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Principal Investigator: HARRIS GOLDSTEIN
Organization: ALBERT EINSTEIN COLLEGE OF MEDICINE
Fiscal Year: 2024
Award: $734,317
Funding agency: National Institute of Allergy and Infectious Diseases
To enable sustained remission of HIV recurrence in the absence of antiretroviral therapy (ART), we aim to
develop a strategy to provide people with HIV (PWH) with robust and sustained anti-HIV T cell and antibody
responses. We will develop injectable cell-specific lentiviral vector (LV) technology to direct in vivo generation of
T cells expressing anti-HIV chimeric antigen receptor (CAR) and/or broadly neutralizing antibody (bNAb) genes.
We hypothesize that by establishing broad and sustained anti-HIV immune surveillance in vivo, reactivated
latently infected cells will be rapidly eliminated before they can initiate disseminated infection together with cells
newly infected by HIV produced by distal reservoirs. We developed and validated the safety and efficacy of a
highly potent and broad anti-HIV duoCAR-T cell therapy that is demonstrably superior to monoCAR-T cell
therapy. These duoCAR-T cells target two highly conserved independent gp120 epitopes, enabling highly
effective inhibition of HIV infection, while also being extremely resistant to HIV infection and providing sufficient
broad reactivity to inhibit the emergence of immune escape epitopes. Our preclinical studies demonstrating the
safety and efficacy of duoCAR-T cells and their great promise to provide PWH with sustained remission after
cessation of ART enabled FDA-approval, which has advanced them into clinical trials in PWH (NCT04648046).
We have also developed LV capable of engineering T cells to produce therapeutic levels of bNAb in vivo.
However, generating duoCAR-T cells or T cells secreting bNAbs using standard ex vivo LV transduction and
reinfusion into patients requires complex logistics which greatly limits wider use, particularly in resource-poor
settings with the highest incidence of HIV infection. This proposal is highly significant and very responsive to the
RFA, specifically our focus on developing and evaluating innovative approaches to engineer lentiviral vectors
(LV) to deliver in vivo T-cell targeted gene therapy to confer T cells with potent cellular and humoral anti-HIV
activity. We propose several innovative strategies to achieve our goal which include: (1) development and
optimization of novel CD3-targeted LVPs directing selective in vivo transduction of T cells to produce optimized
anti-HIV duoCAR-T cells; (2) identification of the CD3- or peptide-MHC conjugate-targeted LV most capable of
generating optimized anti-HIV duoCAR-T cells that potently suppress HIV infection in vitro and in vivo; and (3)
development and optimization of CD3-targeted LV to selectively transduce T cells in vivo to enable them to
produce bNAb. We hypothesize that administration of T cell-specific therapeutic LV will direct selective in vivo
generation of duoCAR-T cells and bNAb-producing T cells capable of exerting potent and sustained anti-HIV
immune surveillance, either alone or together, to provide PWH with ART-free remission. We will also examine
whether novel gp120-exosomes and multifunctional cytokine complexes consisting of IL-15 and a TGFβ inhibitor
or IL-7, IL-15 and IL-21 stimulate in vivo expansion of duoCAR-T cells to further augment their anti-HIV activity.
Terms: <AIDS Virus><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Adverse effects><Animal Model><Animal Models and Related Studies><Antibody Response><Antigenic Determinants><Binding><Binding Determinants><Bone-Derived Transforming Growth Factor><Brain><Brain Nervous System><CAR T cells><CAR modified T cells><CAR-T><CAR-Ts><CD3><CD3 Antigens><CD3 Complex><CD3 molecule><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><CMV><Cardiac Diseases><Cardiac Disorders><Cell Body><Cell Communication and Signaling><Cell Signaling><Cell secretion><Cells><Cellular Secretion><Clinical Trials><Collaborations><Complex><Cytomegalovirus><Development><Disease remission><Distal><Encephalon><Engineering><Engraftment><Epitopes><FDA approved><Gene Delivery><Generations><Genes><Goals><HCMV><HIV><HIV Envelope Glycoprotein gp120><HIV Envelope Protein gp120><HIV Infections><HIV env Protein gp120><HTLV-III Infections><HTLV-III gp120><HTLV-III-LAV Infections><Heart Diseases><Human Immunodeficiency Viruses><Human T-Lymphotropic Virus Type III Infections><IL-15><IL-7><IL-7 Gene><IL15><IL15 Protein><IL21><IL7><IL7 Protein><IL7 gene><IgG1><Immune><Immune Surveillance><Immune response><Immunes><Immunologic Surveillance><Immunologic Surveillances><Immunological Surveillance><Immunological Surveillances><Immunological response><Immunosurveillance><In Vitro><Incidence><Infection><Infrastructure><Infusion><Infusion procedures><Injectable><Injury to Liver><Interleukin 7 Precursor><Interleukin 7 Precursor Gene><Interleukin-15><Interleukin-15 Precursor><Interleukin-7><Interleukin-7 Gene><Interruption><Intracellular Communication and Signaling><LAV-HTLV-III><Lentiviral Vector><Lentivirus Vector><Light><Link><Logistics><Low-resource area><Low-resource community><Low-resource environment><Low-resource region><Low-resource setting><Lymphadenopathy-Associated Virus><Lymphopoietin-1><MGC9721><Membrane><Mice><Mice Mammals><Milk Growth Factor><Molecular Interaction><Murine><Mus><OKT3 antigen><PBMC><Patients><Peptide-MHC><Peptide-Major Histocompatibility Protein Complex><Peptide/MHC Complex><Peptides><Peripheral Blood Mononuclear Cell><Persons><Phenotype><Photoradiation><Platelet Transforming Growth Factor><Recurrence><Recurrent><Remission><Research><Resistance><Resource-constrained area><Resource-constrained community><Resource-constrained environment><Resource-constrained region><Resource-constrained setting><Resource-limited area><Resource-limited community><Resource-limited environment><Resource-limited region><Resource-limited setting><Resource-poor area><Resource-poor community><Resource-poor environment><Resource-poor region><Resource-poor setting><Safety><Salivary Gland Viruses><Signal Transduction><Signal Transduction Systems><Signaling><Spinal Column><Spine><Surface><T cell based therapeutics><T cell based therapy><T cell directed therapies><T cell targeted therapeutics><T cell therapy><T cells for CAR><T memory cell><T-Cell Activation><T-Cells><T-Lymphocyte><T-cell therapeutics><T-cell transfer therapy><T3 Antigens><T3 Complex><T3 molecule><T4 Cells><T4 Lymphocytes><TGF B><TGF-beta><TGF-β><TGFbeta><TGFβ><Technology><Therapeutic><Transforming Growth Factor beta><Transforming Growth Factor-Beta Family Gene><Treatment Efficacy><VSV><Variant><Variation><Vertebral column><Vesicular Stomatitis Virus><Vesicular stomatitis Indiana virus><Vesiculovirus><Viral><Viremia><Virus><Virus-HIV><activate T cells><adoptive T cell transfer><adoptive T-cell therapy><antiretroviral therapy><antiretroviral treatment><backbone><biological signal transduction><cell transduction><cellular transduction><chimeric antigen T cell receptor><chimeric antigen receptor><chimeric antigen receptor (CAR) T cells><chimeric antigen receptor T cells><chimeric antigen receptor fusion protein T-cells><chimeric antigen receptor modified T cells><cytokine><cytomegalovirus group><design><design and construct><design and construction><designing><developmental><engineered T cells><exosome><gene therapeutics><gene-based therapeutic><gene-based therapeutics><gene-based treatment><gene-directed therapy><gene-targeted therapy><gene-targeted treatment><genes therapeutic><genes therapeutics><genetically engineered T-cells><gp120><gp120 ENV Glycoprotein><gp120(HIV)><heart disorder><hepatic damage><hepatic injury><host response><humanized mice><humanized mouse><immune system response><immunoresponse><in vivo><infusions><inhibitor><innovate><innovation><innovative><interleukin-21><intervention efficacy><liver damage><liver injury><manufacture><membrane structure><memory T lymphocyte><model of animal><mouse model><murine model><neuropsychiatric><neuropsychiatry><neutralizing antibody><next generation><novel><pMHC><particle><pre-clinical><pre-clinical study><preclinical><preclinical study><prevent><preventing><resistant><side effect><synergism><therapeutic T-cell platform><therapeutic efficacy><therapeutic gene><therapy efficacy><thymus derived lymphocyte><transduced cells><transgenic T- cells><vector><viraemia><viral sepsis><virusemia>