title: Natural expression of the CD19 antigen impacts the long-term engraftment but not antitumor activity of CD19-specific engineered T cells.
abstract: T cells gene-modified to express chimeric Ag receptors (CARs) have shown potent antitumor activity in vivo and are in clinical trials at locations worldwide. However, CAR activity has been investigated in mouse models in which Ag expression is restricted to the tumor. To explore the impact of normal tissue expression of the target Ag, we developed a mouse CD19-specific CAR to investigate antitumor efficacy against a syngeneic B cell lymphoma cell line within a background of normal CD19(+) host B cells. Mouse T cells engrafted with the amCD19CD3zeta CAR specifically lysed A20 lymphoma targets and B cells in vitro. These T cells also eradicated a 12-d established disseminated A20 lymphoma in mice preconditioned with 6 Gy total body irradiation. In the short-term (7 d after adoptive transfer), amCD19z T cells underwent Ag-dependent proliferation in vivo with a concomitant depletion in host B cell levels. However, the levels of amCD19z CAR(+) T cells decreased significantly at later time points, at which point host B cells returned, eventually reaching normal levels. In contrast, CAR(+) T cells lacking a signaling domain or specificity for mCD19 persisted over extended periods in blood and spleen. Importantly, no overt clinical signs of autotoxicity were observed in tumor-free or tumor-bearing mice treated with amCD19z T cells over an extended period of time. These observations highlight the importance of studying the activity of CAR(+) T cells in autologous models that have the normal range of tissue expression of Ag.
authors.affiliation: Cellular Therapy Group, Department of Medical Oncology, Paterson Institute for Cancer Research, The University of Manchester, Manchester, UK. echeadle@picr.man.ac.uk
authors.forename: Eleanor J
authors.initials: EJ
authors.lastname: Cheadle
authors.forename: Robert E
authors.initials: RE
authors.lastname: Hawkins
authors.forename: Hayley
authors.initials: H
authors.lastname: Batha
authors.forename: Allison L
authors.initials: AL
authors.lastname: O'Neill
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Dovedi
authors.forename: David E
authors.initials: DE
authors.lastname: Gilham
mesh_terms: D019264:Adoptive Transfer / Q000379:methods; D000818:Animals; D018941:Antigens, CD19 / Q000096:biosynthesis* / Q000235:genetics* / Q000276:immunology; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D018390:Gene Targeting / Q000379:methods; D005822:Genetic Vectors / Q000235:genetics / Q000276:immunology; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D011993:Recombinant Fusion Proteins / Q000235:genetics; D012190:Retroviridae / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism* / Q000637:transplantation; D019172:Transplantation Conditioning
chemical_list: D018941:Antigens, CD19; D000970:Antineoplastic Agents; D018984:Epitopes, T-Lymphocyte; D011993:Recombinant Fusion Proteins