Vaccination of cancer patients against telomerase induces functional antitumor CD8+ T lymphocytes

Clin Cancer Res. 2004 Feb 1;10(3):828-39. doi: 10.1158/1078-0432.ccr-0620-3.

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.

Publication types

  • Clinical Trial
  • Clinical Trial, Phase I
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Aged
  • Breast Neoplasms / immunology
  • CD8-Positive T-Lymphocytes / immunology*
  • Cancer Vaccines*
  • Cell Separation
  • DNA-Binding Proteins
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Flow Cytometry
  • HLA-A2 Antigen / metabolism
  • Hemocyanins / metabolism
  • Humans
  • Immunoenzyme Techniques
  • Major Histocompatibility Complex
  • Male
  • Middle Aged
  • Mutation
  • Neoplasms / immunology*
  • Neoplasms / prevention & control*
  • Peptides / chemistry
  • Phenotype
  • Prostatic Neoplasms / immunology
  • Telomerase / genetics
  • Telomerase / metabolism*
  • Vaccines

Substances

  • Cancer Vaccines
  • DNA-Binding Proteins
  • HLA-A2 Antigen
  • Peptides
  • Vaccines
  • Hemocyanins
  • Telomerase
  • keyhole-limpet hemocyanin