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1.
Mol Ther ; 27(6): 1126-1138, 2019 06 05.
Article in English | MEDLINE | ID: mdl-31005597

ABSTRACT

Clinical success of autologous CD19-directed chimeric antigen receptor T cells (CAR Ts) in acute lymphoblastic leukemia and non-Hodgkin lymphoma suggests that CAR Ts may be a promising therapy for hematological malignancies, including multiple myeloma. However, autologous CAR T therapies have limitations that may impact clinical use, including lengthy vein-to-vein time and manufacturing constraints. Allogeneic CAR T (AlloCAR T) therapies may overcome these innate limitations of autologous CAR T therapies. Unlike autologous cell therapies, AlloCAR T therapies employ healthy donor T cells that are isolated in a manufacturing facility, engineered to express CARs with specificity for a tumor-associated antigen, and modified using gene-editing technology to limit T cell receptor (TCR)-mediated immune responses. Here, transcription activator-like effector nuclease (TALEN) gene editing of B cell maturation antigen (BCMA) CAR Ts was used to confer lymphodepletion resistance and reduced graft-versus-host disease (GvHD) potential. The safety profile of allogeneic BCMA CAR Ts was further enhanced by incorporating a CD20 mimotope-based intra-CAR off switch enabling effective CAR T elimination in the presence of rituximab. Allogeneic BCMA CAR Ts induced sustained antitumor responses in mice supplemented with human cytokines, and, most importantly, maintained their phenotype and potency after scale-up manufacturing. This novel off-the-shelf allogeneic BCMA CAR T product is a promising candidate for clinical evaluation.


Subject(s)
B-Cell Maturation Antigen/immunology , Cell Transplantation/methods , Immunotherapy, Adoptive/methods , Multiple Myeloma/therapy , Receptors, Chimeric Antigen/immunology , T-Lymphocytes/immunology , T-Lymphocytes/transplantation , Animals , Antineoplastic Agents, Immunological/therapeutic use , B-Cell Maturation Antigen/genetics , Blood Donors , Cell Line, Tumor , Cell Transplantation/adverse effects , Cytotoxicity, Immunologic/genetics , Gene Editing , Genetic Vectors , Graft vs Host Disease/therapy , Humans , Immunotherapy, Adoptive/adverse effects , Mice , Mice, Inbred NOD , Mice, SCID , Multiple Myeloma/pathology , Progression-Free Survival , Receptors, Chimeric Antigen/genetics , Receptors, Chimeric Antigen/metabolism , Rituximab/therapeutic use , T-Lymphocytes/metabolism , Transcription Activator-Like Effector Nucleases/genetics , Transduction, Genetic , Transplantation, Homologous/methods
2.
Invest Ophthalmol Vis Sci ; 59(2): 662-673, 2018 02 01.
Article in English | MEDLINE | ID: mdl-29392311

ABSTRACT

Purpose: A large body of evidence supports a central role for complement activation in the pathobiology of age-related macular degeneration (AMD), including plasma complement component 5a (C5a). Interestingly, C5a is a chemotactic agent for monocytes, a cell type also shown to contribute to AMD. However, the role monocytes play in the pathogenesis of "dry" AMD and the pharmacologic potential of targeting C5a to regulate these cells are unclear. We addressed these questions via C5a blockade in a unique model of early/intermediate dry AMD and large panel flow cytometry to immunophenotype monocytic involvement. Methods: Heterozygous complement factor H (Cfh+/-) mice aged to 90 weeks were fed a high-fat, cholesterol-enriched diet (Cfh+/-∼HFC) for 8 weeks and were given weekly intraperitoneal injections of 30 mg/kg anti-C5a (4C9, Pfizer). Flow cytometry, retinal pigmented epithelium (RPE) flat mounts, and electroretinograms were used to characterize anti-C5a treatment. Results: Aged Cfh+/- mice developed RPE damage, sub-RPE basal laminar deposits, and attenuation of visual function and immune cell recruitment to the choroid that was accompanied by expression of inflammatory and extracellular matrix remodeling genes following 8 weeks of HFC diet. Concomitant systemic administration of an anti-C5a antibody successfully inhibited local recruitment of mononuclear phagocytes to the choroid-RPE interface but did not ameliorate these AMD-like pathologies in this mouse model. Conclusions: These results show that immunotherapy targeting C5a is not sufficient to block the development of the AMD-like pathologies observed in Cfh+/-∼HFC mice and suggest that other complement components or molecules/mechanisms may be driving "early" and "intermediate" AMD pathologies.


Subject(s)
Antibodies, Blocking/therapeutic use , Choroidal Neovascularization/therapy , Complement C5a/antagonists & inhibitors , Disease Models, Animal , Geographic Atrophy/therapy , Immunotherapy , Animals , Cholesterol, Dietary/administration & dosage , Choroidal Neovascularization/immunology , Choroidal Neovascularization/pathology , Complement Activation , Complement C5a/immunology , Electroretinography , Enzyme-Linked Immunosorbent Assay , Flow Cytometry , Geographic Atrophy/immunology , Geographic Atrophy/pathology , Injections, Intraperitoneal , Male , Mice , Mice, Inbred C57BL , Retinal Pigment Epithelium/pathology
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