the limiting factor for craniofacial bone regeneration is efficient angiogenic-immunomodulatory coupling at the defect-implant margins. I will describe efforts to create a composite biomaterial to shape patterns of angiogenic-osteogenic-immunomodulatory coupling at the craniofacial bone defect-biomaterial margin. We have developed a porous mineralized collagen biomaterial composite that can be shaped intraoperatively to conformally fit complex defects, and have optimized its innate osteogenic potency for MSCs and adipose-derived stem cells (ASCs). Scaffold structural, mechanical, and compositional properties can be used to alter MSC/ASC trajectories as well as reciprocal interactions with macrophages to establish a pro-regenerative phenotype. I will also discuss ongoing efforts to create new approach methodologies to examine implant-defect integration. While traditional in vivo models of implant integration are low-throughput, time-intensive, and costly, we developed a scalable in vitro wound assay, implanting scaffolds into punch defects made in a gelatin hydrogel containing self-assembled vascular networks. This in vitro wound model suggest ways to accelerate the design-build-test-learn cycles necessary to optimize regenerative activity. |