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Principal Investigator: Hamideh Parhiz
Organization: FRED HUTCHINSON CANCER CENTER
Fiscal Year: 2024
Award: $849,858
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY/ABSTRACT
Modification of autologous T cells with chimeric antigen receptor (CAR) molecules was first proposed nearly 30
years ago as a therapy for people living with HIV. Since then, CAR-T cells have emerged as a potent and highly
successful therapy for liquid tumors, while HIV-specific CAR-T cells have only begun to show efficacy in large
animal models and clinical trials. Based on our longstanding interest in CAR-T cell therapies for HIV, we posit
three primary barriers that limit the curative potential of this approach. First, low levels of HIV-1 antigen at the
cell surface (namely Env protein), especially during antiretroviral therapy (ART), render latently infected cells
nearly invisible to CAR-T cells and other virus-specific immune effectors. Second, the wealth of knowledge
regarding cellular trafficking of the viral Env protein has yet to be thoroughly applied in the context of Env-
dependent HIV cure strategies. Third, CAR-T cell persistence and function wane over time, prior to complete
clearance of the latent HIV reservoir. Our groundbreaking preliminary data outlines a path to overcome these
limitations. We recently reported findings in four rhesus macaques that were infected with an HIV-like virus,
suppressed by ART and then infused with virus-specific CAR-T cells containing the CD4 extracellular domain
(CD4CAR). To expand these potent antiviral effectors in vivo, animals were next boosted with an irradiated cell
line stably expressing HIV-1 Env. Following ART treatment interruption (ATI), viral control was observed in 2 of
4 animals, consistent with robust and Env-dependent expansion of CD4CAR-T cells. The central goal of this
proposal is to increase the potency and feasibility of this approach. In AIM 1, we will transition our Env boosting
strategy from an immortalized cell line to an FDA-approved mRNA lipid nanoparticle (mRNA-LNP) platform,
analogous to the Moderna and Pfizer/BioNTech vaccines for SARS-CoV-2. Env immunogens will be optimized
for CD4CAR T cell interactions and developed as Env mRNA-LNP vaccines. In AIM 2, we will use CRISPR-
Cas9 gene editing to extend the durability and function of CD4CAR-T cells. We will compare a series of CAR
products that carry inactivated immune checkpoint alleles, which we hypothesize will support more durable
function and efficiently clear persistent viral reservoirs. In AIM 3, we will benchmark Env mRNA-LNP and immune
checkpoint gene editing strategies in our vetted nonhuman primate (NHP) model of HIV gene therapy. These
experiments will feature a powerful competitive repopulation study design, providing critical information on basic
CAR biology that cannot be gathered in clinical studies. Together, these aims build on what we believe to be the
most promising anti-HIV cell and gene therapy approach reported to date. Our unique and highly informative
NHP model of HIV persistence and CAR-T cell therapy will fill in critical gaps in knowledge regarding CAR-T cell
safety and function in limited antigen environments, and facilitate clinical translation both in developed and
developing nations. The lessons we learn from these studies will be applicable not only as a curative therapy for
HIV-1, but for a range of diseases such as solid tumors where CAR-T cell therapies must be similarly augmented.
Terms: <2019-nCoV vaccine><AIDS Virus><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Address><Alleles><Allelomorphs><Allogeneic Transplantation><Animal Model><Animal Models and Related Studies><Animals><Antibodies><Antigens><Assay><Autologous><B blood cells><B cell><B cell malignancy><B cells><B lymphoid malignancy><B-Cells><B-Lymphocytes><B-cell><BNT 162b2><BNT162b2><Bar Codes><Benchmarking><Berlin><Best Practice Analysis><Bioassay><Biological Assay><Biology><Blood Plasma><Blood Precursor Cell><C-C CKR-5><C-C CKR-5 Gene><C-C Chemokine Receptor Type 5><C-C Chemokine Receptor Type 5 Gene><CAR T cell therapy><CAR T cells><CAR T therapy><CAR modified T cells><CAR-T><CAR-Ts><CC Chemokine Receptor 5><CC-CKR-5><CC-CKR-5 Gene><CC-CKR5><CCCKR5><CCCKR5 Gene><CCR-5><CCR-5 Gene><CCR5><CCR5 Protein><CCR5 Receptors><CCR5 gene><CD152><CD152 Antigen><CD152 Gene><CD195 Antigen><CD195 Antigen Gene><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><CHEMR13><CHEMR13 Gene><CKR-5><CKR-5 Gene><CKR5><CKR5 Gene><CKR5 Receptors><CMKBR5><CMKBR5 Gene><COVID-19 vaccination><COVID-19 vaccine><CRISPR><CRISPR approach><CRISPR based approach><CRISPR method><CRISPR methodology><CRISPR technique><CRISPR technology><CRISPR tools><CRISPR-CAS-9><CRISPR-based method><CRISPR-based technique><CRISPR-based technology><CRISPR-based tool><CRISPR/CAS approach><CRISPR/Cas method><CRISPR/Cas system><CRISPR/Cas technology><CRISPR/Cas9><CRISPR/Cas9 technology><CTLA 4><CTLA-4 Gene><CTLA4><CTLA4 gene><CTLA4-TM><Cancer Patient><Cancers><Cas nuclease technology><Cell Body><Cell Communication><Cell Function><Cell Interaction><Cell Line><Cell Physiology><Cell Process><Cell Therapy><Cell surface><Cell-to-Cell Interaction><CellLine><Cells><Cellular Function><Cellular Physiology><Cellular Process><Chemokine (C-C Motif) Receptor 5><Chemokine (C-C) Receptor 5><Chemokine (C-C) Receptor 5 Gene><Chromosomal dislocation><Chromosomal translocation><Clinic><Clinical Research><Clinical Study><Clinical Trials><Clustered Regularly Interspaced Short Palindromic Repeats><Clustered Regularly Interspaced Short Palindromic Repeats approach><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><Cytotoxic T-Lymphocyte Protein 4><Cytotoxic T-Lymphocyte-Associated Antigen 4><Cytotoxic T-Lymphocyte-Associated Protein 4><Cytotoxic T-Lymphocyte-Associated Serine Esterase-4><DNA Therapy><Data><Developing Countries><Developing Nations><Disease><Disease remission><Disorder><Dose><Early-Stage Clinical Trials><Envelope Protein><Environment><Event><Experimental Designs><External Domain><Extracellular Domain><FDA approved><Future><Gene Transfer Clinical><Genes><Genetic Intervention><Genetic Translocation><Goals><Graft-Versus-Tumor Induction><HIV><HIV therapy><HIV-1><HIV-1 Fusion Co-Receptor><HIV-1 Fusion Co-Receptor Gene><HIV-I><HIV1><Hematologic Cancer><Hematologic Malignancies><Hematologic Neoplasms><Hematological Malignancies><Hematological Neoplasms><Hematological Tumor><Hematopoietic Cancer><Hematopoietic Cell Tumor><Hematopoietic Malignancies><Hematopoietic Neoplasms><Hematopoietic Neoplasms including Lymphomas><Hematopoietic Progenitor Cells><Hematopoietic Tumor><Hematopoietic and Lymphoid Cell Neoplasm><Hematopoietic and Lymphoid Neoplasms><Hematopoietic stem cells><Homologous Transplantation><Human Immunodeficiency Virus Type 1><Human Immunodeficiency Viruses><Human immunodeficiency virus 1><Immune><Immunes><Individual><Infection><Interruption><K-562><K562><K562 Cells><K562 blasts><Knowledge><LAV-HTLV-III><Learning><Less-Developed Countries><Less-Developed Nations><Leukemic Cell><Liquid substance><London><Lymphadenopathy-Associated Virus><Lymphoma cell><M mulatta><M. mulatta><Macaca mulatta><Malignant><Malignant - descriptor><Malignant Cell><Malignant Hematologic Neoplasm><Malignant Hematopoietic Neoplasm><Malignant Neoplasms><Malignant Tumor><Messenger RNA><Modeling><Modification><Molecular><Nature><New York><PD 1><PD-1><PD-1 blockade><PD1><PD1 blockade><Pathway interactions><Patients><Persons><Pfizer covid19 vaccine><Pfizer-BioNTech COVID-19 vaccine><Pfizer-BioNTech coronavirus disease 2019 vaccine><Pfizer/BioNTech vaccine><Phase 1 Clinical Trials><Phase I Clinical Trials><Plasma><Plasma Serum><Population Study><Procedures><Property><Public Health><Recrudescences><Refractory><Remission><Reporting><Research Design><Resistance><Reticuloendothelial System, Serum, Plasma><Rhesus Macaque><Rhesus Monkey><SARS-CoV-2 vaccination><SARS-CoV-2 vaccine><SARS-coronavirus-2 vaccine><SIV><Safety><Series><Severe Acute Respiratory Syndrome CoV 2 vaccine><Severe acute respiratory syndrome coronavirus 2 vaccination><Severe acute respiratory syndrome coronavirus 2 vaccine><Simian Immunodeficiency Viruses><Solid Neoplasm><Solid Tumor><Strains Cell Lines><Study Type><Subcellular Process><Supplementation><Supporting Cell><T cells for CAR><T-Cells><T-Lymphocyte><T4 Cells><T4 Lymphocytes><Technology><Third-World Countries><Third-World Nations><Time><Under-Developed Countries><Under-Developed Nations><Validation><Viral><Viral Antigens><Viral Burden><Viral Envelope Proteins><Viral Load><Viral Load result><Viral reservoir><Virus><Virus reservoir><Virus-HIV><aPD-1><aPD1><anti programmed cell death 1><anti-PD-1><anti-PD-1 blockade><anti-PD1><anti-PD1 blockade><anti-programmed cell death protein 1><antiPD-1><antiPD1><antiretroviral therapy><antiretroviral treatment><barcode><benchmark><blood cancer><blood cell progenitor><blood progenitor><blood stem cell><blood-forming stem cell><cancer cell><cancer of blood><cancer of the blood><cell immortalization><cell mediated therapies><cell-based therapeutic><cell-based therapy><cellular therapeutic><cellular therapy><check point blockade><checkpoint blockade><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><chromosome dislocation><chromosome translocation><clinical translation><clinically translatable><coronavirus disease 2019 vaccination><coronavirus disease 2019 vaccine><coronavirus disease-19 vaccine><cultured cell line><curative intervention><curative therapeutic><curative therapy><curative treatments><cytotoxic T-lymphocyte antigen 4><developing country><developing nation><env Antigens><env Gene Products><env Polyproteins><env Protein><exhaustion><experiment><experimental research><experimental study><experiments><fluid><gene editing method><gene editing methodology><gene editing strategy><gene editing techniques><gene repair therapy><gene therapy><gene-based therapy><gene-editing approach><genetic therapy><genomic therapy><genotoxicity><graft-versus-tumor><hematopoietic progenitor><hematopoietic stem progenitor cell><hemopoietic progenitor><hemopoietic stem cell><high risk><immune check point><immune check point blockade><immune checkpoint><immune checkpoint blockade><immunecheckpoint><immunogen><in vivo><interest><latent HIV reservoir><latent HIV-1 reservoir><latent HIV1 reservoir><lipid based nanoparticle><lipid nanoparticle><liquid><mRNA><mRNA lipid nano particle vaccine><mRNA-LNP based vaccine><mRNA-LNP combination vaccines><mRNA-LNP vaccines><malignancy><manufacturing process><model of animal><nCoV vaccine><nCoV-19 vaccine><nCoV19 vaccine><nano particle delivery><nanoparticle delivered><nanoparticle delivery><neoplasm/cancer><next generation><non-human primate><nonhuman primate><novel><pathway><phase I protocol><population-based study><population-level study><prevent><preventing><programmed cell death 1><programmed cell death protein 1><programmed death 1><programs><resistant><safety assessment><scRNA-seq><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><sle2><stable cell line><studies of populations><study design><study of the population><success><systemic lupus erythematosus susceptibility 2><thymus derived lymphocyte><trafficking><tumor><vaccinate against COVID-19><vaccinate against SARS-CoV-2><vaccinate against coronavirus disease 2019><vaccinate against severe acute respiratory syndrome coronavirus 2><vaccination against COVID-19><vaccination against SARS-CoV-2><vaccination against Severe acute respiratory syndrome coronavirus 2><vaccination against coronavirus disease 2019><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><validations><viral rebound><virus antigen><virus rebound><αPD-1><αPD1>