Systemic lupus erythematosus (SLE) is a complex, chronic autoimmune disease with no cure which affects 1.5 million Americans. SLE is a rheumatic disease which can lead to severe organ dysfunction, including end stage renal disease. Autoreactive B cells have emerged as primary drivers of the disease and the presence of anti-nuclear antibodies is a biomarker for diagnosis. Therapies targeting B cells and the B cell activating factor (BAFF) signaling axis, including belimumab, a monoclonal antibody targeting BAFF, have shown promising results in reducing severity of disease in B cell associated autoimmunity, but these treatments are not curative. A recent studying using CD19 Chimeric antigen receptor (CAR) T cell therapy led to B cell clearance and disease remission in 4 of 5 patients. Each of these patients were in early-stage lupus, but the one who did not respond had the longest-term disease at 9 years. This study indicates B cell clearance can resolve SLE disease progression, but the CD19-CAR treatment was limited in targeting all the autoreactive B cells, including long-lived plasma cells which produce autoreactive antibody but do not express CD19. We thus seek to circumvent this issue in a new treatment for SLE using an allogeneic BAFF-ligand based CAR γδ T cell product. The BAFF family receptors BAFFR, TACI, and BCMA are highly expressed on B cells at different proportions depending on their maturation state including plasma cells. We hypothesize that elimination of all autoreactive B cells, including long-lived plasma cells in the bone marrow, will reduce the production of autoantibodies and lead to long term remission. The use of γδ T cells allows for the mass production of allogeneic CAR T cells from a single T cell donor, reducing cost and increasing safety oversight during manufacturing. We have produced preliminary data that confirms our ability to use the non-viral TcBuster DNA transposon system to generate γδ T cells with BAFF-CAR expression and show that these cells are effective at eliminating cells expressing the BAFF family of receptors. To test the efficacy of the CAR in the context of SLE, we propose two complementary aims that will assess the expression of BAFF receptors in SLE patient B cells and test the activity and selectivity of these cells against patient B cells in vitro. Finally, we will test the efficacy of the BAFF-CAR γδ T cells in reducing inflammation, renal disease, and autoantibody production in a humanized mouse model of SLE. We hope to improve outcomes in SLE by advancing this technology to IND-enabling studies.
Public Health Relevance Statement: Project Narrative This proposal describes a novel allogeneic chimeric antigen receptor (CAR)-T cell therapy that aims to improve outcomes for patients with Systemic Lupus Erythematosus. Our approach improves upon current immunotherapies by engineering γδ T cells in a unique way to express a novel CAR directed against inflammatory cytokine and autoantibody producing B cells. We expect immunotherapeutic delivery of these modified T cells will improve patient outcomes and reduce long-term pathology by reducing inflammation and increasing safety through our allogeneic γδ T cell platform.
Project Terms: new therapy; next generation therapeutics; novel drug treatments; novel drugs; novel pharmaco-therapeutic; novel pharmacological therapeutic; novel therapy; novel therapeutics; murine model; mouse model; treatment strategy; bio-markers; biologic marker; biomarker; Biological Markers; full scale manufacturing; large scale manufacturing; mass production; large scale production; efficacy testing; humane end point; humane endpoint; chimeric antigen T cell receptor; chimeric antigen receptor; Lung Inflammation; Pneumonitis; Pulmonary Inflammation; improved outcome; humanized mice; humanized mouse; Gamma-delta T cells; γδT cells; γδ T cells; B cell depletion therapy; B cell directed therapy; B cell targeted therapy; B cell therapies; B cell therapy; in vivo testing; in vivo evaluation; CAR T cells; CAR modified T cells; CAR-T; CAR-Ts; T cells for CAR; chimeric antigen receptor (CAR) T cells; chimeric antigen receptor fusion protein T-cells; chimeric antigen receptor modified T cells; chimeric antigen receptor T cells; CAR T therapy; chimeric antigen receptor (CAR) T cell therapy; chimeric antigen receptor T cell therapy; CAR T cell therapy; autoimmune attack; autoimmune destruction; autoimmune pathogenesis; manufacture; Affect; Antinuclear Factors; anti-DNA autoantibody; anti-Sm; antiDNA autoantibody; Antinuclear Antibodies; Clinical Treatment Moab; mAbs; monoclonal Abs; Monoclonal Antibodies; immunogen; Antigens; Autoantibodies; autoimmune antibody; autoreactive antibody; self reactive antibody; Autoimmune Diseases; autoimmune condition; autoimmune disorder; autoimmunity disease; Autoimmunity; Autoimmune Status; B-Lymphocytes; B blood cells; B cell; B cells; B-Cells; B-cell; Biological Assay; Assay; Bioassay; Biologic Assays; Blood; Blood Reticuloendothelial System; Blood Circulation; Bloodstream; Bone Marrow; Bone Marrow Reticuloendothelial System; Cell Compartmentation; Cell Compartmentations; Cells; Cell Body; Clinical Trials; Diagnosis; Disease; Disorder; Engineering; Family; Human; Modern Man; Immunotherapy; Immune mediated therapy; Immunologically Directed Therapy; immune therapeutic approach; immune therapeutic interventions; immune therapeutic regimens; immune therapeutic strategy; immune therapy; immune-based therapies; immune-based treatments; immuno therapy; In Vitro; Inflammation; Kidney; Kidney Urinary System; renal; Kidney Diseases; Nephropathy; Renal Disease; kidney disorder; renal disorder; Natural Killer Cells; Cytotoxic cell; K lymphocyte; NK Cells; Ligands; Lung; Lung Respiratory System; pulmonary; Systemic Lupus Erythematosus; Lupus Erythematosus Disseminatus; SLE; Systemic Lupus Erythematous; Systemic Lupus Erythmatosus; disseminated lupus erythematosus; systemic lupus erythematosis; monocyte; Blood monocyte; Marrow monocyte; Mus; Mice; Mice Mammals; Murine; Nephritis; Pathology; Patients; Pilot Projects; pilot study; Plasma; Blood Plasma; Plasma Serum; Reticuloendothelial System, Serum, Plasma; Plasma Cells; Blood Plasma Cell; Plasmacytes; plasmocyte; Production; Proteinuria; Relaxation; Rheumatism; Musculoskeletal Pain Disorder; Rheumatic Diseases; Rheumatologic Diseases; Rheumatologic Disorder; RNA; Non-Polyadenylated RNA; RNA Gene Products; Ribonucleic Acid; Safety; Signal Transduction; Cell Communication and Signaling; Cell Signaling; Intracellular Communication and Signaling; Signal Transduction Systems; Signaling; biological signal transduction; Spleen; Spleen Reticuloendothelial System; Survival Rate; T-Lymphocyte; T-Cells; thymus derived lymphocyte; Technology; Testing; Time; Tissues; Body Tissues; Transplantation; transplant; B-Lymphocyte Subsets; B-Cell Subsets; cytokine; B Cell-Activating Factor Receptor; CD124 Antigens; CDw124 Antigen; IL-4 Receptors; IL4 Receptors; Interleukin-4 Receptor Alpha; Interleukin 4 Receptor; Anticardiolipin Antibodies; Organ; improved; biologic; Biological; peripheral blood; Disease Progression; Dysfunction; Physiopathology; pathophysiology; Functional disorder; disease onset; disorder onset; Onset of illness; Co-culture; Cocultivation; Coculture; Coculture Techniques; Engraftment; Inflammatory; Complex; Source; cell type; System; Antibody titer measurement; antibody titering; Musculoskeletal; Severity of illness; disease severity; Disease remission; Remission; Ablation; American; experience; Membrane; membrane structure; receptor; Receptor Protein; receptor expression; polarized cell; cell killing; Animal Model; Animal Models and Related Studies; model of animal; DNA Transposons; transposon element; Histopathology; novel; member; Memory B-Lymphocyte; Memory B Cell; TNF gene; (TNF)-a; Cachectin; Macrophage-Derived TNF; Monocyte-Derived TNF; TNF; TNF A; TNF Alpha; TNF-a; TNFA; TNFa; Tumor Necrosis Factor; Tumor Necrosis Factor-alpha; Immunotherapeutic agent; immune drugs; immune-based therapeutics; immunologic therapeutics; immunotherapeutics; immunotherapy agent; activated B cells; B-Cell Activation; Molecular Interaction; Binding; ESRD; End-Stage Kidney Disease; End-Stage Renal Disease; End stage renal failure; CAMLG gene; CAML; CAMLG; CD19 gene; CD19; Address; B-Cell Development; Data; Mature B-Lymphocyte; Mature B-Cell; Allogenic; Cell Maturation; Patient-Focused Outcomes; Patient outcome; Patient-Centered Outcomes; patient oriented outcomes; Development; developmental; pre-clinical; preclinical; belimumab; Benlysta; autoreactive B cell; chronic autoimmune disease; cost; anti-dsDNA antibody; anti-dsDNA antibodies; Lupus; cost effective; innovate; innovative; innovation; clinical applicability; clinical application; early therapy; Early treatment; new drug treatments; new drugs; new pharmacological therapeutic; new therapeutics
