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Principal Investigator: Fang-Yi Su
Organization: GEORGIA INSTITUTE OF TECHNOLOGY
Fiscal Year: 2024
Award: $110,905
Funding agency: National Cancer Institute
Engineered T cells that express chimeric antigen receptors (CARs) have shown remarkable efficacy against
hematological malignancies. However, broad implementation of CAR T cell therapies is limited by the lengthy
(3–5 weeks) and costly ($350K–450K per treatment) ex vivo manufacturing pipeline. This proposal seeks to
develop antigen-presenting nanoparticles (APNs) for in situ programming of virus-specific T cells for rapid and
cost-efficient CAR T cell manufacturing. Virus-specific T cells present a promising opportunity to enhance CAR
T cell therapy, as they have improved persistence and proliferation potential, and allow for viral vaccination to
augment CAR therapy through their endogenous receptors. This proposal will focus on influenza A virus (IAV)-
specific T cells to exploit the existing seasonal influenza vaccination to boost CAR activities. To deliver CAR to
IAV-specific T cells, APNs will comprise lipid nanoparticles (LNPs) that encapsulate CAR-encoded mRNA and
are decorated with HLA-A peptide-major histocompatibility complex (pMHC) displaying influenza peptide
epitopes. This proposal will use APNs to deliver human B-cell maturation antigen (BCMA) CAR in the context of
multiple myeloma with future goals to expand to other CAR specificities and indications, including CD19 positive
cancers. The goal in Aim 1 is to develop APNs for transfection of human influenza-specific T cells with αBCMA
CAR in vivo, and characterize the CAR transfection specificity in the target IAV-specific T cells versus other
major cell populations. Aim 2 will be focused on validating the anti-cancer efficacy of αBCMA CAR T cells after
in situ transfection using a mouse model recapitulating human multiple myeloma. The vaccination strategy to
expand IAV-specific T cells and to boost their effector functions will be tested using inactivated influenza virions
to vaccinate the CAR-expressing, IAV-specific T cells and compare the resulting anti-cancer potency with the
unvaccinated cohort. In Aim 3, CRISPR/Cas9 will be implemented with APNs for in vivo gene editing of T cells
with CAR for durable CAR expression and enhanced anti-cancer potency by delaying T-cell differentiation and
exhaustion. The success of this proposal will challenge existing paradigms of T cell engineering, reduce the cost
of CAR T cell therapy, and enhance anti-cancer activity through influenza vaccination to ultimately democratize
CAR T cells for cancer therapy. Through this work, the candidate will close the knowledge gaps by the
mentorship of an exceptional advisory committee: (1) Gabe Kwong, Ph.D. (CAR T cell engineering), (2) Phil
Santangelo, Ph.D. (mRNA therapeutics and CRISPR/Cas), (3) Rafi Ahmed, Ph.D. (anti-viral T cell immunity and
memory/exhaustion T cell biology), and (4) Madhav Dhodapkar, M.D. (hematology/oncology and myeloma
cancer models). This strong mentoring team and the abundant resources provided by Georgia Tech and Emory
University constitute a fertile mentoring environment for attaining the candidate's career goal of leading an
independent research program focused on developing new technologies to improve patient access and
treatment outcome of T-cell immunotherapy against cancer.
Terms: <Adoptive Transfer><Advisory Committees><Antibodies><Antigen Presentation><Antigen-Presenting Cells><Antigenic Determinants><Antigens><Assay><Autoimmune><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><Benchmarking><Best Practice Analysis><Binding Determinants><Bioassay><Biodistribution><Biological Assay><Biotinylation><Blood><Blood Reticuloendothelial System><Bypass><CAR T cell therapy><CAR T cells><CAR T therapy><CAR modified T cells><CAR-T><CAR-Ts><CD19><CD19 gene><CRISPR approach><CRISPR based approach><CRISPR based therapeutics><CRISPR based treatment><CRISPR method><CRISPR methodology><CRISPR technique><CRISPR technology><CRISPR therapeutics><CRISPR tools><CRISPR treatment><CRISPR-CAS-9><CRISPR-Cas based therapeutics><CRISPR-based disease therapeutics><CRISPR-based method><CRISPR-based technique><CRISPR-based technology><CRISPR-based therapy><CRISPR-based tool><CRISPR/CAS approach><CRISPR/Cas method><CRISPR/Cas technology><CRISPR/Cas therapeutics><CRISPR/Cas9><CRISPR/Cas9 technology><CRISPR/Cas9 therapeutics><CRISPR/Cas9 therapy><CRISPR/Cas9 treatment><CRISPR/Cas9-based therapy><Cancer Model><Cancer Patient><Cancer Treatment><CancerModel><Cancers><Cas nuclease technology><Cas9 based therapeutics><Cell Body><Cell Line><Cell Maturation><CellLine><Cells><Cellular biology><Class I Antigens><Class I Major Histocompatibility Antigens><Clinical><Clustered Regularly Interspaced Short Palindromic Repeats approach><Clustered Regularly Interspaced Short Palindromic Repeats based therapeutics><Clustered Regularly Interspaced Short Palindromic Repeats method><Clustered Regularly Interspaced Short Palindromic Repeats methodology><Clustered Regularly Interspaced Short Palindromic Repeats technique><Clustered Regularly Interspaced Short Palindromic Repeats technology><Clustered Regularly Interspaced Short Palindromic Repeats therapeutics><Co-culture><Cocultivation><Coculture><Coculture Techniques><Complex Class 1><DNA><Democracy><Deoxyribonucleic Acid><Development><Disease><Disorder><Doctor of Medicine><Doctor of Philosophy><Dose><Effectiveness><Encapsulated><Environment><Epitopes><Face><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Flu vaccination><Frequencies><Future><Genes><Genome><Genome engineering><Goals><Grippe><HLA-A><HLA-A gene><HLA-A2.1><HLAA><Hematologic Cancer><Hematologic Malignancies><Hematologic Neoplasms><Hematological Malignancies><Hematological Neoplasms><Hematological Tumor><Hematology><Hematopoietic Cancer><Histocompatibility Antigens Class I><Histocompatibility Complex><Histocompatibility Complices><Human><Immune mediated therapy><Immunity><Immunologically Directed Therapy><Immunotherapy><In Situ><Influenza><Influenza A><Influenza A virus><Influenza Virus><Influenza Viruses Type A><Influenza immunization><Influenza vaccination><Influenzavirus A><Kinetics><Knowledge><Lead><Lentivirinae><Lentivirus><Liver><Lytotoxicity><M.D.><MHC Class I Molecule><MHC Class I Protein><MHC Receptor><MHC class I antigen><Major Histocompatibility Complex><Major Histocompatibility Complex Class 1><Major Histocompatibility Complex Receptor><Major Histocompatibility Complices><Malignant Cell><Malignant Hematologic Neoplasm><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Memory><Mentors><Mentorship><Messenger RNA><Mice><Mice Mammals><Modern Man><Multiple Myeloma><Murine><Mus><Oncology><Oncology Cancer><Orthomyxovirus Type A><PBMC><Patients><Pb element><Peptides><Peripheral Blood Mononuclear Cell><Ph.D.><PhD><Phase><Phenotype><Plasma-Cell Myeloma><Polymers><Population><Production><Prophylactic vaccination against influenza><Receptor Protein><Recombinants><Regulatory T-Lymphocyte><Research><Research Resources><Resources><Safety><Self Tolerance><Specificity><Spleen><Spleen Reticuloendothelial System><Staining method><Stains><Strains Cell Lines><System><T cell based therapeutics><T cell based therapy><T cell differentiation><T cell directed therapies><T cell targeted therapeutics><T cell therapy><T cells for CAR><T-Cell Antigen Receptors><T-Cell Proliferation><T-Cell Receptor><T-Cell Subsets><T-Cells><T-Lymphocyte><T-Lymphocyte Subsets><T-cell therapeutics><T-cell transfer therapy><Task Forces><Testing><Therapeutic Studies><Therapy Research><Time><Toxic effect><Toxicities><Transfection><Transgenes><Translations><Treatment Efficacy><Treatment outcome><Treg><Type A Influenza><Universities><Vaccinated><Vaccination><Viral><Viral Diseases><Virion><Virus><Virus Diseases><Virus Particle><Work><accessory cell><adoptive T cell transfer><adoptive T-cell therapy><advisory team><anti-cancer><anti-cancer therapy><anti-viral immunity><anticancer activity><antigen-specific T cells><antiviral immunity><benchmark><bioluminescence imaging><bioluminescent imaging><cancer cell><cancer therapy><cancer-directed therapy><career><cell biology><cell killing><cell type><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 T therapy><chimeric antigen receptor fusion protein T-cells><chimeric antigen receptor modified T cells><cohort><cost><cost efficient><cultured cell line><cytokine><cytotoxicity><deliver mRNA><deliver messenger RNA><delivery system for mRNA><developmental><engineered T cells><exhaustion><experiment><experimental research><experimental study><experiments><faces><facial><flow cytophotometry><flu immunisation><flu infection><flu virus infection><genetically engineered T-cells><heavy metal Pb><heavy metal lead><hepatic body system><hepatic organ system><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immunization strategy><immuno therapy><immunogen><improved><in vivo><infected with flu><infected with flu virus><infected with influenza><infected with influenza virus><influenza infection><influenza virus infection><influenza virus vaccination><influenzavirus><intervention efficacy><lipid based nanoparticle><lipid nanoparticle><mRNA><mRNA delivery><malignancy><manufacture><manufacturing process><messenger RNA delivery><mouse model><murine model><myeloma><myelomatosis><nano particle><nano-sized particle><nanoparticle><nanosized particle><neoplasm/cancer><new approaches><new technology><non vaccinated><not vaccinated><novel approaches><novel strategies><novel strategy><novel technologies><peptide I><polymer><polymeric><programs><proliferation potential><receptor><receptor expression><recombinant virus><regulatory T-cells><seasonal flu><seasonal influenza><success><therapeutic T-cell platform><therapeutic efficacy><therapy efficacy><thymus derived lymphocyte><transgene><transgenic T- cells><translation><unvaccinated><vaccination against influenza><vaccination strategy><viral infection><virus infection><virus-induced disease>