title: CMVpp65 Vaccine Enhances the Antitumor Efficacy of Adoptively Transferred CD19-Redirected CMV-Specific T Cells.
abstract: OBJECTIVE
  T cells engineered with chimeric antigen receptors (CAR) recognizing CD19 can induce complete remission of B-cell malignancies in clinical trials; however, in some disease settings, CAR therapy confers only modest clinical benefit due to attenuated persistence of CAR T cells. The purpose of this study was to enhance persistence and augment the antitumor activity of adoptively transferred CD19CAR T cells by restimulating CAR(+) T cells through an endogenous cytomegalovirus (CMV)-specific T-cell receptor.
  
  
  METHODS
  CMV-specific T cells from CMV seropositive healthy donors were selected after stimulation with pp65 protein and transduced with clinical-grade lentivirus expressing the CD19R:CD28:ζ/EGFRt CAR. The resultant bispecific T cells, targeting CMV and CD19, were expanded via CD19 CAR-mediated signals using CD19-expressing cells.
  
  
  RESULTS
  The bispecific T cells proliferated vigorously after engagement with either endogenous CMVpp65 T-cell receptors or engineered CD19 CARs, exhibiting specific cytolytic activity and IFNγ secretion. Upon adoptive transfer into immunodeficient mice bearing human lymphomas, the bispecific T cells exhibited proliferative response and enhanced antitumor activity following CMVpp65 peptide vaccine administration.
  
  
  CONCLUSIONS
  We have redirected CMV-specific T cells to recognize and lyse tumor cells via CD19CARs, while maintaining their ability to proliferate in response to CMV antigen stimulation. These results illustrate the clinical applications of CMV vaccine to augment the antitumor activity of adoptively transferred CD19CAR T cells in patients with B-cell malignancies.
authors.affiliation: Departments of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California. xiuwang@coh.org SForman@coh.org.
authors.forename: Xiuli
authors.initials: X
authors.lastname: Wang
authors.affiliation: Departments of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California.
authors.forename: ChingLam W
authors.initials: CW
authors.lastname: Wong
authors.affiliation: Departments of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California.
authors.forename: Ryan
authors.initials: R
authors.lastname: Urak
authors.affiliation: Departments of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California.
authors.forename: Armen
authors.initials: A
authors.lastname: Mardiros
authors.affiliation: Departments of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California.
authors.forename: Lihua E
authors.initials: LE
authors.lastname: Budde
authors.affiliation: Departments of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California.
authors.forename: Wen-Chung
authors.initials: WC
authors.lastname: Chang
authors.affiliation: Departments of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California.
authors.forename: Sandra H
authors.initials: SH
authors.lastname: Thomas
authors.affiliation: Departments of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California.
authors.forename: Christine E
authors.initials: CE
authors.lastname: Brown
authors.affiliation: Division of Translational Vaccine Research, Beckman Research Institute of the City of Hope, Duarte, California.
authors.forename: Corinna
authors.initials: C
authors.lastname: La Rosa
authors.affiliation: Division of Translational Vaccine Research, Beckman Research Institute of the City of Hope, Duarte, California.
authors.forename: Don J
authors.initials: DJ
authors.lastname: Diamond
authors.affiliation: Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, Washington.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Jensen
authors.affiliation: Departments of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California.
authors.forename: Ryotaro
authors.initials: R
authors.lastname: Nakamura
authors.affiliation: Department of Virology, Beckman Research Institute of the City of Hope, Duarte, California.
authors.forename: John A
authors.initials: JA
authors.lastname: Zaia
authors.affiliation: Departments of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California. xiuwang@coh.org SForman@coh.org.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Forman
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D018941:Antigens, CD19 / Q000096:biosynthesis / Q000235:genetics*; D000970:Antineoplastic Agents / Q000494:pharmacology; D019496:Cancer Vaccines / Q000276:immunology; D045744:Cell Line, Tumor; D000068818:Cetuximab / Q000494:pharmacology; D003587:Cytomegalovirus / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008223:Lymphoma / Q000276:immunology / Q000628:therapy* / Q000821:virology; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010750:Phosphoproteins / Q000276:immunology*; D011991:Receptors, Virus / Q000096:biosynthesis / Q000235:genetics; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000821:virology; D047368:Tumor Burden; D014611:Vaccination; D014763:Viral Matrix Proteins / Q000276:immunology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D018941:Antigens, CD19; D000970:Antineoplastic Agents; D019496:Cancer Vaccines; D010750:Phosphoproteins; D011991:Receptors, Virus; D014763:Viral Matrix Proteins; C065418:cytomegalovirus matrix protein 65kDa; D000068818:Cetuximab
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