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Clinical Cancer Research Vol. 10, 828-839, February 2004
© 2004 American Association for Cancer Research

Clinical Trials

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

Robert H. Vonderheide3, Susan M. Domchek1,2, Joachim L. Schultze1,2, Daniel J. George1,2, Kara M. Hoar1, Dih-Yih Chen3, Katherine F. Stephans1, Kenkichi Masutomi1, Massimo Loda1, Zhinan Xia1, Karen S. Anderson1,2, William C. Hahn1,2 and Lee M. Nadler1,2

1 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts; 2 Department of Medicine, Brigham and Women’s Hospital, Harvard Medical, Boston, Massachusetts; and 3 Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania

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.




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Copyright © 2004 by the American Association for Cancer Research.