title: Enhanced antilymphoma efficacy of CD19-redirected influenza MP1-specific CTLs by cotransfer of T cells modified to present influenza MP1.
abstract: To enhance the in vivo antitumor activity of adoptively transferred, CD19-specific chimeric antigen receptor (CAR)-redirected cytotoxic T lymphocytes (CTLs), we studied the effect of restimulating CAR(+) CTLs through their endogenous virus-specific T-cell antigen receptor (TcR) by the cotransfer of engineered T-cell antigen-presenting cells (T-APCs). Using influenza A matrix protein 1 (MP1) as a model antigen, we show that ex vivo-expanded CD4(+) and CD8(+) T-APCs expressing a hygromycin phosphotransferase-MP1 fusion protein (HyMP1) process and present MP1 to autologous human leukocyte antigen (HLA)-restricted, MP1-specific CD4(+) and CD8(+) CTL precursors. The MP1-specific CTLs are amenable to subsequent genetic modification to express a CD19-specific CAR, designated CD19R, and acquire HLA-unrestricted reactivity toward CD19(+) leukemia and lymphoma tumor targets while maintaining HLA-restricted MP1 specificity. The restimulation of MP1xCD19 dual-specific CTLs in vivo by the adoptive transfer of irradiated HyMP1(+) T-APCs resulted in the enhanced antilymphoma potency of bispecific effector cells, as measured by elimination of the biophotonic signal of established firefly luciferase-expressing Burkitt lymphoma xenografts in nonobese diabetic/severe combined immunodeficiency (NOD/scid) animals compared with control groups restimulated by Hy(+)MP1(neg) T-APCs. Engineered T-APCs are a novel and versatile antigen-delivery system for generating antigen-specific T cells in vitro and enhancing the in vivo effector functioning of CAR-redirected antitumor effector cells.
authors.affiliation: Beckman Research Institute, Division of Pediatric Hematology/Oncology, City of Hope National Medical Center, Duarte, CA 91010-3000, USA. lcooper@coh.org
authors.forename: Laurence J N
authors.initials: LJ
authors.lastname: Cooper
authors.forename: Zaid
authors.initials: Z
authors.lastname: Al-Kadhimi
authors.forename: Lisa Marie
authors.initials: LM
authors.lastname: Serrano
authors.forename: Timothy
authors.initials: T
authors.lastname: Pfeiffer
authors.forename: Simon
authors.initials: S
authors.lastname: Olivares
authors.forename: Adrian
authors.initials: A
authors.lastname: Castro
authors.forename: Wen-Chung
authors.initials: WC
authors.lastname: Chang
authors.forename: Sergio
authors.initials: S
authors.lastname: Gonzalez
authors.forename: David
authors.initials: D
authors.lastname: Smith
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Forman
authors.forename: Michael C
authors.initials: MC
authors.lastname: Jensen
mesh_terms: D019264:Adoptive Transfer / Q000379:methods; D000818:Animals; D017951:Antigen Presentation / Q000235:genetics; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism / Q000821:virology; D018941:Antigens, CD19 / Q000096:biosynthesis / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology; D002460:Cell Line; D002461:Cell Line, Transformed; D018920:Coculture Techniques; D003601:Cytotoxicity Tests, Immunologic / Q000379:methods; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology*; D018014:Gene Transfer Techniques; D006801:Humans; D009980:Influenza A virus / Q000235:genetics / Q000276:immunology; D020014:K562 Cells; D008213:Lymphocyte Activation / Q000235:genetics; D008223:Lymphoma / Q000235:genetics / Q000276:immunology* / Q000628:therapy* / Q000821:virology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics; D010957:Plasmids; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000637:transplantation* / Q000821:virology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D014763:Viral Matrix Proteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
chemical_list: D018941:Antigens, CD19; D018984:Epitopes, T-Lymphocyte; C488936:M1 protein, Influenza A virus; D014763:Viral Matrix Proteins; D017853:Phosphotransferases (Alcohol Group Acceptor); C063242:hygromycin-B kinase