Telomerase mRNA-transfected dendritic cells stimulate antigen-specific CD8+ and CD4+ T cell responses in patients with metastatic prostate cancer.
Telomerase reverse transcriptase (hTERT) represents an attractive target for cancer immunotherapy because hTERT is reactivated in most human tumors. A clinical trial was initiated in which hTERT mRNA-transfected dendritic cells (DC) were administered to 20 patients with metastatic prostate cancer. Nine of these subjects received DC transfected with mRNA encoding a chimeric lysosome-associated membrane protein-1 (LAMP) hTERT protein, allowing for concomitant induction of hTERT-specific CD8+ and CD4+ T cell responses. Treatment was well tolerated. Intense infiltrates of hTERT-specific T cells were noted at intradermal injection sites after repeated vaccination. In 19 of 20 subjects, expansion of hTERT-specific CD8+ T cells was measured in the peripheral blood of study subjects, with 0.9-1.8% of CD8+ T cells exhibiting Ag specificity. Patients immunized with the chimeric LAMP hTERT vaccine developed significantly higher frequencies of hTERT-specific CD4+ T cells than subjects receiving DC transfected with the unmodified hTERT template. Moreover, CTL-mediated killing of hTERT targets was enhanced in the LAMP hTERT group, suggesting that an improved CD4+ response could augment a CTL response. Vaccination was further associated with a reduction of prostate-specific Ag velocity and molecular clearance of circulating micrometastases. Our findings provide a rationale for further development of hTERT-transfected DC vaccines in the treatment of prostate and other cancers.
Su
Zhen
Z
Genitourinary Cancer Immunotherapy Program, Division of Urology, Duke University Medical Center, Durham, NC 27710, USA.
Dannull
Jens
J
Yang
Benjamin K
BK
Dahm
Philipp
P
Coleman
Doris
D
Yancey
Donna
D
Sichi
Sylvia
S
Niedzwiecki
Donna
D
Boczkowski
David
D
Gilboa
Eli
E
Vieweg
Johannes
J
D000368:Aged; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000009:adverse effects / Q000235:genetics / Q000494:pharmacology; D004268:DNA-Binding Proteins; D003713:Dendritic Cells / Q000201:enzymology* / Q000276:immunology*; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D008297:Male; D008875:Middle Aged; D011471:Prostatic Neoplasms / Q000276:immunology* / Q000556:secondary / Q000628:therapy*; D012333:RNA, Messenger / Q000235:genetics; D012449:Safety; D019098:Telomerase / Q000235:genetics* / Q000276:immunology*; D014162:Transfection
D019496:Cancer Vaccines; D004268:DNA-Binding Proteins; D012333:RNA, Messenger; D019098:Telomerase