title: Feasibility and Safety of RNA-transfected CD20-specific Chimeric Antigen Receptor T Cells in Dogs with Spontaneous B Cell Lymphoma.
abstract: Preclinical murine models of chimeric antigen receptor (CAR) T cell therapy are widely applied, but are greatly limited by their inability to model the complex human tumor microenvironment and adequately predict safety and efficacy in patients. We therefore sought to develop a system that would enable us to evaluate CAR T cell therapies in dogs with spontaneous cancers. We developed an expansion methodology that yields large numbers of canine T cells from normal or lymphoma-diseased dogs. mRNA electroporation was utilized to express a first-generation canine CD20-specific CAR in expanded T cells. The canine CD20 (cCD20) CAR expression was efficient and transient, and electroporated T cells exhibited antigen-specific interferon-gamma (IFN-γ) secretion and lysed cCD20+ targets. In a first-in-canine study, autologous cCD20-ζ CAR T cells were administered to a dog with relapsed B cell lymphoma. Treatment was well tolerated and led to a modest, but transient, antitumor activity, suggesting that stable CAR expression will be necessary for durable clinical remissions. Our study establishes the methodologies necessary to evaluate CAR T cell therapy in dogs with spontaneous malignancies and lays the foundation for use of outbred canine cancer patients to evaluate the safety and efficacy of next-generation CAR therapies and their optimization prior to translation into humans.
authors.affiliation: Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: M Kazim
authors.initials: MK
authors.lastname: Panjwani
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Jenessa B
authors.initials: JB
authors.lastname: Smith
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Keith
authors.initials: K
authors.lastname: Schutsky
authors.affiliation: Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Josephine
authors.initials: J
authors.lastname: Gnanandarajah
authors.affiliation: CAVU Biotherapies, Houston, Texas, USA.
authors.forename: Colleen M
authors.initials: CM
authors.lastname: O'Connor
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Powell
authors.affiliation: Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Mason
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism; D018951:Antigens, CD20 / Q000276:immunology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D045744:Cell Line, Tumor; D003520:Cyclophosphamide / Q000627:therapeutic use; D004285:Dogs; D004317:Doxorubicin / Q000627:therapeutic use; D018274:Electroporation; D015870:Gene Expression; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods; D007376:Interleukin-2 / Q000494:pharmacology; D007378:Interleukins / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000276:immunology; D016393:Lymphoma, B-Cell / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism / Q000628:therapy; D051379:Mice; D011241:Prednisone / Q000627:therapeutic use; D012333:RNA, Messenger; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D014162:Transfection; D016896:Treatment Outcome; D014750:Vincristine / Q000627:therapeutic use; D000098546:Interleukin-21
chemical_list: D018951:Antigens, CD20; D007376:Interleukin-2; D007378:Interleukins; D012333:RNA, Messenger; D011948:Receptors, Antigen, T-Cell; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D000098546:Interleukin-21; D011241:Prednisone