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 S. Anderson, William C. Hahn, Lee M. Nadler

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219 Scopus citations

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

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Vonderheide, R. H., Domchek, S. M., Schultze, J. L., George, D. J., Hoar, K. M., Chen, D. Y., Stephans, K. F., Masutomi, K., Loda, M., Xia, Z., Anderson, K. S., Hahn, W. C., & 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