Feasibility of Telomerase-Specific Adoptive T-cell Therapy for B-cell Chronic Lymphocytic Leukemia and Solid Malignancies
| Autor: | Chiara Cavallini, Sara Bobisse, Manuela Iezzi, Federico Boschi, Sara Sandri, Silvia Sartoris, Andrea Sbarbati, Vincenzo Bronte, Kelly Moxley, Giovanna Ferrarini, Maria Teresa Scupoli, Rudi W. Hendriks, Stefano Ugel, Francesco De Sanctis, Alessia Lamolinara, Michael I. Nishimura, Giulio Fracasso |
|---|---|
| Přispěvatelé: | Pulmonary Medicine |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
HLA-A2–restricted T-cell receptor Cancer Research Adoptive cell transfer Telomerase mice T cell medicine.medical_treatment Chronic lymphocytic leukemia Receptors Antigen T-Cell Mice Transgenic chemical and pharmacologic phenomena Biology telomerase Immunotherapy Adoptive 03 medical and health sciences 0302 clinical medicine SDG 3 - Good Health and Well-being Cell Line Tumor medicine Cytotoxic T cell Animals Humans B cell Immunotherapy medicine.disease Leukemia Lymphocytic Chronic B-Cell Mice Inbred C57BL Disease Models Animal in vivo 030104 developmental biology medicine.anatomical_structure Oncology 030220 oncology & carcinogenesis Immunology Humanized mouse Cancer research adoptive immunotherapy high-avidity T-cell receptor Feasibility Studies T-Lymphocytes Cytotoxic |
| Zdroj: | Cancer Research, 76(9), 2540-2551. American Association for Cancer Research Inc. |
| ISSN: | 0008-5472 |
| Popis: | Telomerase (TERT) is overexpressed in 80% to 90% of primary tumors and contributes to sustaining the transformed phenotype. The identification of several TERT epitopes in tumor cells has elevated the status of TERT as a potential universal target for selective and broad adoptive immunotherapy. TERT-specific cytotoxic T lymphocytes (CTL) have been detected in the peripheral blood of B-cell chronic lymphocytic leukemia (B-CLL) patients, but display low functional avidity, which limits their clinical utility in adoptive cell transfer approaches. To overcome this key obstacle hindering effective immunotherapy, we isolated an HLA-A2–restricted T-cell receptor (TCR) with high avidity for human TERT from vaccinated HLA-A*0201 transgenic mice. Using several relevant humanized mouse models, we demonstrate that TCR-transduced T cells were able to control human B-CLL progression in vivo and limited tumor growth in several human, solid transplantable cancers. TERT-based adoptive immunotherapy selectively eliminated tumor cells, failed to trigger a self–MHC-restricted fratricide of T cells, and was associated with toxicity against mature granulocytes, but not toward human hematopoietic progenitors in humanized immune reconstituted mice. These data support the feasibility of TERT-based adoptive immunotherapy in clinical oncology, highlighting, for the first time, the possibility of utilizing a high-avidity TCR specific for human TERT. Cancer Res; 76(9); 2540–51. ©2016 AACR. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|