Telomerase mRNA-Transfected Dendritic Cells Stimulate Antigen-Specific CD8+ and CD4+ T Cell Responses in Patients with Metastatic Prostate Cancer
Abstract
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.
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Antigen-encoding RNA constructs used currently for preclinical studies have poly(A) tails measuring 30 to 70 nucleotides, whereas those administered in clinical trials measure 64 nucleotides.
“Antigen-encoding RNA constructs used currently for preclinical studies have poly(A) tails measuring 30 to 70 nucleotides in length, 4,5 whereas those administered in clinical trials measure 64 nucleotides in length.8,12”
From Modification of antigen-encoding RNA increases stability, translational efficacy, and T-cell stimulatory capacity of dendritic cells (2006) · cites this paper as [8]
Early clinical trials of RNA-based vaccines showed feasibility, lack of toxicity, and promising efficacy based on immunologic and clinical read-outs.
“Early clinical trials showed feasibility, lack of toxicity, and promising efficacy based on immunologic and clinical read-outs.[8][9][10][11][12]”
From Modification of antigen-encoding RNA increases stability, translational efficacy, and T-cell stimulatory capacity of dendritic cells (2006) · cites this paper as [8]
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- Authors
- Su, Z., Dannull, J., Yang, B. K., Dahm, P., Coleman, D., Yancey, D., Sichi, S., Niedzwiecki, D., Boczkowski, D., Gilboa, E., & Vieweg, J.
- Affiliations
- Duke University (US)
- Duke Medical Center (US)
- ORCID
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2005-03
- Volume
- 174
- Issue
- 6
- Pages
- 3798-3807
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- OpenAlex
- W1521418395
- Cited by
- 359
- References
- 5
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 14 · 2023: 4 · 2022: 6 · 2021: 7 · 2020: 16 · 2019: 8 · 2018: 7 · 2017: 10 · 2016: 15 · 2015: 9 · 2014: 11 · 2013: 23 · 2012: 16
- FWCI
- 14.53
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- NSUWorks (Nova Southeastern University) (submittedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Treatment and Research
- Keywords
- telomerase reverse transcriptase, hTERT, dendritic cell vaccine, mRNA transfection, metastatic prostate cancer, cancer immunotherapy, antigen-specific T cell responses, CD8+ T cells, CD4+ T cells, cytotoxic T lymphocytes, prostate-specific antigen, micrometastases
- MeSH terms
- Aged, Dendritic Cells, DNA-Binding Proteins, Humans, Immunotherapy, Male, Middle Aged, Prostatic Neoplasms, RNA, Messenger, Safety, Transfection, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Telomerase, Cancer Vaccines
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