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Principal Investigator: RONALD LEVY
Organization: STANFORD UNIVERSITY
Fiscal Year: 2022
Award: $512,443
Funding agency: National Cancer Institute
Project Summary: Cancer is a leading global cause of mortality. The goal of this multi-disciplinary
project is to pre-clinically advance a novel concept for selective and efficient mRNA delivery that enables a
highly promising vaccination strategy for cancer immunotherapy. Given the potential of cancer vaccination
to both generate new antigen-specific T cell responses against tumor cells and amplify existing responses,
cancer vaccination could be an especially effective therapy on its own or in combination with, e.g., check-
point blockade. Through a unique collaboration of chemists, cancer immunologists and biostatisticians we
propose to advance just such a method called CART-RNA which in preliminary studies has produced
cures of up to 80% in animals with established tumors.
The critical technological challenge for mRNA and all gene-based therapies is the development of
safe, effective, accessible and selective mRNA delivery vectors. This project exploits a unique class of
charge-altering releasable transporters (CARTs) that complex, protect and selectively deliver mRNA to
target cells/organs and then release mRNA intracellularly through an unprecedented charge-altering
mechanism, mediating exceptionally effective translation to proteins both in cell culture and in live animals.
The three interrelated specific aims are directed at the design and evaluation of novel CARTs that
deliver mRNA to a variety of cell types, elicit functional protein expression, and induce a therapeutic
immunological response. Aim 1 leverages the synthetic expertise of the team and the ease of formulation
of CART-RNA vectors to assess the relationship of CART chemical structure, formulation and
administration to the efficiency and selectivity of protein expression in culture and in live animals. Aim 2 is
directed at the evaluation of CART-RNA vaccination to elicit protective immunological responses in
validated mouse models for cancer immunotherapy. Aim 3 focuses on pre-clinical investigations to elicit
protective immunity against clinically-relevant antigens (specifically B- and T-cell lymphoma idiotypes) in
primary human cells from human patients.
This project exploits an interdisciplinary approach that integrates materials design and synthesis,
chemistry, microbiology, non-invasive cellular and live animal imaging, immunology and biostatistics to
develop, evaluate and refine strategies for the development of novel vaccines based on the new CART-
RNA platform. Cellular and live animal imaging techniques will be employed to assess the efficiency of
both mRNA delivery and expression as a function of mode of administration in mice. This research will
identify and clarify design criteria for engineering effective mRNA delivery systems and the effectiveness
of mRNA-based approaches for immunotherapy. This project is directed at new families of superior
transfecting agents for mRNA delivery and mRNA vaccination for treating and curing cancer.
Terms: <Address><Adoptive Cell Transfers><Amides><Amines><Animals><Antigens><Antineoplastic Vaccine><Antitumor Response><Autologous><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><Biometrics><Biometry><Biostatistics><Blocking Antibodies><Body Tissues><Cancer Model><Cancer Treatment><Cancer Vaccines><CancerModel><Cancers><Catalysis><Cations><Cell Body><Cell Culture Techniques><Cells><Charge><Chemical Structure><Clinic><Clinical Research><Clinical Study><Collaborations><Complex><Confocal Microscopy><Cryo-electron Microscopy><Cryoelectron Microscopy><DNA Molecular Biology><DNA Therapy><Development><Drug Delivery><Drug Delivery Systems><Effectiveness><Electron Cryomicroscopy><Electroporation><Engineering><Evaluation><Family><Formulation><Gene Expression><Gene Transfer Clinical><Genetic Engineering><Genetic Engineering Biotechnology><Genetic Engineering Molecular Biology><Genetic Intervention><Germinoblastic Sarcoma><Germinoblastoma><Goals><Human><Hybrids><Idiotype><Imaging Procedures><Imaging Technics><Imaging Techniques><Immune mediated therapy><Immune response><Immune system><Immunity><Immunoglobulin Idiotypes><Immunological response><Immunologically Directed Therapy><Immunologist><Immunology><Immunotherapeutic agent><Immunotherapy><In Vitro><Lactams><Length><Lipids><Lymphatic cell><Lymphocyte><Lymphocytic><Lymphoma><Lytotoxicity><MHC Receptor><Major Histocompatibility Complex Receptor><Malignant Lymphoma><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Mediating><Medicinal Chemistry><Messenger RNA><Methods><Mice><Mice Mammals><Microbiology><Modeling><Modern Man><Molecular Biology><Molecular Immunology><Morbidity><Morbidity - disease rate><Murine><Mus><NEO Gene><Neomycin resistance gene><Neoplasm Vaccines><Non-Polyadenylated RNA><Non-Viral Vector><Organ><Patients><Pharmaceutic Chemistry><Pharmaceutical Chemistry><Pre-Clinical Model><Preclinical Models><Procedures><Proteins><RNA><RNA Gene Products><RNA immunization><RNA vaccination><Recombinant DNA Technology><Research><Reticulolymphosarcoma><Ribonucleic Acid><Signal Pathway><Specificity><Structure><Synthesis Chemistry><Synthetic Chemistry><System><T cell response><T-Cell Antigen Receptors><T-Cell Lymphoma><T-Cell Non-Hodgkin's Lymphoma><T-Cell NonHodgkins Lymphoma><T-Cell Receptor><T-Cell and NK-Cell Non-Hodgkin's Lymphoma><T-Cells><T-Lymphocyte><Technology><Teff cell><Testing><Therapeutic><Tissues><Toxic effect><Toxicities><Translations><Tumor Cell><Tumor Vaccines><Tumor-Derived><Tumor-Infiltrating Lymphocytes><VAC-TX><Vaccinated><Vaccination><Vaccine Therapy><Vaccines><Variant><Variation><Viral Vector><adoptive cell therapy><adoptive cellular therapy><allergic/immunologic body system><allergic/immunologic organ system><amine><animal imaging><anti-cancer immunotherapy><anti-cancer therapy><anti-tumor response><anti-tumor vaccine><anticancer immunotherapy><anticancer therapy><antigen-specific T cells><antitumor vaccine><assess effectiveness><base><cancer immunotherapy><cancer therapy><cancer vaccination><cancer-directed therapy><cell culture><cell cultures><cell type><check point blockade><checkpoint blockade><chimeric antigen T cell receptor><chimeric antigen receptor><clinical investigation><clinical relevance><clinically relevant><combinatorial><cryo-EM><cryoEM><cytotoxicity><delivery vector><delivery vehicle><density><design><designing><determine effectiveness><developmental><disease prevention><disorder prevention><effective therapy><effective treatment><effectiveness assessment><effectiveness evaluation><effector T cell><electroporative delivery><evaluate effectiveness><gene electrotransfer><gene repair therapy><gene therapy><gene-based therapy><genetic therapy><genetically engineered><genomic therapy><host response><immune check point blockade><immune checkpoint blockade><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><immunization strategy><immuno therapy><immunogen><immunogenicity><immunologic preparation><immunologic therapeutics><immunoresponse><immunotherapeutics><immunotherapy agent><immunotherapy for cancer><immunotherapy of cancer><improved><in vivo><interdisciplinary approach><iterative design><lipid based nanoparticle><lipid nanoparticle><lymph cell><mRNA><mRNA Expression><mRNA delivery><mRNA immunization><mRNA vaccination><malignancy><mortality><mouse model><multidisciplinary><multidisciplinary approach><murine model><neo-antigen><neo-epitopes><neoantigens><neoepitopes><neomycin resistant gene><neoplasm/cancer><neoplastic cell><new vaccines><next generation vaccines><nonviral vector><novel><novel vaccines><patient population><pre-clinical><preclinical><protein expression><response><therapeutic vaccination><thymus derived lymphocyte><tumor><tumor vaccination><uptake><vaccination strategy><vaccine for cancer><vector><zeta potential>