Vaccination of Cancer Patients Against Telomerase Induces Functional Antitumor CD8+ T Lymphocytes

Robert H. Vonderheide, Susan M. Domchek, Joachim L. Schultze, Daniel J. George, Kara M. Hoar, Dih Yih Chen, Katherine F. Stephans, Kenkichi Masutomi, Massimo Loda, Zhinan Xia, Karen Anderson, William C. Hahn, Lee M. Nadler

Research output: Contribution to journalArticle

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Abstract

Purpose: High-level expression of the telomerase reverse transcriptase (hTERT) in >85% of human cancers, in contrast with its restricted expression in normal adult tissues, points to hTERT as a broadly applicable molecular target for anticancer immunotherapy. CTLs recognize peptides derived from hTERT and kill hTERT+ tumor cells of multiple histologies in vitro. Moreover, because survival of hTERT+ tumor cells requires functionally active telomerase, hTERT mutation or loss as a means of escape may be incompatible with sustained tumor growth. Experimental Design: A Phase I clinical trial was performed to evaluate the clinical and immunological impact of vaccinating advanced cancer patients with the HLA-A2-restricted hTERT I540 peptide presented with keyhole limpet hemocyanin by ex vivo generated autologous dendritic cells. Results: As measured by peptide/MHC tetramer, enzyme-linked immunospot, and cytotoxicity assays, hTERT-specific T lymphocytes were induced in 4 of 7 patients with advanced breast or prostate carcinoma after vaccination with dendritic cells pulsed with hTERT peptide. Tetramer-guided high-speed sorting and polyclonal expansion achieved highly enriched populations of hTERT-specific cells that killed tumor cells in an MHC- restricted fashion. Despite concerns of telomerase activity in rare normal cells, no significant toxicity was observed. Partial tumor regression in 1 patient was associated with the induction of CD8+ tumor infiltrating lymphocytes. Conclusions: These results demonstrate the immunological feasibility of vaccinating patients against telomerase and provide rationale for targeting self-antigens with critical roles in oncogenesis.

Original languageEnglish (US)
Pages (from-to)828-839
Number of pages12
JournalClinical Cancer Research
Volume10
Issue number3
DOIs
StatePublished - Feb 1 2004
Externally publishedYes

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Telomerase
Vaccination
T-Lymphocytes
Neoplasms
Dendritic Cells
Peptides
Tumor-Infiltrating Lymphocytes
HLA-A2 Antigen
Enzyme-Linked Immunospot Assay
Clinical Trials, Phase I
Autoantigens
Immunotherapy
Prostate
Histology
Carcinogenesis
Breast
Research Design

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Vonderheide, R. H., Domchek, S. M., Schultze, J. L., George, D. J., Hoar, K. M., Chen, D. Y., ... Nadler, L. M. (2004). Vaccination of Cancer Patients Against Telomerase Induces Functional Antitumor CD8+ T Lymphocytes. Clinical Cancer Research, 10(3), 828-839. https://doi.org/10.1158/1078-0432.CCR-0620-3

Vaccination of Cancer Patients Against Telomerase Induces Functional Antitumor CD8+ T Lymphocytes. / Vonderheide, Robert H.; Domchek, Susan M.; Schultze, Joachim L.; George, Daniel J.; Hoar, Kara M.; Chen, Dih Yih; Stephans, Katherine F.; Masutomi, Kenkichi; Loda, Massimo; Xia, Zhinan; Anderson, Karen; Hahn, William C.; Nadler, Lee M.

In: Clinical Cancer Research, Vol. 10, No. 3, 01.02.2004, p. 828-839.

Research output: Contribution to journalArticle

Vonderheide, RH, Domchek, SM, Schultze, JL, George, DJ, Hoar, KM, Chen, DY, Stephans, KF, Masutomi, K, Loda, M, Xia, Z, Anderson, K, Hahn, WC & Nadler, LM 2004, 'Vaccination of Cancer Patients Against Telomerase Induces Functional Antitumor CD8+ T Lymphocytes', Clinical Cancer Research, vol. 10, no. 3, pp. 828-839. https://doi.org/10.1158/1078-0432.CCR-0620-3
Vonderheide, Robert H. ; Domchek, Susan M. ; Schultze, Joachim L. ; George, Daniel J. ; Hoar, Kara M. ; Chen, Dih Yih ; Stephans, Katherine F. ; Masutomi, Kenkichi ; Loda, Massimo ; Xia, Zhinan ; Anderson, Karen ; Hahn, William C. ; Nadler, Lee M. / Vaccination of Cancer Patients Against Telomerase Induces Functional Antitumor CD8+ T Lymphocytes. In: Clinical Cancer Research. 2004 ; Vol. 10, No. 3. pp. 828-839.
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AU - Domchek, Susan M.

AU - Schultze, Joachim L.

AU - George, Daniel J.

AU - Hoar, Kara M.

AU - Chen, Dih Yih

AU - Stephans, Katherine F.

AU - Masutomi, Kenkichi

AU - Loda, Massimo

AU - Xia, Zhinan

AU - Anderson, Karen

AU - Hahn, William C.

AU - Nadler, Lee M.

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N2 - Purpose: High-level expression of the telomerase reverse transcriptase (hTERT) in >85% of human cancers, in contrast with its restricted expression in normal adult tissues, points to hTERT as a broadly applicable molecular target for anticancer immunotherapy. CTLs recognize peptides derived from hTERT and kill hTERT+ tumor cells of multiple histologies in vitro. Moreover, because survival of hTERT+ tumor cells requires functionally active telomerase, hTERT mutation or loss as a means of escape may be incompatible with sustained tumor growth. Experimental Design: A Phase I clinical trial was performed to evaluate the clinical and immunological impact of vaccinating advanced cancer patients with the HLA-A2-restricted hTERT I540 peptide presented with keyhole limpet hemocyanin by ex vivo generated autologous dendritic cells. Results: As measured by peptide/MHC tetramer, enzyme-linked immunospot, and cytotoxicity assays, hTERT-specific T lymphocytes were induced in 4 of 7 patients with advanced breast or prostate carcinoma after vaccination with dendritic cells pulsed with hTERT peptide. Tetramer-guided high-speed sorting and polyclonal expansion achieved highly enriched populations of hTERT-specific cells that killed tumor cells in an MHC- restricted fashion. Despite concerns of telomerase activity in rare normal cells, no significant toxicity was observed. Partial tumor regression in 1 patient was associated with the induction of CD8+ tumor infiltrating lymphocytes. Conclusions: These results demonstrate the immunological feasibility of vaccinating patients against telomerase and provide rationale for targeting self-antigens with critical roles in oncogenesis.

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