title: Adoptive Transfer of MAGE-A4 T-cell Receptor Gene-Transduced Lymphocytes in Patients with Recurrent Esophageal Cancer.
abstract: OBJECTIVE
  Preparative lymphodepletion, the temporal ablation of the immune system, has been reported to promote persistence of transferred cells along with increased rates of tumor regression in patients treated with adoptive T-cell therapy. However, it remains unclear whether lymphodepletion is indispensable for immunotherapy with T-cell receptor (TCR) gene-engineered T cells.
  
  
  METHODS
  We conducted a first-in-man clinical trial of TCR gene-transduced T-cell transfer in patients with recurrent MAGE-A4-expressing esophageal cancer. The patients were given sequential MAGE-A4 peptide vaccinations. The regimen included neither lymphocyte-depleting conditioning nor administration of IL2. Ten patients, divided into 3 dose cohorts, received T-cell transfer.
  
  
  RESULTS
  TCR-transduced cells were detected in the peripheral blood for 1 month at levels proportional to the dose administered, and in 5 patients they persisted for more than 5 months. The persisting cells maintained ex vivo antigen-specific tumor reactivity. Despite the long persistence of the transferred T cells, 7 patients exhibited tumor progression within 2 months after the treatment. Three patients who had minimal tumor lesions at baseline survived for more than 27 months.
  
  
  CONCLUSIONS
  These results suggest that TCR-engineered T cells created by relatively short-duration in vitro culture of polyclonal lymphocytes in peripheral blood retained the capacity to survive in a host. The discordance between T-cell survival and tumor regression suggests that multiple mechanisms underlie the benefits of preparative lymphodepletion in adoptive T-cell therapy.
authors: Department of Immuno-Gene Therapy, Mie University Graduate School of Medicine, Mie, Japan. kageyama@clin.medic.mie-u.ac.jp shiku@clin.medic.mie-u.ac.jp.
authors: Shinichi
authors: S
authors: Kageyama
authors: Department of Immuno-Gene Therapy, Mie University Graduate School of Medicine, Mie, Japan.
authors: Hiroaki
authors: H
authors: Ikeda
authors: Department of Immuno-Gene Therapy, Mie University Graduate School of Medicine, Mie, Japan.
authors: Yoshihiro
authors: Y
authors: Miyahara
authors: Department of Immuno-Gene Therapy, Mie University Graduate School of Medicine, Mie, Japan.
authors: Naoko
authors: N
authors: Imai
authors: Cancer Center, Mie University Hospital, Mie, Japan.
authors: Mikiya
authors: M
authors: Ishihara
authors: Department of Hematology and Oncology, Mie University Graduate School of Medicine, Mie, Japan.
authors: Kanako
authors: K
authors: Saito
authors: Department of Immuno-Gene Therapy, Mie University Graduate School of Medicine, Mie, Japan.
authors: Sahoko
authors: S
authors: Sugino
authors: Kitano Hospital, Tazuke Kofukai Medical Research Institute, Osaka, Japan.
authors: Shugo
authors: S
authors: Ueda
authors: Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors: Takeshi
authors: T
authors: Ishikawa
authors: Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors: Satoshi
authors: S
authors: Kokura
authors: Matsusaka Chuo Hospital, Mie, Japan.
authors: Hiroaki
authors: H
authors: Naota
authors: Blood Transfusion Service, Mie University Hospital, Mie, Japan.
authors: Kohshi
authors: K
authors: Ohishi
authors: Department of Pathologic Oncology, Mie University Graduate School of Medicine, Mie, Japan.
authors: Taizo
authors: T
authors: Shiraishi
authors: Takara Bio Inc., Shiga, Japan.
authors: Naoki
authors: N
authors: Inoue
authors: Takara Bio Inc., Shiga, Japan.
authors: Masashige
authors: M
authors: Tanabe
authors: Takara Bio Inc., Shiga, Japan.
authors: Tomohide
authors: T
authors: Kidokoro
authors: Takara Bio Inc., Shiga, Japan.
authors: Hirofumi
authors: H
authors: Yoshioka
authors: Takara Bio Inc., Shiga, Japan.
authors: Daisuke
authors: D
authors: Tomura
authors: Takara Bio Inc., Shiga, Japan.
authors: Ikuei
authors: I
authors: Nukaya
authors: Takara Bio Inc., Shiga, Japan.
authors: Junichi
authors: J
authors: Mineno
authors: Takara Bio Inc., Shiga, Japan.
authors: Kazutoh
authors: K
authors: Takesako
authors: Department of Hematology and Oncology, Mie University Graduate School of Medicine, Mie, Japan.
authors: Naoyuki
authors: N
authors: Katayama
authors: Department of Immuno-Gene Therapy, Mie University Graduate School of Medicine, Mie, Japan. kageyama@clin.medic.mie-u.ac.jp shiku@clin.medic.mie-u.ac.jp.
authors: Hiroshi
authors: H
authors: Shiku
mesh_terms: D019264:Adoptive Transfer; D000328:Adult; D000368:Aged; D000951:Antigens, Neoplasm / Q000235:genetics*; D002294:Carcinoma, Squamous Cell / Q000276:immunology / Q000628:therapy*; D002470:Cell Survival; D002478:Cells, Cultured; D004938:Esophageal Neoplasms / Q000276:immunology / Q000628:therapy*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics*; D009364:Neoplasm Recurrence, Local / Q000276:immunology / Q000628:therapy*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics*; D013601:T-Lymphocytes / Q000276:immunology* / Q000637:transplantation; D014161:Transduction, Genetic; D016896:Treatment Outcome
chemical_list: D000951:Antigens, Neoplasm; C095204:MAGEA4 protein, human; D009363:Neoplasm Proteins; D011948:Receptors, Antigen, T-Cell