title: Phase I Clinical Trial of 4-1BB-based Adoptive T-Cell Therapy for Epstein-Barr Virus (EBV)-positive Tumors.
abstract: Although adoptive cell therapy using Ag-specific T cells has been tested successfully in the clinic, the production of these T cells has been challenging. By applying our simple and practical 4-1BB-based method for the generation of Ag-specific CD8 T cells, here we determined the maximum tolerated dose, toxicity profile, immunologic responses, and clinical efficacy of autologous Epstein-Barr virus (EBV)/LMP2A-specific CD8 T cells (EBV-induced Natural T cell; EBViNT) in patients with relapsed/refractory EBV-positive tumors. This was a single-center, phase I, dose-escalation trial study evaluating 4 escalating dosing schedules of single injected EBViNT. CD8 T-cell responses against different LMP2A peptides in each patient were determined, and the most effective peptides were used to produce EBViNT. The produced autologous EBViNTs were single infused to patients with EBV-associated malignancy who had failed to standard treatments and were of HLA-A02 or A24 type. Of 11 patients enrolled, 8 patients received a single infusion of EBViNT: 4 with nasopharyngeal carcinomas, 1 with Hodgkin lymphoma, 2 with extranodal NK/T lymphomas, and 1 with diffuse large B-cell lymphoma. Single infusion of EBViNT was well tolerated by all the patients and generated objective antitumor responses in 3 of them. EBViNT infusion induced 2 waves of interferon-γ response: 1 approximately 1 week and the other 4-8 weeks after the treatment. The strength of the second wave was related to the efficacy of the treatment. The current trial shows that EBViNT therapy is safe and may provide a new option for treating EBV-positive recurrent cancer patients resistant to conventional therapy.
authors.affiliation: *Hematologic Oncology Clinic, Center for Specific Organs Cancer, National Cancer Center, Korea †Center for Clinical Trial, National Cancer Center, Korea ‡Cancer Immunology Branch, Division of Cancer Biology §Immune Cell Production Unit, Program for Immunotherapeutic Research, Research Institute and Hospital, National Cancer Center, Ilsandong-gu, Goyang, Gyeonggi ∥Department of Hematology-Oncology, Chonnam National University Medical School, Gwangju, Korea ¶Department of Medicine, Tulane University Health Sciences Center, New Orleans, LA.
authors.forename: Hyeon-Seok
authors.initials: HS
authors.lastname: Eom
authors.forename: Beom K
authors.initials: BK
authors.lastname: Choi
authors.forename: Youngjoo
authors.initials: Y
authors.lastname: Lee
authors.forename: Hyewon
authors.initials: H
authors.lastname: Lee
authors.forename: Tak
authors.initials: T
authors.lastname: Yun
authors.forename: Young H
authors.initials: YH
authors.lastname: Kim
authors.forename: Je-Jung
authors.initials: JJ
authors.lastname: Lee
authors.forename: Byoung S
authors.initials: BS
authors.lastname: Kwon
mesh_terms: D000368:Aged; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D064987:Cell- and Tissue-Based Therapy; D003131:Combined Modality Therapy; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D020031:Epstein-Barr Virus Infections / Q000150:complications* / Q000276:immunology* / Q000821:virology; D005260:Female; D004854:Herpesvirus 4, Human / Q000276:immunology*; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods; D007371:Interferon-gamma / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000175:diagnosis / Q000209:etiology* / Q000628:therapy*; D049268:Positron-Emission Tomography; D037182:T-Cell Antigen Receptor Specificity / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000235:genetics / Q000276:immunology*; D014763:Viral Matrix Proteins / Q000276:immunology
chemical_list: C037662:EBV-associated membrane antigen, Epstein-Barr virus; D018984:Epitopes, T-Lymphocyte; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D014763:Viral Matrix Proteins; D007371:Interferon-gamma