Shinichi Kageyama 1 , Hiroaki Ikeda 2 , Yoshihiro Miyahara 2 , Naoko Imai 2 , Mikiya Ishihara 3 , Kanako Saito 4 , Sahoko Sugino 2 , Shugo Ueda 5 , Takeshi Ishikawa 6 , Satoshi Kokura 6 , Hiroaki Naota 7 , Kohshi Ohishi 8 , Taizo Shiraishi 9 , Naoki Inoue 10 , Masashige Tanabe 10 , Tomohide Kidokoro 10 , Hirofumi Yoshioka 10 , Daisuke Tomura 10 , Ikuei Nukaya 10 , Junichi Mineno 10 , Kazutoh Takesako 10 , Naoyuki Katayama 4 , Hiroshi Shiku 1 Show Affiliations »
Abstract
PURPOSE: 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. EXPERIMENTAL DESIGN: 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. ©2015 American Association for Cancer Research.
PURPOSE: 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. EXPERIMENTAL DESIGN: 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. ©2015 American Association for Cancer Research.
Entities: Disease
Gene
Species
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Year: 2015
PMID： 25855804 DOI： 10.1158/1078-0432.CCR-14-1559
Source DB: PubMed Journal: Clin Cancer Res ISSN： 1078-0432 Impact factor: 12.531