Darrell J Irvine - US grants

0348259
Irvine
Vaccination has produced some of the most spectacular successes in modern medicine, including the elimination of smallpox and the control of diseases such as polio and tuberculosis. However, traditional vaccines have failed to initiate primary immune responses that provide protection against persistent viral infections (e.g. HIV, hepatitis C, malaria) and also have not succeeded in a therapeutic setting, as might be desirable for treatment of cancer patients. During the primary immune response, dendritic cells (DCs) are key 'sentinel' cells responsible for the collection of foreign antigen, which is broken down into peptides and presented on Major Histocompatibility Complex (MHC) molecules to activate naive T cells.

The investigators hypothesize that improved vaccines can be obtained by addressing 3 limitations of current vaccination strategies: failure to ensure co-delivery of antigen and DC activation signals, lack of antigen loading on class I MHC, and limited numbers of DCs 'vaccinated'. The approach taken is to deliver DC-specific molecular cues using engineered synthetic polymers that sequentially attract dendritic cells, provide activation signals, and deliver large quantities of antigen to intracellular MHC loading pathways. Delivery will be achieved by the synthesis of two components: hydrogel nanoparticles that deliver encapsulated antigen and trigger DC activation through surface-immobilized ligands, and degradable microspheres that release chemokines at a controlled rate to create an in situ DC-specific attractant gradient at the vaccination site. These two components will be assembled into colloidal micelles formed by linking the antigen delivery/DC activation gel particles to the surface of the chemoattractant-releasing microspheres, promoting physical co-localization of the gel particle signaling component of the vaccine with the source of the chemoattractant gradient. The platform technology developed will allow specific antigen and DC activation signals to be readily tailored to program dendritic cells to respond in the most effective manner in a given clinical setting.

The specific aims are: 1) synthesize antigen delivery/DC activation nanoparticle gels and characterize their function in vitro, to determine how coupling particle-based antigen to activation signal delivery affects the function of dendritic cell; 2) synthesize chemoattraction microspheres and characterize dendritic cell attraction to the microspheres in vitro, to determine how DC accumulation by a chemoattracting vaccine varies with the identity of the chemoattractant and quantitative temporal/spatial characteristics of the chemoattractant concentration profile and 3) combine the components from Aims 1 and 2 by fabricating nanoparticle-microsphere colloidal micelles, and characterize in vitro dendritic cell attraction and antigen loading by the complete vaccine, to determine whether physical co-localization of vaccine components can increase the number of activated, antigen-loaded DCs.

The educational goals focused on exposing undergraduate students and school-aged students to the excitement and growing possibilities in research at the interface of materials and biology. Specific activities include the development of a summer program recruiting undergraduates to design laboratory experiment modules that will be used 1) as teaching tools in the MIT undergraduate materials science curriculum and 2) as outreach demonstrations to teach elementary and high school-aged students about the content of materials science and its application to biotechnology and bioengineering.

[unreadable] DESCRIPTION (provided by applicant): In order to provide prophylactic protection against HIV, a successful vaccine will need to elicit mucosal immunity, in order to fight the virus at the mucosal sites that are major points of entry. Among the potential routes for vaccines to promote mucosal immunity, oral delivery is of great interest as a simple, needle-free mode of administration, but is made challenging by the need to protect vaccines during transit through the gastrointestinal tract and achieve sufficient uptake of the vaccine by the mucosal tissue. We have recently developed a polymeric vaccine system comprised of chemokines and antigen-loaded nanoparticles co-delivered within alginate hydrogel microsphere carriers. Alginate microspheres are candidate materials for oral drug delivery due to their stability at low pH, and alginate particles have previously been reported to promote mucosal immunity via oral vaccination. Thus, we propose that the alginate microsphere carriers we have developed can (1) protect antigen/co-delivered chemokine (or cytokine) during transit through the gastrointestinal (Gl) tract and (2) promote uptake by the gut-associated lymphoid tissues (GALT). Microparticles are known to be transcytosed by M cells overlying Peyer's patches, and extracellular deposition of alginate carriers in the GALT would allow for local generation of dendritic cell (DC)-attracting chemokine gradients that would draw DCs to these microdepots of antigen-loaded nanoparticles. We propose here to perform initial tests of this concept for the generation of oral vaccines that could prime mucosal immunity to HIV. The specific aims are: Aim 1: We will characterize the ability of alginate microsphere carriers prepared by different means to protect antigen delivery nanoparticles and co-delivered chemokines from simulated gastric fluid in vitro and to be taken up by gut mucosa in vivo, and characterize GALT uptake of alginate carriers as a function of particle size. Aim 2: Using optimal carrier sizes and compositions defined from the studies in Aim 1, we will measure immune responses triggered by nanoparticles delivering gp120 antigen and CpG alone or with co-delivery of the chemokine CCL20, and analyze antigen dissemination and dendritic cell trafficking in response to these vaccine particles. The studies described will enable the rationale design of microsphere carriers that can promote strong mucosal and systemic immune responses to recombinant HIV antigens, as a step toward a prophylactic HIV vaccine. [unreadable] [unreadable] [unreadable]

AIDS Virus; ATGN; Acquired Immune Deficiency Syndrome Virus; Acquired Immunodeficiency Syndrome Virus; Adjuvant; Adsorption; Affect; Affinity; Antibodies; Antibody Formation; Antibody Production; Antibody Response; Antigenic Determinants; Antigens; Auricle Helix; B blood cells; B-Cell Activation; B-Cells; B-Lymphocytes; Binding; Binding (Molecular Function); Binding Determinants; Bursa-Dependent Lymphocytes; Bursa-Equivalent Lymphocyte; CD4 Positive T Lymphocytes; CD4 T cells; CD4 lymphocyte; CD4+ T cell; CD4+ T-Lymphocyte; CD4-Positive Lymphocytes; Caliber; Cell Membrane Lipids; Cells; Cells, CD4; Chemicals; Chimera Protein; Chimeric Proteins; Class Switching; Collaborations; Condition; Core Particle; Data; Dendritic Cells; Dendritic cell activation; Development; Diameter; Dioxanedione Polymer with Dimethyldioxanedione Polymer; Dose; Drugs, Nonproprietary; Encapsulated; Envelope Glycoprotein gp120, HIV; Epitopes; Epitopes, T-Lymphocyte; Figs; Figs - dietary; Fusion Protein; Generations; Generic Drugs; Glycolic-Lactic Acid Polyester; HIV; HIV Envelope Protein gp120; HIV vaccine; HIV/AIDS Vaccines; HTLV-III; HTLV-III gp120; Helix; Helix (Snails); Helix of ear; Helper Cells; Helper T-Cells; Helper-Inducer T-Lymphocyte; Human Immunodeficiency Viruses; Human T-Cell Leukemia Virus Type III; Human T-Cell Lymphotropic Virus Type III; Human T-Lymphotropic Virus Type III; Immune response; Immune system; Immunization; Immunoglobulin Class Switching; Immunologic Stimulation; Immunological Stimulation; Immunostimulation; Inducer Cells; Isotype Switching; LAV-HTLV-III; Lead; Ligand Binding; Ligands; Lipids; Lymph; Lymph node proper; Lymphadenopathy-Associated Virus; Mammals, Mice; Mediating; Membrane; Membrane Lipids; Mice; Molecular Configuration; Molecular Conformation; Molecular Interaction; Molecular Stereochemistry; Murine; Mus; Nature; Nucleosome Core; Nucleosome Core Particle; Oligo; Oligonucleotides; PADRE 45; PADRE peptide; PL-PG copolymer; PLG polymer; PLGA; Pattern; Pb element; Peptides; Phenotype; Poly(Glycolide Lactide)Copolymer; Poly(Lactide-Co-Glycolide); Poly(Lactide-Co-Glycoside); Polyglactin; Proteins; Relative; Relative (related person); Reticuloendothelial System, Lymph; Reticuloendothelial System, Lymph Node; Sensitization, Immunologic; Sensitization, Immunological; Specificity; Surface; Switchings, Class; Switchings, Immunoglobulin Class; Switchings, Isotype; T-Cell Activation; T-Cell Epitopes; T-Cells, Helper-Inducer; T-Lymphocyte Epitopes; T-Lymphocytes, Helper; T-Lymphocytes, Inducer; T4 Cells; T4 Lymphocytes; TLR protein; TLR3; TLR3 gene; TLR4; TLR4 gene; TLR7; TLR7 gene; TOLL; Testing; Toll-like receptors; Vaccines; Veiled Cells; Virion; Virus Particle; Virus-HIV; Work; World Health; antibody biosynthesis; base; biodegradable polymer; bioresorbable polymer; body system, allergic/immunologic; conformation; conformational state; degradable polymer; density; ear helix; env Protein gp120, HIV; gene product; generic; gp120; gp120 ENV Glycoprotein; gp120(HIV); hToll; heavy metal Pb; heavy metal lead; helper T cell; host response; human immunodeficiency virus vaccine; immunogen; immunoglobulin biosynthesis; immunoresponse; improved; in vivo; lymph gland; lymph nodes; lymphatic fluid; membrane structure; nano particle; nanoparticle; neutralizing antibody; novel; organ system, allergic/immunologic; pan HLA DR-binding epitope; particle; poly(glycolide-co-lactide); polylactic acid-polyglycolic acid copolymer; polylactic-co-glycolic acid copolymer; prophylactic; response; size; trafficking; uptake

DESCRIPTION (provided by applicant): Successful vaccination against HIV will likely require the generation of coordinated humoral and cellular immunity. Among current strategies, protein vaccines fail to stimulate cellular responses, while plasmid DNA or live recombinant vectors capable of promoting cellular and humoral responses together face other issues, such as potency in humans (DNA), or challenges of vector-specific immunity and/or safety (live vectors). We propose here a new class of lipid-based vesicles for protein vaccine delivery, composed of multilamellar lipid vesicles stabilized by the introduction of crosslinks connecting the bilayers of the structure. These novel materials are synthesized and encapsulate protein antigens in a mild all-aqueous process, favoring the preservation of epitopes on complex antigens. In preliminary studies, we show that these novel vaccine carriers can be repeatedly administered for homologous boosting: Following a prime and 2 booster immunizations with a model antigen, these particles massively expand antigen-specific CD8+ T-cells, to the best of our knowledge substantially stronger than any previously reported protein vaccine. These T-cells were functional in terms of their capacity to produce IFN-?, and formed a substantial memory population a month after the second boost. In other preliminary studies, we found that this same system drives potent humoral responses against a candidate malaria antigen. Based on these promising initial results, we propose here to test the promise of this new vaccine delivery approach in the context of HIV vaccination, aiming to determine whether potent, durable T-cell and humoral responses can be elicited against HIV gag and env antigens. In addition, we will explore whether particular aspects of this vaccine system (e.g., the deposition of particles at the injection site) can be exploited to direct the localization of memory cells to key mucosal tissue sites that could promote protection against HIV infection. Our specific aims are: (1) How do the humoral and cellular responses to gag and env antigens evolve as a function of antigen dose and boosting with ICMV particle vaccination? (2) Are alternative clinically-relevant TLR agonist/danger signals capable of eliciting stronger immune responses than MPLA when delivered by ICMV vectors? (3) How do particles retained at the injection site influence memory/effector cell trafficking following ICMV particle immunization, compared to traditional protein immunization? (4) Can microneedle delivery be used to allow repeated needle-free particle boosting to be performed, without the need for refrigerated vaccines? Identification of ICMV formulations that can raise immune responses against HIV immunogens comparable to those shown in our preliminary data for OVA or malaria antigens will set the stage for subsequent testing in macaque protection models (either using ICMV vaccination alone or in tandem with other strong HIV vaccine candidates.

DESCRIPTION (provided by applicant): Cell-based immunotherapies are in active development for treatment of cancer, and adoptive cell therapy (ACT) with ex vivo activated/expanded T-cells is one of the most promising treatments currently being tested in patients. In ACT, autologous tumor-reactive T-cells are activated/expanded ex vivo and then reinfused to combat metastatic tumors. However, strategies to protect T-cells from the highly immuno-suppressive environment generated by tumors are needed to increase the frequency and durability of objective responses. We recently demonstrated that the efficacy of ACT can be dramatically enhanced by conjugation of cytokine- loaded nanoparticles (NPs) to the surfaces of T-cells ex vivo prior to transfer into tumor-bearing recipients (Stephan et al. Nat. Med. 2010). T-cell-bound particles provided pseudo-autocrine drug delivery to the transferred cells that greatly increased the effective potency of adjuvant cytokines while simultaneously eliminating systemic exposure to the drug. However, a limitation of this approach is the one-time nature of the intervention: ACT T-cells can only be loaded once with a cargo of adjuvant drug prior to transfer, and the duration of stimulation is inherently limited by expansion of the cell population in vivo. What is needed is a strategy to arm T-cells with nanoparticle drug carriers in vivo, directly in th blood or tissues, so that a single population of anti-tumor lymphocytes transferred into a patient could be repeatedly stimulated with supporting adjuvant drugs that are targeted to this cell population. We propose a set of approaches to achieve this goal, based on the injection of nanoparticles that carry immunosuppression-blocking adjuvant drugs, which are designed to bind to tumor cells and/or ACT T-cells, and which could be re-administered at will to continuously provide supporting signals to lymphocytes during ACT therapy. As a proof of concept, we will focus on delivery of a small-molecule inhibitor of the key T-cell phosphatase Shp1, which is a downstream target of a broad spectrum of negative regulatory signals in the tumor microenvironment including IL-10, TGF-¿, CTLA-4, and PD-1. We propose to test 3 major strategies, which are not mutually exclusive: (i) non-specific in situ targeting of NPs to tumor cells and lymphocytes via thiol-reactive particles; (ii) antibody-targeted NP delivery of Shp inhibitors specifically to ACT T-cells; and (iii) combined costimulation and targeting of ACT T-cells, by targeting Shp inhibitor-carrying NPs to ACT T-cells via stimulatory ligands that both target NPs to the T-cells and provide an activating/costimulatory signal to the recipient cells. As a final goal we will test whether the most potent of these approaches can synergize with vaccination to allow endogenous T-cell responses to have anti-tumor efficacy, thereby eliminating the need for adoptive transfer of T-cells for potent tumor rejection.

? DESCRIPTION (provided by applicant): Therapeutic strategies aiming to promote immune responses against tumors are of great interest for their potential to destroy metastatic cancer despite its genetic heterogeneity and ability to evade traditional chemotherapy or targeted drugs. Therapeutic vaccines are particularly compelling, because of their low toxicity and broad applicability to diverse human cancers. Recently, the first signs of therapeutic efficacy in cancer vaccines have begun to be reported, and the first cancer vaccine to be approved by the FDA (the cellular vaccine Provenge) was licensed in 2010. Vaccines based on polypeptide antigens, such as long peptides (peptides of 20-40 amino acids that can be processed and presented by diverse human HLAs) are much simpler to manufacture and have also recently begun to show signs of efficacy in patients. However, such vaccines, typically formulated as soluble polypeptides mixed with various adjuvant compounds, leave much room for improvement in terms of their potency in promoting T-cell responses. In an effort to enhance polypeptide vaccines, we sought a readily translatable strategy to enhance vaccine targeting to lymph nodes, where immune responses are initiated. Taking cues from another area of clinical cancer management, we noted that identification of sentinel lymph nodes (LNs) draining sites of primary tumor resection is often performed by the injection of dyes that avidly bind to the ubiquitous serum protein albumin. Albumin-binding dyes are efficiently carried through lymphatics and accumulate in the lymph node, allowing visual identification of the draining nodes following surgery. Mimicking this process, we designed molecular vaccines composed of peptide antigens or immunostimulatory oligonucleotides (single-stranded CpG oligos) conjugated to lipophilic tails with an intervening polymer or oligonucleotide spacer. Strikingly, when these lipid-polar block vaccine amphiphiles were synthesized with (i) lipophilic tails exhibiting high affinity for albumin and (ii) long polar spacers/cargos, they exhibited dramaticall enhanced (>10-fold) accumulation in LNs following parenteral injection relative to soluble peptide/CpG. This enhanced LN targeting of both antigens and molecular adjuvants elicited dramatically enhanced CD8+ T-cell responses, comparable to viral vectors. Based on this promising preliminary data, we propose to establish the mechanisms by which these albumin-hitchhiking amphiphile vaccines function and to test the extensibility of this approach to other adjuvant and immunomodulatory factors. In addition, we have discovered that amph-vaccines efficiently transit across the airway mucosa, and we will test the capacity of pulmonary amphiphiles to serve as simultaneous vaccines priming new T-cell responses in draining LNs and direct modulators of the lung tumor microenvironment in models of lung metastasis and primary GEM lung adenocarcinomas.

PI: Irvine, Darrell J. Project Summary/Abstract: Strategies to promote the magnitude and quality of T cell and antibody responses following immunization have broad relevance for the development of new prophylactic and therapeutic vaccines for the treatment of cancer and infectious diseases. Recent studies, including work from our own laboratories, have demonstrated that the kinetic pattern of antigen and adjuvant exposure to lymphoid tissues has a substantial impact on the immune response to vaccination. However, active control over the temporal pattern of antigen/inflammatory cue delivery to lymph nodes is lacking in all current vaccine approaches. Here we propose an approach applying methods from synthetic biology to create nucleic acid-based vaccines where vaccine antigen/adjuvant expression dynamics can be controlled by (i) exogenous regulation by orally-available FDA-approved small molecule drugs or (ii) intrinsically programmed in genetic circuits carried by the RNA. Based on the promising features of RNA-based vaccines, in preliminary studies we established a lipid nanoparticle-delivered self- replicating alphavirus replicon RNA as the platform for these regulated vaccines. We will systematically study the impact of vaccine antigen and adjuvant kinetics on the immune response to vaccination, create pre- programmed vaccine kinetic patterns, and test the capacity of regulated replicons to enable single-shot vaccines with prime and boost controlled by an orally-available small molecule drug. Our specific aims are (1) To optimize small molecule-regulated expression of antigen and molecular adjuvants from RNA replicons, (2) To use the regulated replicon platform to define optimal kinetics of antigen and adjuvant expression during vaccination, (3) To design RNA-based replicon genetic circuits with pre-programmed temporal patterns, and (4) To determine factors limiting replicon expression lifetimes in vivo, and engineer strategies to prolong expression toward the goal of small molecule-regulated prime-boost regimens. These studies will lead to fundamental discoveries in basic immunology, provide a framework for rationally designing immunization regimens, and create technologies to practically implement them.

Project Abstract Although modern therapies have dramatically improved the outlooks for people living with HIV they are unable to cure infection, leaving these individuals burdened by a lifelong commitment to antiretroviral (ARV) medication. For any given individual, maintaining lifelong adherence to medication can present substantial challenges. Moreover, these expensive medications are not accessible for many individuals, in particular those in resource poor settings. It would therefore be of tremendous value to develop novel therapies that can drive HIV into remission, by which we mean into a state where levels of virus remain low or undetectable even when one stops taking ARV medication. At present, no such therapeutic intervention exists. Recent studies have shown that a type of molecule called BCL-2/BCL-XL antagonists is able to promote the death of HIV-infected cells, which could potentially lead to remission. A concern of these BCL-2/BCL-XL antagonists, however, is that they are associated with side-effects that are likely to be considered unacceptable. Relatedly, these molecules are not highly specific to HIV-infected cells and can also cause the death of some uninfected 'bystander' cells. We have developed a technology that allows for the selective targeting of drug-loaded gold nanoparticles to certain cell populations in vivo. In the current proposal we aim to use this technology to more selectively target BCL-2/BCL-XL antagonists to infected cell populations. In Aim 2, this targeting will be relatively broad ? for example, targeting all memory CD4+ T-cells. In Aim 3, we will test approaches to specifically target delivery to only HIV infected cells. For both of these approaches 'latency reversing agents (LRAs)' may also be needed to induce some expression of HIV and promote the death of infected cells. In Aim 2, these LRAs will be provided along with BCL-2/BCL-XL antagonist be co-loading gold nanoparticles. In Aim 3, LRAs will be provided first in order to induce HIV expression, allowing subsequent specific targeting of BCL-2/BCL-XL antagonists to HIV-infected cells. Our proposal will take both of these complementary approaches from in vitro experiments through to an in vivo preclinical model. Our ultimate objective is to observe efficacy of the novel therapeutics developed by this project in these preclinical models. If observed, this would enable future clinical trials of these new therapies in people living with HIV, and potentially leading to viral remission without the need for ongoing ARV therapy.

Microscopy Core: Project Summary/Abstract Central to the mission of the Koch Institute is to understand the molecular and cellular changes associated with cancer development and progression and to apply that knowledge to developing new treatments and diagnostic approaches. Advanced state-of-the-art imaging tools are essential for these studies. The Koch Institute Microscopy Core provides a broad range of light microscopy-based imaging systems and related image analysis platforms that enable both ex vivo and intravital imaging of nanoparticles, cells, tissues and tumors. In the current funding period, the capabilities of this Core have been expanded and enhanced. This includes the acquisition of new instrumentation and upgrades to many imaging systems, with support from Institutional funding. Importantly, we have recruited Dr. Jeffrey Kuhn to the Core Leader position. Dr. Kuhn is an interdisciplinary expert in cell biology, single molecule biochemistry, and imaging instrument and software development. Core use by Koch Institute Investigators has been strong during this funding cycle: 77% of Center Members use the Core, account for 94% of Core service use, and include investigators from all three Research Programs. In the upcoming funding period, the Microscopy Core will continue to offer a wide range of state-of-the-art services to support Center Member research programs. The Microscopy Core is committed to maintaining instrumentation and capabilities at the leading edge, and will continue to closely monitor technological improvements and evaluate emerging capabilities in the context of Center Member needs and interests. A primary goal is to conduct a hands-on and complete assessment of Core capabilities and Center Member needs with respect to both instrumentation and data analysis capabilities. Replacement of older instruments and acquisition of new capabilities and upgrades will be guided by Center Member research needs and will be funded by Institutional sources. Specific planned initiatives include: enhancing expertise in single molecule localization microscopy; expanding hands-on training opportunities; developing resources to support advanced image processing, visualization, quantitation and machine learning; and collaborating with other Koch Institute Cores to develop a monthly workshop series to support Center Members? access to imaging technology platforms and data analysis. This Shared Resource is essential to the success of the Koch Institute mission and provides exceptional value to the CCSG. The requested CCSG budget for Year 49 is increased by 27.2% over the Core CCSG budget for the current period (Year 48), reflecting increased support for expert personnel. The CCSG budgets of other Koch Institute Cores have been reduced to offset the proposed increase in this, and other, Cores.

Project Summary/Abstract Combination treatments aiming to stimulate synergistic immune pathways employing cytokines or immunomodulatory antibodies are generally more effective than monotherapies in preclinical models of cancer immunotherapy. However when given systemically, these combination treatments suffer from high toxicity from on-target off-tumor stimulation as well as low local concentrations at the tumor site due to poor tumor penetrance and high clearance rates. Local intratumoral therapy is a viable approach to bypass some of the challenges associated with systemic delivery, but requires optimization to promote retention of the therapeutic agent at the injection site and minimize leakage into the circulation. We have recently developed an approach to enhance vaccine efficacy by engineering the binding of immunogens to the commonly used adjuvant aluminum hydroxide (alum) via a site-specific phosphoserine (pSer) peptide tag. The pSer moieties undergo a ligand-exchange reaction with free hydroxyl groups on the surface of alum leading to stable anchoring of proteins on alum particles. We propose here to apply this alum-anchoring platform in the context of cancer to retain potent immune agonists within the tumor site, promoting a robust systemic immune response with minimal toxicity. Our preliminary results show that this simple approach can be used to load stimulatory cytokines onto alum for retention at the tumor site up to a month, stimulating a strong anti-tumor response from a single shot treatment. We plan to develop and optimize this translational strategy through the following specific aims: (1) use in-cell phosphorylation to produce phosphoserine-tagged cytokines and other candidate immune agonists for optimal alum binding, (2) determine optimal treatment regimens for these intratumoral alum-bound therapeutic agents in vivo in multiple tumor models, (3) define the mechanism of action through which this therapy elicits a response, (4) evaluate the systemic immune response and assess strategies to enhance abscopal effects by promoting the transfer of immunostimulatory payloads to motile lymphocytes for trafficking to distal untreated tumors. These studies will establish a robust technology platform capable of safely delivering treatments currently viewed as too toxic, by addressing key limitations in existing localized therapeutic strategies

SpongeBot represents a new class of genetically modified cells to address the COVID-19 pandemic, leveraging a novel antiviral platform developed under the proposer team?s existing NIH NIBIB R01 project. This antiviral platform facilitates rapid, targeted SpongeBot development and deployment against SARS-CoV-2, its viral mutations, as well as entirely new viruses - providing a barrier to future viral pandemics. SARS-CoV-2 is highly communicable and individuals can transmit the disease even prior to becoming symptomatic, sharply increasing the rate of disease spread. During the first two weeks following infection, the innate immune system attempts to slow down the rapidly multiplying pathogen to provide time for the adaptive immune system to develop more specific and effective mechanisms to destroy the virus. However, in individuals with decreased or compromised immune responses, the excessive viral load can lead to elevated inflammation, severe tissue damage, and ultimately death. SpongeBot, our bioengineered cell-based therapy solution, provides vital support to the body?s immune system, through its genetically designed ability to sequester and destroy SARS-CoV-2 viral particles at sites of injury, in addition to attenuation of the immune system?s hyperinflammatory response to the virus. Administering SpongeBot cells to an infected individual reduces and keeps viral load below dangerous thresholds, prevents harmful hyperinflammation, and provides the adaptive immune system the time required to mount an effective defense against the virus. SpongeBot can be administered prophylactically to at-risk populations (e.g., healthcare workers, the elderly, or immunocompromised individuals), or therapeutically at any stage during the course of viral infection. Importantly, SpongeBot therapy is extremely safe; the base technology has a long proven clinical safety track record. Unlike the lengthy development times necessary for vaccines or antiviral medications, a targeted SpongeBot therapy against a predicted virus can be placed in clinical trials immediately. SpongeBot development for a novel virus would be ready for deployment in only about 12 weeks.