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Blood, 15 October 2005, Vol. 106, No. 8, pp. 2663-2670.
Prepublished online as a Blood First Edition Paper on July 7, 2005; DOI 10.1182/blood-2004-09-3742.
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GENE THERAPY
Genomic stability and functional activity may be lost in telomerase-transduced human CD8+ T lymphocytes
Marco W. J. Schreurs,
Mario A. J. A. Hermsen,
Ramon I. Klein Geltink,
Kirsten B. J. Scholten,
Antoinette A. T. P. Brink,
Esther W. M. Kueter,
Marianne Tijssen,
Chris J. L. M. Meijer,
Bauke Ylstra,
Gerrit A. Meijer, and
Erik Hooijberg
From the Department of Pathology, Vrije Universiteit (VU) University Medical Center, Amsterdam, The Netherlands.
To obtain the large amount of T cells required for adoptive immunotherapy in a clinical setting, T-cell lifespan extension by human telomerase reverse transcriptase (hTERT) transduction is of particular interest. However, constitutive expression of hTERT is associated with malignant transformation and thus warrants a detailed evaluation of the safety of hTERT-transduced T cells before clinical application. In view of this, we performed an extensive cytogenetic analysis of hTERT-transduced MART-1 (melanoma antigen recognized by T cell 1)–and human papillomavirus type 16 (HPV16) E7–specific human CD8+ cytotoxic T lymphocytes (CTLs), reactive against melanoma and cervical carcinoma, respectively. Our results, obtained by (spectral) karyotyping and array comparative genomic hybridization, showed the development of minor chromosomal aberrations in an hTERT-transduced MART-1–specific CTL clone, whereas severe clonal aberrations were detected in an hTERT-transduced HPV16 E7–specific CTL clone. Furthermore, hTERT transduction did not protect CTLs from immunosenescence, because the HPV16 E7–specific, hTERT-transduced CTL clone showed a decreased functional activity on prolonged culture. Although the general frequency of major chromosomal aberrations in hTERT-transduced CTLs and the in vivo significance of our observations remain still unclear at this point, the currently available data suggest that clinical application of hTERT-transduced CTLs should proceed with caution.
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