Bcl-2 overexpression enhances tumor-specific T-cell survival

被引:103
作者
Charo, J [1 ]
Finkelstein, SE [1 ]
Grewal, N [1 ]
Restifo, NP [1 ]
Robbins, PF [1 ]
Rosenberg, SA [1 ]
机构
[1] Natl Canc Inst, NIH, Surg Branch, Bethesda, MD 20892 USA
关键词
D O I
10.1158/0008-5472.CAN-04-2006
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Although immunotherapy based on the adoptive transfer of tumor-specific T lymphocytes has been shown to result in dramatic clinical responses in some patients, the relatively low levels of engraftment and persistence of the adoptively transferred cells may limit these responses in many patients. In an attempt to develop strategies for prolonging the survival of adoptively transferred T cells, we have carried out studies in which T cells obtained from healthy donors as well as tumor-specific T cells were transduced with a retrovirus expressing the human Bcl-2 gene. Our results indicate that these transduced T cells overexpress Bcl-2, are resistant to death, and have a survival advantage following interleukin-2 withdrawal compared with control T cells transduced with a retrovirus expressing green fluorescent protein. Tumor-specific T cells overexpressing Bcl-2 maintained their ability to specifically recognize and respond to target cells. Furthermore, we show that adoptive immunotherapy of an established B16 tumor can be significantly enhanced by overexpressing Bcl-2 in melanoma-specific T-cell receptor transgenic T cells. Our data suggest that adoptive immunotherapy approaches to the treatment of cancer patients may be enhanced using Bcl-2-modified tumorreactive T cells.
引用
收藏
页码:2001 / 2008
页数:8
相关论文
共 46 条
[1]   Bcl2 reduces lymphomagenesis in Delta V-TCR beta transgenic mice [J].
Acton, D ;
Jacobs, H ;
Domen, J ;
Berns, A .
ONCOGENE, 1997, 14 (21) :2497-2501
[2]   Role of Bcl-2 family of proteins in malignancy [J].
Baliga, BC ;
Kumar, S .
HEMATOLOGICAL ONCOLOGY, 2002, 20 (02) :63-74
[3]   Proapoptotic Bcl-2 relative bim required for certain apoptotic responses, leukocyte homeostasis, and to preclude autoimmunity [J].
Bouillet, P ;
Metcalf, D ;
Huang, DCS ;
Tarlinton, DM ;
Kay, TWH ;
Köntgen, F ;
Adams, JM ;
Strasser, A .
SCIENCE, 1999, 286 (5445) :1735-1738
[4]   Small interfering RNA (siRNA) inhibits the expression of the Her2/neu gene, upregulates HLA class I and induces apoptosis of Her2/neu positive tumor cell lines [J].
Choudhury, A ;
Charo, J ;
Parapuram, SK ;
Hunt, RC ;
Hunt, DM ;
Seliger, B ;
Kiessling, R .
INTERNATIONAL JOURNAL OF CANCER, 2004, 108 (01) :71-77
[5]  
Clay TM, 1999, J IMMUNOL, V163, P507
[6]  
Dudley ME, 2002, SCIENCE, V298, P850, DOI 10.1126/science.1076514
[7]   Adoptive transfer of cloned melanoma-reactive T lymphocytes for the treatment of patients with metastatic melanoma [J].
Dudley, ME ;
Wunderlich, J ;
Nishimura, MI ;
Yu, D ;
Yang, JC ;
Topalian, SL ;
Schwartzentruber, DJ ;
Hwu, P ;
Marincola, FM ;
Sherry, R ;
Leitman, SF ;
Rosenberg, SA .
JOURNAL OF IMMUNOTHERAPY, 2001, 24 (04) :363-373
[8]   Retroviral transduction of human peripheral blood lymphocytes with bcl-xL promotes in vitro lymphocyte survival in pro-apoptotic conditions [J].
Eaton, D ;
Gilham, DE ;
O'Neill, A ;
Hawkins, RE .
GENE THERAPY, 2002, 9 (08) :527-535
[9]   Generation of high quantities of viral and tumor-specific human CD4+and CD8+T-cell clones using peptide pulsed mature dendritic cells [J].
Fonteneau, JF ;
Larsson, M ;
Somersan, S ;
Sanders, C ;
Münz, C ;
Kwok, WW ;
Bhardwaj, N ;
Jotereau, F .
JOURNAL OF IMMUNOLOGICAL METHODS, 2001, 258 (1-2) :111-126
[10]   T cell fitness determined by signal strength [J].
Gett, AV ;
Sallusto, F ;
Lanzavecchia, A ;
Geginat, J .
NATURE IMMUNOLOGY, 2003, 4 (04) :355-360