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Principal Investigator: Chang Yoon Moon
Organization: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
Fiscal Year: 2024
Award: $42,724
Funding agency: National Cancer Institute
PROJECT SUMMARY
In the first 6 months after COVID-19 vaccine approval, 3.4 billion doses were administered globally, potentially
saving 7.2 million lives. Lipid nanoparticle (LNP)-mRNA based COVID-19 vaccines have been able to induce
both a strong T cell- and antibody-mediated responses against SARS-CoV-2 by triggering myeloid antigen
presenting cells (APCs) such as dendritic cells (DCs), demonstrating the efficacy of LNP-mRNA technology to
modulate the immune system. Partly due to the success of COVID-19 vaccines, there has been a renewed
attention in engineering novel LNP formulations to better modulate the myeloid APC compartment by 1) either
fine-tuning the adjuvanticity of the LNP lipid formulation or 2) improving in vivo targeting efficiency of LNPs
towards myeloid APCs. Although the advancements in LNP lipid chemistry enrich our arsenal of LNP
formulations suited to modulate the immune system, there hasn't been a corresponding detailed understanding
of the molecular and cellular changes induced upon the uptake of LNPs in specific cell types and tissues. In
fact, attempts to elucidate the innate mechanisms of LNP immunogenicity have often led to conflicting
conclusions and have in turn suggested that the mechanisms of LNP immunogenicity are rather LNP
formulation-dependent. The lack of consensus on the innate mechanisms of LNP immunogenicity further
highlight that the immunogenicity of each LNP is a complex function of a) its lipid formulation and the nature of
its payload, b) the pattern recognition receptor (PRR) profile unique to each immune subset, c) LNP targeting
efficiency in each cell type and d) cell, tissue and disease context of LNP treatment. Without the parallel efforts
to gain mechanistic understanding of immunogenicity of each LNP formulation, it remains difficult to rationally
select LNP formulations that are tailored to a particular disease context, including cancer. In using LNPs as a
cancer immunotherapeutic, my central hypothesis states that LNP lipid formulations that drive up their
immunogenicity combined with an engineering strategy to increase specific targeting of DCs in vivo can
synergize with immunostimulatory payloads (i.e. IL-12) to reprogram DC cell states and enhance anti-tumor
immunity. In Aim 1, I will characterize the changes in DC phenotype, function and transcriptional profile upon
uptake of DC-targeted LNPs in both steady state and tumoral contexts using DC-T cell co-cultures, bulk and
scRNA-seq of sorted LNP transfected DCs. In Aim 2, I will engineer Clec9a targeted bi-specific antibodies to
improve LNP transfection of DCs in vivo. The outcome of this project is both a mechanistic understanding of
the interplay between LNPs and DCs that occurs upon LNP uptake and a novel bi-specific antibody-based
strategy to increase DC targeting in vivo.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><2019-nCoV vaccine><Adjuvanticity><Antibodies><Antigen-Presenting Cells><Attention><Bi-specific antibodies><Bifunctional Antibodies><Binding><Bispecific Antibodies><Body Tissues><Bone Marrow><Bone Marrow Reticuloendothelial System><COVID-19 vaccine><COVID-19 virus><COVID19 virus><Cancers><Cell Body><Cell Compartmentation><Cell Compartmentations><Cells><Clinical Trials><Co-culture><CoV-2><CoV2><Cocultivation><Coculture><Coculture Techniques><Complex><Consensus><Dendritic Cells><Dendritic cell activation><Development><Disease><Disorder><Dose><Edodekin Alfa><Engineering><Expression Signature><Formulation><Foundations><Gene Expression Profile><Gene Transcription><Genetic Transcription><IL-12><IL12><Immune><Immune Targeting><Immune response><Immune system><Immunes><Immunity><Immunological response><Immunomodulation><In Vitro><Inflammatory><Interleukin-12><KO mice><Knock-out Mice><Knockout Mice><Lipid Chemistry><Lipids><Lung><Lung Respiratory System><Malignant Neoplasms><Malignant Tumor><Mediating><Mediator><Messenger RNA><Methods><Mice><Mice Mammals><Molecular><Molecular Interaction><Murine><Mus><Myelogenous><Myeloid><NKSF><Natural Killer Cell Stimulatory Factor><Nature><Null Mouse><Outcome><Pattern recognition receptor><Phenotype><Proteins><RNA Expression><RNA Seq><RNA sequencing><RNAseq><Receptor Signaling><Reporting><Research><Resolution><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 vaccine><SARS-CoV2><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-coronavirus-2 vaccine><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome CoV 2 vaccine><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 vaccine><Severe acute respiratory syndrome related corona virus 2><Sorting><T-Cells><T-Lymphocyte><Technology><Testing><Therapeutic><Tissues><Training><Transcription><Transfection><Tumor Immunity><Veiled Cells><Wuhan coronavirus><accessory cell><anti-cancer immunotherapy><anti-tumor effect><anti-tumor immunity><anticancer immunotherapy><antitumor effect><antitumor immunity><bsAb><cancer immune therapeutics><cancer immunity><cancer immunotherapeutics><cancer immunotherapy><career><cell type><clinical efficacy><coronavirus disease 2019 vaccine><coronavirus disease 2019 virus><coronavirus disease-19 vaccine><coronavirus disease-19 virus><developmental><gene expression pattern><gene expression signature><gene therapeutics><gene-based therapeutic><gene-based therapeutics><genes therapeutic><genes therapeutics><hCoV19><host response><immune modulation><immune regulation><immune system response><immune-based cancer therapies><immunogenic><immunogenicity><immunologic reactivity control><immunomodulatory><immunoregulation><immunoregulatory><immunoresponse><immunotherapy for cancer><immunotherapy of cancer><improved><in vivo><innovate><innovation><innovative><lipid based nanoparticle><lipid mediator><lipid nanoparticle><mRNA><mRNA lipid nano particle vaccine><mRNA-LNP based vaccine><mRNA-LNP combination vaccines><mRNA-LNP vaccines><malignancy><mouse model><multidisciplinary><murine model><nCoV vaccine><nCoV-19 vaccine><nCoV19 vaccine><nCoV2><neoplasm/cancer><novel><programs><pulmonary><rational design><resolutions><response><scRNA-seq><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><success><synergism><therapeutic gene><thymus derived lymphocyte><transcriptional profile><transcriptional signature><transcriptome sequencing><transcriptomic sequencing><tumor><uptake><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 novel coronavirus><vaccines preventing COVID><vaccines to prevent COVID>