Abstract CT212: Adoptive transfer of wild-type TCR gene transduced T lymphocytes targeting MAGE-A4 antigen to patients with refractory esophageal cancer
Authors: Kageyama Shinichi , Ikeda Hiroaki , Imai Naoko , Ishihara Mikiya , Miyahara Yoshihiro , Ueda Shugo , Ishikawa Takeshi , 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 
Published: May 2015

Abstract
Introduction:
Engineering an antigen receptor gene in patients' lymphocytes is one promising strategy to create antigen-specific lymphocytes without senescent phenotypes. The strategy provides an opportunity to extend the application of adoptive T cell therapy for cancer patients. However, this concept has not been tested in epithelial cancer patients.
Material and methods:
MAGE-A4-specific TCR α and β chains were isolated from a human T cell clone that recognizes MAGE-A4 143-151 peptide in an HLA-A*24:02 restricted manner. This T cell clone did not show any cross reactivity to the peptides with a homology to the MAGE-A4 epitope. A retroviral vector that encodes these TCR chains without any artificial modification was constructed; the lymphocytes transduced with the retroviral vector killed the MAGE-A4 expressing tumor in vitro and inhibited the tumor growth in the NOG immmunodeficient mice.
Patients were eligible if they had previously-treated recurrent MAGE-A4-expressing esophageal cancer, and were positive for HLA-A*24;02. Lymphocytes harvested from the patients were infected with the retroviral vector. The TCR-gene transduced T lymphocytes were once transferred to the patients without lymphocyte-depleting treatment, and MAGE-A4 peptide was given 2 and 4 weeks after. The cell doses were divided into 3 cohorts of 2x108 1x109 and 5x109, with a dose-escalating design, by evaluating the safety.
Results:
10 patients received the TCR-gene transduced T lymphocytes. No adverse events related to the cell transfer were observed. The TCR-gene transduced lymphocytes were detected in their peripheral blood in all 10 patients, which showed a dose-dependent appearance during the first 14 days, reaching peak and plateau levels from 3 to 7 days, and declined within 14 days. The cells persisted at 0.5% to 1% level in the peripheral mononuclear cells from day 14 to 63 after the cell transfer. In 6 patients whose blood samples had been collected for over 6 months, 3 patients maintained stable levels as long as 16 months, maintaining the immune reactivity to MAGE-A4-expressing tumor cells. In one patient, whose esophageal tumor was biopsied after the transfer, the TCR-gene transduced cells were detected in the tumor site.
7 patients developed tumor progressions within 2 months after the transfer. Their overall survivals were ranged from 3 to 18+ months, with a median of 10. 3 patients who had minimal tumor lesions at baseline have been free from disease-progression for 12, 15, and 19 months, respectively.
Conclusion:
Wild-type TCR-gene transduced lymphocytes targeting MAGE-A4 antigen were safely given to refractory esophageal cancer patients. The cells persisted in their peripheral blood in a dose-dependent manner in the early phase, and they have been stably persisting over 6 months. Three patients are free from disease progression more than a year. These results encourage us to proceed to further phase trials.
Citation Format: Shinichi Kageyama, Hiroaki Ikeda, Naoko Imai, Mikiya Ishihara, Yoshihiro Miyahara, Shugo Ueda, Takeshi Ishikawa, Hiroaki Naota, Kohshi Ohishi, Taizo Shiraishi, Naoki Inoue, Masashige Tanabe, Tomohide Kidokoro, Hirofumi Yoshioka, Daisuke Tomura, Ikuei Nukaya, Junichi Mineno, Kazutoh Takesako, Naoyuki Katayama, Hiroshi Shiku. Adoptive transfer of wild-type TCR gene transduced T lymphocytes targeting MAGE-A4 antigen to patients with refractory esophageal cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT212. doi:10.1158/1538-7445.AM2014-CT212