Document text
Principal Investigator: MICHAEL ANDREW FISCHBACH
Organization: STANFORD UNIVERSITY
Fiscal Year: 2024
Award: $751,181
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY/ABSTRACT
Eliciting or suppressing an adaptive immune response has become central to oncology, autoimmunity, and
infectious disease. Checkpoint inhibitors have revolutionized the treatment of cancer, while TNF inhibitors and
other immune-suppressive biologics have become the standard of care in autoimmune diseases. Vaccines are
a stunning accomplishment of biomedical research; the mRNA vaccines for SARS-2 are only the latest example.
CAR-T cells induce long-term remission in acute lymphoblastic leukemia, a previously incurable disease.
However, current methods for modulating adaptive immunity have serious limitations. Checkpoint inhibitors and
biologics only work in a subset of patients, and global stimulation or suppression of immune function frequently
leads to autoimmunity or opportunistic infection. Despite their extraordinary properties, many vaccines require a
needle and a cold chain, making them difficult to deploy in low- and middle-income countries, and they fail to
induce mucosal immunity, so vaccinated people can infect others. Engineered T cells have not been successful
against solid tumors to date, and ex vivo T cell engineering is costly and difficult to scale.
Here, we propose to address these challenges by tapping into the host’s ‘colonist interaction program’. Certain
bacterial strains from the microbiome elicit a strikingly potent, specific, and durable immune response. In a new
unpublished project in the lab that inspired the work we propose here, we showed that the anti-commensal
immune response can be redirected against the host by engineering commensal bacteria to express host
antigens on their surface. Commensal bacteria have all the key attributes of an ideal vaccine vector: they induce
highly potent, antigen-specific T and B cell responses; colonization is durable on the timescale of years to
decades (experimental evidence suggests the same is true for the immune response they elicit); and colonists
modulate immune function safely, in a way that spares host tissue from autoimmune attack.
Our vision is to create a general platform for eliciting a potent and durable adaptive immune response in a way
that is safe and inexpensive. The kernel of our idea is to develop a set of vaccine scaffolds in which a
commensal is the adjuvant and colonization is the mode of administration. We propose a four-part process
to build the foundations of commensal vaccines: Goal 1: identify a core set of commensals with immune
modulatory properties; Goal 2: optimize CD8+ T cell induction for antitumor therapy; Goal 3: enhance B cell
induction for preventing viral infection; and Goal 4: redirect colonist-specific Tregs against autoimmune disease.
These goals can proceed in parallel, and success in any one of them would have a great deal of impact. We
note that although this work is applied, it will create useful tools for basic research into immune modulation by
the microbiome, just as biologics and methods for T cell engineering have done for other sub-disciplines of
immunology.
Terms: <(TNF)-α><2019-nCoV vaccine><Acute Lymphoblastic Leukemia><Acute Lymphocytic Leukemia><Acute Lymphoid Leukemia><Adaptive Immune System><Address><Adjuvant><Antigens><Antineoplastic Vaccine><Area><Autoimmune><Autoimmune Diseases><Autoimmune Status><Autoimmunity><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><Bacteria><Basic Research><Basic Science><Biological Agent><Biological Products><Biomedical Research><Body Tissues><CAR T cells><CAR modified T cells><CAR-T><CAR-Ts><CD19><CD19 gene><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><COVID-19 vaccine><Cachectin><Cancer Treatment><Cancer Vaccines><Cancers><Cell Body><Cell Function><Cell Physiology><Cell Process><Cells><Cellular Function><Cellular Immune Function><Cellular Physiology><Cellular Process><Characteristics><Checkpoint inhibitor><Cold Chains><Communicable Diseases><Cotton Plant><Data><Discipline><Disease><Disease remission><Disorder><Ear><Endowment><Engineering><Epithelium><Failure><Foundations><Goals><Gossypium><Head><Human><Human Microbiome><Immune><Immune checkpoint inhibitor><Immune response><Immune system><Immunes><Immunity><Immunoactivators><Immunoadjuvants><Immunochemical Immunologic><Immunologic><Immunologic Adjuvants><Immunological><Immunological response><Immunologically><Immunologics><Immunology><Immunomodulation><Immunopotentiators><Immunostimulants><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><Infection><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Intravenous><LMIC><Macrophage-Derived TNF><Malignant Cell><Malignant Melanoma><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Melanoma><Metastasis to the Lung><Metastatic Neoplasm to the Lung><Metastatic Tumor to the Lung><Methods><Mice><Mice Mammals><Modality><Modeling><Modern Man><Monocyte-Derived TNF><Mucosal Immune Responses><Mucosal Immunity><Murine><Mus><Nature><Needles><Neoplasm Vaccines><Oncology><Oncology Cancer><Opportunistic Infections><Organism><Patients><Precursor Cell Lymphoblastic Leukemia><Precursor Lymphoblastic Leukemia><Process><Property><RNA vaccine><RNA-based vaccine><Regulatory T-Lymphocyte><Remission><Respiratory Disease><Respiratory System Disease><Respiratory System Disorder><S epidermidis><S. epidermidis><SARS-CoV-2 vaccine><SARS-coronavirus-2 vaccine><Sampling><Severe Acute Respiratory Syndrome CoV 2 vaccine><Severe acute respiratory syndrome coronavirus 2 vaccine><Side><Sight><Skin><Solid Neoplasm><Solid Tumor><Specificity><Staphylococcus epidermidis><Subcellular Process><Surface><Swab><T cells for CAR><T-Cells><T-Lymphocyte><T8 Cells><T8 Lymphocytes><TNF><TNF A><TNF Alpha><TNF gene><TNF-α><TNFA><TNFα><Therapeutic><Therapeutic Uses><Tissues><Topical Drug Administration><Topical application><Toxic effect><Toxicities><Treg><Tumor Antigens><Tumor Cell><Tumor Necrosis Factor><Tumor Necrosis Factor-alpha><Tumor Vaccines><Tumor-Associated Antigen><Upper respiratory tract><Vaccinee><Vaccines><Viral Diseases><Virus Diseases><Vision><Wild Type Mouse><Work><aPD-1><aPD1><acquired immune system><acute lymphatic leukemia><acute lymphogenous leukemia><acute lymphomatic leukemia><adaptive immune response><adaptive immunity><administer topically><anti programmed cell death 1><anti-PD-1><anti-PD1><anti-cancer therapy><anti-programmed cell death protein 1><anti-tumor vaccine><anti-viral immunity><antiPD-1><antiPD1><antigen-specific T cells><antiviral immunity><apply topically><autoimmune attack><autoimmune condition><autoimmune destruction><autoimmune disorder><autoimmune pathogenesis><autoimmunity disease><biologics><biopharmaceutical><biotherapeutic agent><cancer antigens><cancer cell><cancer therapy><cancer-directed therapy><cell type><check point blockade><checkpoint blockade><chimeric antigen T cell receptor><chimeric antigen receptor (CAR) T cells><chimeric antigen receptor T cells><chimeric antigen receptor fusion protein T-cells><chimeric antigen receptor modified T cells><commensal bacteria><commensal bacterial species><coronavirus disease 2019 vaccine><coronavirus disease-19 vaccine><cost><cotton><deliver topically><engineered T cells><genetically engineered T-cells><host response><human-associated microbiome><immune check point blockade><immune check point inhibitor><immune checkpoint blockade><immune function><immune modulation><immune regulation><immune suppression><immune suppressive activity><immune suppressive function><immune system response><immunogen><immunologic reactivity control><immunomodulatory><immunoregulation><immunoregulatory><immunoresponse><immunosuppressive activity><immunosuppressive function><immunosuppressive response><inhibitor><innovate><innovation><innovative><insight><living system><low and middle-income countries><lung metastasis><mRNA vaccine><mRNA-based vaccine><malignancy><metastasize to the lung><microbiome><nCoV vaccine><nCoV-19 vaccine><nCoV19 vaccine><neoplasm/cancer><neoplastic cell><non-Native><non-human primate><nonhuman primate><nonnative><pandemic pathogen><patient subclass><patient subcluster><patient subgroups><patient subpopulations><patient subsets><patient subtypes><plasmid vaccine><prevent><preventing><programs><pulmonary metastasis><regulatory T-cells><response><scaffold><scaffolding><side effect><standard of care><subcutaneous><subdermal><success><thymus derived lymphocyte><tool><topical administration><topical delivery><topical drug application><topical treatment><topically administered><topically applied><topically delivered><topically treated><transgenic T- cells><treat topically><tumor><tumor-specific antigen><upper airway tract><vaccinated individual><vaccinated participant><vaccinated patient><vaccinated person><vaccinated subject><vaccine against 2019-nCov><vaccine against COVID-19><vaccine against SARS-CoV-2><vaccine against SARS-coronavirus-2><vaccine against Severe Acute Respiratory Syndrome CoV 2><vaccine against Severe acute respiratory syndrome coronavirus 2><vaccine candidates against SARS-CoV-2><vaccine for cancer><vaccine for novel coronavirus><vaccines preventing COVID><vaccines to prevent COVID><vector vaccine><viral infection><virus infection><virus-induced disease><visual function><wildtype mouse><αPD-1><αPD1>