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Principal Investigator: Jordan Green
Organization: JOHNS HOPKINS UNIVERSITY
Fiscal Year: 2023
Award: $560,955
Funding agency: National Cancer Institute
PROJECT SUMMARY
Cancer vaccines have significantly advanced cancer immunotherapy; and recent successes of mRNA
vaccines have raised prospect of generating potent anti-tumor response by specifically delivering mRNAs
encoding tumor-associated antigens to antigen presenting cells (APCs). However, APC activation elicited by
nanoparticles containing antigen mRNAs is rather limited. Circulating monocytes offer a promising cell target as
an abundant APC precursor that can be deposited to spleen, lymph nodes, and tumor tissue following
polarization and activation. The overall objective of this study is to engineer
kinetically assembled poly(beta-
amino ester) (PBAE)
/mRNA nanoparticles (KaNPs) that can specifically deliver mRNAs encoding tumor antigens
and immunoadjuvants into circulating monocytes in vivo and demonstrate the safety and efficacy of this new
mRNA cancer vaccine platform. This study is built on the preliminary results showing biodegradable
PBAE/mRNA KaNPs with an optimized size of 400 nm mediated preferential transfection of circulating
monocytes following intravenous (i.v.) injection, leading to more effective transfection and deposition of
circulating monocytes and a higher level of tumor-killing activity compared to the standard small size
PBAE/mRNA nanoparticles. In this proposed study, we plan to pursue four specific aims: (1) optimize the
composition, size, and surface functionality of PBAE/mRNA KaNPs to improve targeted mRNA delivery efficiency
into circulating monocytes in vivo, (2) characterize pharmacokinetic profile of PBAE/mRNA KaNPs and define
functions of transfected circulating monocytes in vivo, (3) assess the immunotherapeutic efficacy of PBAE/mRNA
KaNPs in suppressing tumor growth in combination with TLR9 and STING agonists in mouse tumor models, and
(4) develop an GMP-compliant, shelf-stable, lyophilized PBAE/mRNA KaNP formulation and validate the efficacy
in a mouse model. If successful, this study will uncover structure-function relationships in a previously
inaccessible size range (200–1000 nm) for gene therapy carriers, demonstrate circulating monocytes as a potent
mRNA therapeutic target and the role of KaNP-transfected circulating monocytes in potentiating antitumor
immune responses, and inspire rational design of new mRNA-based immunotherapies for treatment of solid
tumors and metastatic cancers.
Terms: <Adjuvant><Advanced Cancer><Advanced Malignant Neoplasm><Animal Model><Animal Models and Related Studies><Antigen-Presenting Cells><Antigens><Antineoplastic Vaccine><Antitumor Response><Biodistribution><Blood monocyte><Body Tissues><Bone Marrow><Bone Marrow Reticuloendothelial System><COVID-19><COVID19><CV-19><CV19><Cancer Vaccines><Cell Body><Cells><Checkpoint inhibitor><Chemical Structure><Chemistry><Circulation><DNA Therapy><Deposit><Deposition><Disseminated Malignant Neoplasm><Dose><Drug Kinetics><Engineering><Esters><Formulation><Freeze Drying><Freeze Dryings><Gene Transfer Clinical><Generations><Genetic Intervention><Homing><Immune><Immune Cell Activation><Immune checkpoint inhibitor><Immune mediated therapy><Immune response><Immune system><Immunes><Immunoactivators><Immunoadjuvants><Immunologic Adjuvants><Immunological Adjuvant><Immunological response><Immunologically Directed Therapy><Immunopotentiators><Immunostimulants><Immunotherapeutic agent><Immunotherapy><Infiltration><Kinetics><Ligands><Lymph Node Reticuloendothelial System><Lymph node proper><Lymphatic nodes><Lyophilization><Malignant Melanoma><Marrow monocyte><Mediating><Messenger RNA><Metastatic Cancer><Metastatic Malignant Neoplasm><Methodology><Methods><Mice><Mice Mammals><Modeling><Murine><Mus><Neoplasm Vaccines><Patients><Peripheral><Pharmacokinetics><Polymers><Population><Procedures><Production><Property><RNA vaccine><RNA-based vaccine><Reporter><Role><STING agonists><Safety><Solid Neoplasm><Solid Tumor><Spleen><Spleen Reticuloendothelial System><Standardization><Structure-Activity Relationship><Surface><T-Cell Activation><Testing><Time><Tissues><Training><Transfection><Treatment Efficacy><Tumor Antigens><Tumor Tissue><Tumor Vaccines><Tumor-Associated Antigen><Vaccines><accessory cell><activate T cells><anti-cancer immunotherapy><anti-tumor immune response><anti-tumor response><anti-tumor vaccine><anticancer immunotherapy><antitumor immune response><antitumor vaccine><biocompatibility><biomaterial compatibility><cancer antigens><cancer immunotherapy><cancer microenvironment><chemical structure function><combinatorial><commercial scale manufacturing><corona virus disease 2019><coronavirus disease 2019><coronavirus disease-19><coronavirus infectious disease-19><design><designing><efficacy validation><experience><gene repair therapy><gene therapy><gene-based therapy><genetic therapy><genomic therapy><host response><immune activation><immune adjuvant><immune check point inhibitor><immune drugs><immune system response><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based cancer therapies><immune-based therapeutics><immune-based therapies><immune-based treatments><immuno therapy><immunogen><immunologic therapeutics><immunoresponse><immunotherapeutics><immunotherapy agent><immunotherapy for cancer><immunotherapy of cancer><improved><in vivo><innovate><innovation><innovative><intervention efficacy><intravenous injection><lymph gland><lymph nodes><lymphnodes><mRNA><mRNA delivery><mRNA vaccine><mRNA-based vaccine><manufacturing ramp-up><manufacturing scale-up><melanoma><model of animal><monocyte><mouse model><murine model><nano medicinal><nano medicine><nano particle><nano particle delivery><nano-sized particle><nanomedicinal><nanomedicine><nanoparticle><nanoparticle delivered><nanoparticle delivery><nanosized particle><neo-antigen><neo-epitopes><neoantigens><neoepitopes><plasmid DNA><polycation><polymer><polymeric><programs><rational design><response><scale up batch><scale up production><secondary lymph organ><secondary lymphatic organ><secondary lymphoid organ><site targeted delivery><social role><structure function relationship><success><targeted delivery><therapeutic efficacy><therapeutic target><therapy efficacy><trafficking><tumor><tumor growth><tumor microenvironment><tumor-specific antigen><upscale manufacturing><vaccine for cancer><vaccine platform><validate efficacy>