Adoptive Transfer of MAGE-A4 T-cell Receptor Gene-Transduced Lymphocytes in Patients with Recurrent Esophageal Cancer

• Published in: Clinical cancer research 2015-05, Vol.21 (10), p.2268-2277
• Main Authors: Kageyama, Shinichi, Ikeda, Hiroaki, Miyahara, Yoshihiro, Imai, Naoko, Ishihara, Mikiya, Saito, Kanako, Sugino, Sahoko, Ueda, Shugo, Ishikawa, Takeshi, Kokura, Satoshi, Naota, Hiroaki, Ohishi, Kohshi, Shiraishi, Taizo, Inoue, Naoki, Tanabe, Masashige, Kidokoro, Tomohide, Yoshioka, Hirofumi, Tomura, Daisuke, Nukaya, Ikuei, Mineno, Junichi, Takesako, Kazutoh, Katayama, Naoyuki, Shiku, Hiroshi
• Format: Article
• Language: English
• Subjects: Adoptive Transfer; Adult; Aged; Antigens, Neoplasm - genetics; Carcinoma, Squamous Cell - immunology; Carcinoma, Squamous Cell - therapy; Cell Survival; Cells, Cultured; Esophageal Neoplasms - immunology; Esophageal Neoplasms - therapy; Female; Humans; Male; Middle Aged; Neoplasm Proteins - genetics; Neoplasm Recurrence, Local - immunology; Neoplasm Recurrence, Local - therapy; Receptors, Antigen, T-Cell - genetics; T-Lymphocytes - immunology; T-Lymphocytes - transplantation; Transduction, Genetic; Treatment Outcome
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-14-1559

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. 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. 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. 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.