Enhanced anti-tumor efficacy of IL-7/CCL19-producing human CAR-T cells in orthotopic and patient-derived xenograft tumor models

Shunsuke Goto, Yukimi Sakoda, Keishi Adachi, Yoshitaka Sekido, Seiji Yano, Masatoshi Eto, Koji Tamada

研究成果: Contribution to journalArticle査読

1 被引用数 (Scopus)

抄録

Chimeric antigen receptor (CAR)-T cell therapy has impressive efficacy in hematological malignancies, but its application in solid tumors remains a challenge. Multiple hurdles associated with the biological and immunological features of solid tumors currently limit the application of CAR-T cells in the treatment of solid tumors. Using syngeneic mouse models, we recently reported that CAR-T cells engineered to concomitantly produce interleukin (IL)-7 and chemokine (C–C motif) ligand 19 (CCL19)-induced potent anti-tumor efficacy against solid tumors through an improved ability of migration and proliferation even in an immunosuppressive tumor microenvironment. In this study, for a preclinical evaluation preceding clinical application, we further explored the potential of IL-7/CCL19-producing human CAR-T cells using models that mimic the clinical features of solid tumors. Human anti-mesothelin CAR-T cells producing human IL-7/CCL19 achieved complete eradication of orthotopic pre-established malignant mesothelioma and prevented a relapse of tumors with downregulated antigen expression. Moreover, mice with patient-derived xenograft of mesothelin-positive pancreatic cancers exhibited significant inhibition of tumor growth and prolonged survival following treatment with IL-7/CCL19-producing CAR-T cells, compared to treatment with conventional CAR-T cells. Transfer of IL-7/CCL19-producing CAR-T cells resulted in an increase in not only CAR-T cells but also non-CAR-T cells within the tumor tissues and downregulated the expression of exhaustion markers, including PD-1 and TIGIT, on the T cells. Taken together, our current study elucidated the exceptional anti-tumor efficacy of IL-7/CCL19-producing human CAR-T cells and their potential for clinical application in the treatment of patients with solid tumors.

本文言語英語
ページ(範囲)2503-2515
ページ数13
ジャーナルCancer Immunology, Immunotherapy
70
9
DOI
出版ステータス出版済み - 9 2021

All Science Journal Classification (ASJC) codes

  • 免疫アレルギー学
  • 免疫学
  • 腫瘍学
  • 癌研究

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