Vaccination Targeting Native Receptors to Enhance the Function and Proliferation of Chimeric Antigen Receptor (CAR)-Modified T Cells.
Purpose:The multiple mechanisms used by solid tumors to suppress tumor-specific immune responses are a major barrier to the success of adoptively transferred tumor-specific T cells. As viruses induce potent innate and adaptive immune responses, we hypothesized that the immunogenicity of viruses could be harnessed for the treatment of solid tumors if virus-specific T cells (VST) were modified with tumor-specific chimeric antigen receptors (CAR). We tested this hypothesis using VZV-specific T cells (VZVST) expressing a CAR for GD2, a disialoganglioside expressed on neuroblastoma and certain other tumors, so that the live-attenuated VZV vaccine could be used forin vivostimulation.Experimental Design:We generated GMP-compliant, GD2.CAR-modified VZVSTs from healthy donors and cancer patients by stimulation of peripheral blood mononuclear cells with overlapping peptide libraries spanning selected VZV antigens, then tested their ability to recognize and kill GD2- and VZV antigen-expressing target cells.Results:Our choice of VZV antigens was validated by the observation that T cells specific for these antigens expandedin vivoafter VZV vaccination. VZVSTs secreted cytokines in response to VZV antigens, killed VZV-infected target cells and limited infectious virus spread in autologous fibroblasts. However, while GD2.CAR-modified VZVSTs killed neuroblastoma cell lines on their first encounter, they failed to control tumor cells in subsequent cocultures. Despite this CAR-specific dysfunction, CAR-VZVSTs retained functional specificity for VZV antigens via their TCRs and GD2.CAR function was partially rescued by stimulation through the TCR or exposure to dendritic cell supernatants.Conclusions:Vaccination via the TCR may provide a means to reactivate CAR-T cells rendered dysfunctional by the tumor microenvironment (NCT01953900).Clin Cancer Res; 23(14); 3499-509. ©2017 AACR.
Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital.
Miyuki
M
Tanaka
Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital.
Haruko
H
Tashiro
Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital.|Department of Pediatrics, Division of Hematology and Oncology, Baylor College of Medicine, Houston, Texas.
Bilal
B
Omer
Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital.
Natasha
N
Lapteva
Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital.
Jun
J
Ando
Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital.|Program of Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, Texas.
Minhtran
M
Ngo
Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital.
Birju
B
Mehta
Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital.|Department of Pediatrics, Division of Hematology and Oncology, Baylor College of Medicine, Houston, Texas.|Department of Medicine, Baylor College of Medicine, Houston, Texas.
Gianpietro
G
Dotti
Departments of Ophthalmology, and Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania.
Paul R
PR
Kinchington
Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital.|Department of Pediatrics, Division of Hematology and Oncology, Baylor College of Medicine, Houston, Texas.|Department of Pathology, Division of Immunology, Baylor College of Medicine, Houston, Texas.
Ann M
AM
Leen
University Children's Hospital Muenster, Pediatric Hematology and Oncology, University of Pittsburgh, Pittsburgh, Pennsylvania.
Claudia
C
Rossig
Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital. crooney@bcm.edu.|Department of Pediatrics, Division of Hematology and Oncology, Baylor College of Medicine, Houston, Texas.|Program of Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, Texas.|Department of Pathology, Division of Immunology, Baylor College of Medicine, Houston, Texas.|Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas.
Cliona M
CM
Rooney
D000293:Adolescent; D000328:Adult; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002648:Child; D002675:Child, Preschool; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology; D008297:Male; D051379:Mice; D008875:Middle Aged; D009447:Neuroblastoma / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D015514:Oncogene Proteins, Fusion / Q000008:administration & dosage* / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000037:antagonists & inhibitors / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D059016:Tumor Microenvironment / Q000276:immunology; D014611:Vaccination; D014613:Vaccines, Attenuated / Q000008:administration & dosage / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
D015514:Oncogene Proteins, Fusion; D011948:Receptors, Antigen, T-Cell; D014613:Vaccines, Attenuated