Melanoma reactive TCR-modified T cells generated without activation retain a less differentiated phenotype and mediate a superior in vivo response
| Autor: | Tamson V. Moore, Gina Scurti, Siao Yi Wang, Michael I. Nishimura, Annika Dalheim |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Male Science T cell CD3 T-Lymphocytes Cell- and Tissue-Based Therapy Receptors Antigen T-Cell Cancer immunotherapy Mice SCID Lymphocyte Activation Article Viral vector Cell Line 03 medical and health sciences Mice 0302 clinical medicine Mice Inbred NOD Transduction Genetic medicine Animals Humans Receptor Melanoma Multidisciplinary biology Chemistry Interleukin-7 T-cell receptor Cell Differentiation medicine.disease Telomere 030104 developmental biology medicine.anatomical_structure HEK293 Cells Phenotype 030220 oncology & carcinogenesis Cancer research biology.protein Medicine Female Stem cell Immunologic Memory |
| Zdroj: | Scientific Reports Scientific Reports, Vol 11, Iss 1, Pp 1-11 (2021) |
| ISSN: | 2045-2322 |
| Popis: | Adoptive T cell therapy with T cell receptor (TCR)-modified T cells has shown promise in treating metastatic melanoma and other malignancies. However, studies are needed to improve the efficacy and durability of responses of TCR-modified T cells. Standard protocols for generating TCR-modified T cells involve activating T cells through CD3 stimulation to allow for the efficient transfer of tumor-reactive receptors with viral vectors. T cell activation results in terminal differentiation and shortening of telomeres, which are likely suboptimal for therapy. In these studies, we demonstrate efficient T cell transduction with the melanoma-reactive TIL1383I TCR through culturing with interleukin 7 (IL-7) in the absence of CD3 activation. The TIL1383I TCR-modified T cells generated following IL-7 culture were enriched with naïve (TN) and memory stem cell populations (TSCM) while maintaining longer telomere lengths. Furthermore, we demonstrated melanoma-reactivity of TIL1383I TCR-modified cells generated following IL-7 culture using in vitro assays and a superior response in an in vivo melanoma model. These results suggest that utilizing IL-7 to generate TCR-modified T cells in the absence of activation is a feasible strategy to improve adoptive T cell therapies for melanoma and other malignancies. |
| Databáze: | OpenAIRE |
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