Interleukin-7 Mediates Selective Expansion of Tumor-redirected Cytotoxic T Lymphocytes (CTLs) without Enhancement of Regulatory T-cell Inhibition
| Autor: | Hao Liu, Aruna Mahendravada, Malcolm K. Brenner, Serena K. Perna, Barbara Savoldo, Gianpietro Dotti, Daria Pagliara |
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| Rok vydání: | 2014 |
| Předmět: |
Cancer Research
Adoptive cell transfer CD3 Complex Regulatory T cell Recombinant Fusion Proteins Receptors Antigen T-Cell chemical and pharmacologic phenomena Mice SCID Biology T-Lymphocytes Regulatory Article Mice Neuroblastoma Antigen Mice Inbred NOD In vivo Cell Line Tumor medicine Animals Humans Cytotoxic T cell Cell Proliferation Receptors Interleukin-7 Cell growth Interleukin-7 Interleukin hemic and immune systems Adoptive Transfer Chimeric antigen receptor Tumor Burden medicine.anatomical_structure Oncology Immunology Cancer research Neoplasm Transplantation T-Lymphocytes Cytotoxic |
| Zdroj: | Clinical Cancer Research. 20:131-139 |
| ISSN: | 1557-3265 1078-0432 |
| Popis: | Purpose: The antitumor activity of chimeric antigen receptor (CAR)–redirected CTLs should be enhanced if it were possible to increase their proliferation and function after adoptive transfer without concomitantly increasing the proliferation and function of regulatory T cells (Treg). Here, we explored whether the lack of IL-7Rα in Treg can be exploited by the targeted manipulation of the interleukin-7 (IL-7) cytokine–cytokine receptor axis in CAR-engrafted Epstein–Barr Virus–specific CTLs (EBV-CTLs) to selectively augment their growth and antitumor activity even in the presence of Treg. Experimental Design: We generated a bicistronic retroviral vector encoding a GD2-specific CAR and the IL-7Rα subunit, expressed the genes in EBV-CTLs, and assessed their capacity to control tumor growth in the presence of Treg in vitro and in vivo when exposed to either interleukin-2 (IL-2) or IL-7 in a neuroblastoma xenograft. Results: We found that IL-7, in sharp contrast with IL-2, supports the proliferation and antitumor activity of IL-7Rα.CAR-GD2+ EBV-CTLs both in vitro and in vivo even in the presence of fully functional Treg. Conclusions: IL-7 selectively favors the survival, proliferation, and effector function of IL-7Rα-transgenic/CAR-redirected EBV-CTLs in the presence of Treg both in vitro and in vivo. Thus, IL-7 can have a significant impact in sustaining expansion and persistence of adoptively CAR-redirected CTLs. Clin Cancer Res; 20(1); 131–9. ©2013 AACR. |
| Databáze: | OpenAIRE |
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