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Principal Investigator: Xiaojing J Gao
Organization: STANFORD UNIVERSITY
Fiscal Year: 2023
Award: $1,350,770
Funding agency: National Institute of Biomedical Imaging and Bioengineering
Abstract
The COVID vaccination campaigns have highlighted the promise of mRNA-mediated delivery as a novel
therapeutic modality. One particular application is adoptive cell therapy, where immune cells are equipped with
novel functions to treat diseases, e.g., expressing chimeric antigen receptors (CARs) in T cells to ablate cancer
and other undesirable cells. Compared to DNA-based engineering of immune cells, mRNA has several
advantages as a delivery vector, especially its superior safety profile, because it eliminates the risk of randomly
inserting into the host genome and causing mutations, and its short half-life mitigates long-term adverse effects
due to the persistence of the engineered cellular function. Instead of extracting cells from the patient, engineering
them ex vivo, and then reinducing them, researchers have even directly delivered CAR-encoding mRNAs and
created functional CAR T cells in vivo. This is appealing because it has the potential to make adoptive cell
therapy accessible to the general public, its logistics almost as straightforward as manufacturing, distributing,
and administering vaccine shots, in contrast to the costly ex vivo engineering process that will be limited to the
privileged few.
Despite the great potential of mRNA-mediated adoptive cell therapy, there remains a critical need for
tools that enhance targeting precision. It is very rare for a single surface marker, targeted by CAR, to
unambiguously identify one target cell population. Therefore, “on-target/off-caner” killing is a major concern for
CAR T cell therapies against cancer, and the same concern also applies to scenarios of ablating other cells,
such as active fibroblasts in heart infarction or senescent cells. One elegant solution is synthetic receptors, most
notably synthetic Notch, that detect a second marker and express CAR in response, effectively forming AND
logic, where target cells are only killed when both inputs to the synthetic receptor and CAR are present. However,
to our knowledge, all existing synthetic modular, programmable receptors operate at the DNA level, and are
therefore incompatible with mRNA-mediated delivery.
Here we design and demonstrate the feasibility of a first-in-class synthetic modular receptor that operate
at the RNA level. It converts ligand-induced dimerization events into the expression of arbitrary output proteins.
Through extensive computational simulation and experimental optimization, we will expand the input/output
repertoire of this receptor, establish its design principle, enable its encoding on single transcripts and delivery by
mRNA, and take first steps towards improving the precision of ablating active fibroblasts to treat heart infarction.
The impact of such novel receptors is beyond adoptive cell therapy. For example, they can facilitate basic
research by recording cells’ (e.g., neurons) exposure to specific signals (e.g., dopamine). They will benefit a
variety of other biomedical applications too, from expressing antigens or cytokines in response to extracellular
cues to enhance vaccine efficacy, to generating novel sense-and-respond capabilities for tissue engineering.
Terms: <Ablation><Adoptive Cell Transfers><Adverse effects><Age><Antigens><Basic Research><Basic Science><CAR T cell therapy><CAR T cells><CAR T therapy><CAR modified T cells><CAR-T><CAR-Ts><COVID><Cancers><Cardiac infarction><Cell Body><Cell Communication and Signaling><Cell Extracts><Cell Function><Cell Process><Cell Signaling><Cell physiology><Cells><Cellular Function><Cellular Physiology><Cellular Process><CoV disease><Computer Simulation><Computer based Simulation><Cues><DNA><Deoxyribonucleic Acid><Dimerization><Disease><Disorder><Dopamine><Engineering><Event><Exposure to><Fibroblasts><General Population><General Public><Genetic Alteration><Genetic Change><Genetic defect><Genome><Half-Life><Hydroxytyramine><Immune><Immunes><Intracellular Communication and Signaling><Investigators><Ligands><Logic><Logistics><Malignant Neoplasms><Malignant Tumor><Mediating><Messenger RNA><Modality><Mutation><Myocardial Infarct><Myocardial Infarction><Nerve Cells><Nerve Unit><Neural Cell><Neurocyte><Neurons><Non-Polyadenylated RNA><Output><Patients><Population><Precision therapeutics><Process><Protein Dimerization><Proteins><Public Health><RNA><RNA Gene Products><Receptor Protein><Research Personnel><Researchers><Ribonucleic Acid><Risk><Safety><Signal Transduction><Signal Transduction Systems><Signaling><Subcellular Process><Surface><T cells for CAR><T-Cells><T-Lymphocyte><Tissue Engineering><Transcript><Vaccination><Vaccines><adoptive cell therapy><adoptive cellular therapy><ages><bioengineered tissue><biological signal transduction><cardiac infarct><cell engineering><cellular engineering><chimeric antigen T cell receptor><chimeric antigen receptor><chimeric antigen receptor (CAR) T cell therapy><chimeric antigen receptor (CAR) T cells><chimeric antigen receptor T cell therapy><chimeric antigen receptor T cells><chimeric antigen receptor fusion protein T-cells><chimeric antigen receptor modified T cells><computational simulation><computerized simulation><corona virus disease><coronary attack><coronary infarct><coronary infarction><coronavirus disease><cost><cytokine><delivery vector><delivery vehicle><design><designing><empowerment><engineered immune system><engineered tissue><extracellular><genome mutation><heart attack><heart infarct><heart infarction><immune engineering><immunoengineering><immunogen><improved><in vivo><mRNA><mRNA delivery><malignancy><manufacture><neoplasm/cancer><neuronal><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><notch><notch protein><notch receptors><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><precision therapies><precision treatment><receptor><response><senescence><senescent><thymus derived lymphocyte><tool><vaccine efficacy>