TY - JOUR
T1 - Genomic stability and functional activity may be lost in telomerase-transduced human CD8+ T lymphocytes
AU - Schreurs, Marco W.J.
AU - Hermsen, Mario A.J.A.
AU - Geltink, Ramon I.Klein
AU - Scholten, Kirsten B.J.
AU - Brink, Antoinette A.T.P.
AU - Kueter, Esther W.M.
AU - Tijssen, Marianne
AU - Meijer, Chris J.L.M.
AU - Ylstra, Bauke
AU - Meijer, Gerrit A.
AU - Hooijberg, Erik
PY - 2005/10/1
Y1 - 2005/10/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=27144545010&partnerID=8YFLogxK
U2 - https://doi.org/10.1182/blood-2004-09-3742
DO - https://doi.org/10.1182/blood-2004-09-3742
M3 - Article
C2 - 16002425
SN - 0006-4971
VL - 106
SP - 2663
EP - 2670
JO - Blood
JF - Blood
IS - 8
ER -