| RRC ID |
65457
|
| 著者 |
Goto S, Sakoda Y, Adachi K, Sekido Y, Yano S, Eto M, Tamada K.
|
| タイトル |
Enhanced anti-tumor efficacy of IL-7/CCL19-producing human CAR-T cells in orthotopic and patient-derived xenograft tumor models.
|
| ジャーナル |
Cancer Immunol Immunother
|
| Abstract |
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.
|
| 巻・号 |
70(9)
|
| ページ |
2503-2515
|
| 公開日 |
2021-9-1
|
| DOI |
10.1007/s00262-021-02853-3
|
| PII |
10.1007/s00262-021-02853-3
|
| PMID |
33559069
|
| MeSH |
Animals
Cell Line, Tumor
Chemokine CCL19 / genetics
Chemokine CCL19 / metabolism*
Disease Models, Animal
Female
Humans
Immunophenotyping
Immunotherapy, Adoptive* / methods
Interleukin-7 / genetics
Interleukin-7 / metabolism*
Mesothelin
Mesothelioma, Malignant / etiology
Mesothelioma, Malignant / pathology
Mesothelioma, Malignant / therapy
Mice
Mice, Knockout
Receptors, Chimeric Antigen
Recurrence
T-Lymphocytes / immunology*
T-Lymphocytes / metabolism*
T-Lymphocytes / pathology
Treatment Outcome
Xenograft Model Antitumor Assays
|
| IF |
5.442
|
| リソース情報 |
| ヒト・動物細胞 |
OV2944-HM-1(RCB1483) |
