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Principal Investigator: Elana Ben-Akiva
Organization: JOHNS HOPKINS UNIVERSITY
Fiscal Year: 2020
Award: $45,520
Funding agency: National Cancer Institute
The overall goal of this project is to engineer novel biodegradable cationic polymers for intracellular
delivery of nucleic acid materials to antigen presenting cells (APCs) for cancer immunotherapy applications.
Immune cells are conventionally very difficult to transfect, and the most successful platforms to date are viral
vectors, which are powerful gene delivery vehicles but have important safety concerns associated with their
use in humans. Non-viral vectors are safer and less immunogenic alternatives to viral vectors and have a
larger carrying capacity. However, their success in transfecting immune cells has been somewhat limited. The
novel system developed in this work will address the challenges associated with intracellular delivery to APCs
to achieve targeted and efficient delivery of nucleic acids using safe, biodegradable materials.
Biodegradable polymeric nanoparticles will be developed for both DNA (Specific Aim 1) and mRNA
(Specific Aim 2) delivery to immune cells, specifically APCs, for two cancer immunotherapy applications. In
Specific Aim 1, polymers will be developed for DNA delivery to macrophages in order to develop a
macrophage repolarization therapy for breast cancer treatment. Tumor associated macrophages (TAMs) are
abundant in many cancers and typically display an M2 phenotype that is immunosuppressive and pro-
tumorigenic. However, the phenotype of macrophages is highly plastic and, as such, they can be converted to
a more immunostimulatory and anti-tumorigenic M1 phenotype. Breast cancer is the leading cause of new
cancer cases and cancer deaths in women, and TAMs have been found to play an important role in the
immunosuppressive nature of breast cancer tumor microenvironment and drug resistance.
In Specific Aim 2, I will engineer novel polymeric nanoparticles to deliver mRNA to dendritic cells for a
genetic vaccine for melanoma. Metastatic melanoma is major health concern with increasing prevalence and a
poor five-year survival rate. Genetic cancer vaccines are a promising strategy to treat melanoma, as it is a
highly immunogenic cancer, that utilize the body’s own defense mechanisms by causing dendritic cells to
endogenously produce tumor-associated antigen and present it to T cells. Genetic vaccines have distinct
advantages over conventional vaccines, such as antigen presentation by both MHC I and MHC II, ease and
cost of production, safety, and longer-term persistence of the immunogen. However, there is a need for
increased potency in order for genetic vaccines to be effective in humans. This research aims to develop novel
polymers that address the challenges associated with nucleic acid delivery to dendritic cells to develop an
enhanced genetic vaccine for melanoma. Overall, the research proposed here will lead to significant progress
in the field of gene delivery by developing modular polymeric nanoparticles that can be used to deliver various
types of nucleic acid materials to APCs in vitro and in vivo for cancer immunotherapy applications.
Terms: <Address><Adjuvant><Antigen Presentation><Antigen-Presenting Cells><Antigens><Antineoplastic Vaccine><Breast Cancer><Breast Cancer Model><Breast Cancer Treatment><Breast Cancer therapy><Breast tumor model><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><Cancer Patient><Cancer Vaccines><Cancers><Carrying Capacities><Cations><Cell Body><Cells><Cessation of life><Cytoplasm><DNA><DNA Therapy><DNA delivery><Data><Death><Defense Mechanisms><Dendritic Cells><Deoxyribonucleic Acid><Development><Drug resistance><Engineering><Esters><Gene Delivery><Gene Transfer Clinical><Genetic Enhancement><Genetic Intervention><Goals><Health><Human><Hydrolysis><Immune><Immune response><Immunes><Immunological response><In Vitro><Lead><Libraries><Malignant Cell><Malignant Melanoma><Malignant Neoplasms><Malignant Tumor><Melanoma Vaccine><Messenger RNA><Metastatic Melanoma><Modeling><Modern Man><Nature><Neoplasm Vaccines><Non-Viral Vector><Nucleic Acids><Outcome><Pb element><Phenotype><Plasmids><Play><Polymers><Prevalence><Production><Research><Role><Safety><Structure><Survival Rate><System><T-Cells><T-Lymphocyte><T8 Cells><T8 Lymphocytes><Therapeutic><Toxic effect><Toxicities><Transfection><Treatment Efficacy><Tumor Antigens><Tumor Immunity><Tumor Vaccines><Tumor-Associated Antigen><Tumor-associated macrophages><Vaccines><Veiled Cells><Viral Vector><Virus><Woman><Work><accessory cell><anti-cancer immunotherapy><anti-tumor immunity><anticancer immunotherapy><antigen-specific T cells><antitumor immunity><base><biodegradable polymer><bioresorbable polymer><cancer antigens><cancer cell><cancer genetics><cancer immunity><cancer immunotherapy><cancer microenvironment><cost><degradable polymer><deliver DNA><design><designing><developmental><drug resistant><gene therapy><gene-based therapy><genetic therapy><genetic vaccine><genomic therapy><heavy metal Pb><heavy metal lead><host response><immune-based cancer therapies><immunogen><immunogenic><immunoresponse><immunotherapy for cancer><immunotherapy of cancer><improved><in vivo><intervention efficacy><lipophilicity><mRNA><mRNA delivery><macrophage><malignancy><malignant breast neoplasm><malignant breast tumor><mammary cancer model><mammary tumor model><melanoma><monomer><nano particle><nano particle delivery><nano-sized particle><nanoparticle><nanoparticle delivered><nanoparticle delivery><nanosized particle><neoplasm/cancer><non-viral gene delivery><nonviral gene delivery><nonviral vector><novel><nucleic acid delivery><particle><psychological defense mechanism><resistance to Drug><resistant to Drug><social role><success><therapeutic efficacy><therapeutic nanoparticles><therapeutically effective><therapy efficacy><thymus derived lymphocyte><tumor><tumor microenvironment><tumor-specific antigen><tumorigenic><vaccine for cancer>