Telomerase-based immunotherapy of cancer


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Robert Vonderheide

University of Pennsylvania, Philadelphia, USA

Abstract

Telomerase-based immunotherapy of cancer

T cell immunotherapy relies on the fundamental concept that tumour antigens exist and are presented in the context of MHC molecules for recognition by specific T cells capable of cytolysis. However, heterogeneous expression of most characterized tumour antigens limits the broad applicability of cancer vaccines that target such antigens. Telomerase, on the other hand, represents a prototype of a universal tumour antigen due to both its expression by the vast majority of tumours as well as its functional involvement in oncogenic transformation. Given these attractive features, identification of epitopes within hTERT, the human telomerase reverse transcriptase, has led to the investigation of this tumour antigen as a broadly applicable immunological target. Basic immunological analyses have revealed that hTERT is immunogenic, and initial clinical trials of multiple vaccine formulations have demonstrated that hTERT-specific immune responses can be safely induced in patients and impact clinical outcome. In a clinical trial recently completed at our institution, we induced hTERT-specific T cells in vivo via peptide vaccination in 19 patients with metastatic breast cancer who otherwise had no measurable T-cell responses to hTERT at baseline. Treatment was well tolerated. Tumour-infiltrating lymphocytes (TIL) were evident after, but not before vaccination, with 4% to 13% of postvaccine CD8+ TIL specific for the immunizing hTERT peptide. Induction of TIL manifested clinically with tumour site pain and pruritus and pathologically with alterations in the tumour microenvironment, featuring histiocytic accumulation and widespread tumour necrosis. hTERT-specific CD8+ T cells were also evident after vaccination in the peripheral blood of patients and exhibited multiple effector functions. Landmark analysis revealed that median overall survival was nearly twice as long in those patients who achieved an immune response to hTERT peptide compared with patients who did not. Second-generation vaccines are now addressing strategies to enhance cellular immunity against hTERT without toxicity. Findings obtained from these trials will inform the possibility of broad-spectrum cancer immunotherapy or even immunoprevention.

Declaration of competing interest: Dr. Vonderheide is an inventor on a patent that relates to hTERT as a tumour-associated antigen for cancer immunotherapy.