Full-length dominant-negative survivin for cancer immunotherapy.
OBJECTIVE
The goal of this study is to investigate the possible utility of dendritic cells (DCs) transduced with the human full-length dominant-negative survivin for cancer immunotherapy.


METHODS
Mononuclear cells were collected from HLA-A2-positive healthy volunteers and patients with prostate cancer. DCs were transduced with an adenoviral vector containing a full-length, dominant-negative survivin gene. After three rounds of stimulation, the T-cell response against three different survivin-derived HLA-A2-matching peptides was tested in IFN-gamma enzyme-linked immunospot and CTL assays.


RESULTS
Seven of eight healthy volunteers and cancer patients showed a significant response to at least two different survivin-derived epitopes in the enzyme-linked immunospot assay. One patient responded to only one peptide. All four healthy volunteers and two of three patients tested demonstrated a specific CTL response against T2 target cells loaded with one survivin-derived epitope. Two donors and two patients had a significant CTL response against two different epitopes. Significant cytotoxic activity was seen against HLA-A2-positive MCF-7 tumor cells that express survivin. That response was specific for survivin and was MHC class I restricted. Because survivin is expressed in CD34(+) hematopoietic progenitor cells (HPCs), we tested whether the antisurvivin CTLs can recognize normal HPCs. The incubation of survivin-specific CTLs with CD34(+) cells did not significantly decrease the colony-forming ability of HPCs.


CONCLUSIONS
DCs transduced with dominant-negative survivin induce potent survivin-specific CTL responses able to recognize and kill tumor cells. This response does not significantly affect HPCs. Thus, this study may provide rationale for immunotherapeutic clinical trials using a DC vaccine transduced with the dominant-negative survivin.
Pisarev
Vladimir
V
University of Nebraska Medical Center Eppley Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska, USA.
Yu
Bin
B
Salup
Raoul
R
Sherman
Simon
S
Altieri
Dario C
DC
Gabrilovich
Dmitry I
DI
D000256:Adenoviridae / Q000235:genetics; D000328:Adult; D000368:Aged; D018952:Antigens, CD34 / Q000096:biosynthesis / Q000378:metabolism; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D000939:Epitopes; D005799:Genes, Dominant; D015789:HLA-A2 Antigen / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D051034:Inhibitor of Apoptosis Proteins; D007371:Interferon-gamma / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis* / Q000235:genetics*; D008875:Middle Aged; D009363:Neoplasm Proteins; D009369:Neoplasms / Q000235:genetics / Q000628:therapy*; D010455:Peptides / Q000737:chemistry; D011471:Prostatic Neoplasms / Q000628:therapy; D013234:Stem Cells / Q000378:metabolism; D000077022:Survivin
D018952:Antigens, CD34; C107489:BIRC5 protein, human; D000939:Epitopes; D015789:HLA-A2 Antigen; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D010455:Peptides; D000077022:Survivin; D007371:Interferon-gamma