Preventive Vaccination with Telomerase Controls Tumor Growth in Genetically Engineered and Carcinogen-Induced Mouse Models of Cancer

Abstract

The telomerase reverse transcriptase, TERT, is an attractive target for human cancer vaccination because its expression is reactivated in a conspicuous fraction of human tumors. Genetic vaccination with murine telomerase (mTERT) could break immune tolerance in different mouse strains and resulted in the induction of both CD4 + and CD8 + telomerasespecific T cells. The mTERT-derived immunodominant epitopes recognized by CD8 + T cells were further defined in these mouse strains and used to track immune responses. Antitumor efficacy of telomerase-based vaccination was investigated in two cancer models closely resembling human diseases: the TRAMP transgenic mice for prostate cancer and a carcinogen-induced model for colon cancer. TERT overexpression in tumor lesions was shown in both models by immunohistochemistry, thus reinforcing the similarity of these tumors to their human counterparts. Repeated immunizations with mTERT-encoding DNA resulted in a significant delay of tumor formation and progression in both the prostate cancer and the colon cancer models. Moreover, evaluation of the intratumoral infiltrate revealed the presence of telomerase-specific T cells in vaccinated mice. The safety of vaccination was confirmed by the absence of histomorphologic changes on postnecropsy analysis of several organs and lack of adverse effects on blood cell counts. These results indicate that TERT vaccination can elicit antigen-specific immunosurveillance and imply this antigen as a potential candidate for preventive cancer vaccines. [Cancer Res 2008; 68(23):9865-74]

Autoimmune B-cell lymphopenia after successful adoptive therapy with telomerase-specific T lymphocytes

“…We recently described that DNA-based vaccination in TRAMP mice prevented the progression to adenocarcinoma but had no effect on the incidence of PDC and a modest influence on the overall survival. 14 On the contrary, we describe here, for the first time, that ACT with anti-TERT CTLs has a dramatic effect on both PDC appearance and mouse survival (Figure 4). This finding is relevant for human pathology.…”

“…The low-avidity CTL could only recognize target cells engineered to express the costimulatory molecule B7.1 on cell surface, as previously shown for other low-avidity CTLs. 14,17 Comparable results were obtained by the use of IFN-␥ release assay to assess the recognition patterns (data not shown). These results were also confirmed in vivo in a metastatic B16 melanoma model ( Figure 1D).…”

“…The immunogenic regions were experimentally identified by peptide deconvolution, as described. [14][15][16] Cytotoxicity was measured by 51 Cr release assay as described. 11 T-and B-cell blasts were obtained stimulating 25 ϫ 10 6 splenocytes in complete medium containing either 5 g/mL Concavallin A (ConA; SigmaAldrich) or 10 g/mL lipopolysaccharide (LPS; Sigma-Aldrich) for 5 days.…”

“…10 We previously demonstrated that mTERT is overexpressed in transformed prostates. 14 Because the TRAMP model is characterized by the continuous formation of new cancerous lesions, ACT was repeated 3 times at 8, 13, and 18 weeks of age. Nonmyeloablative irradiation regimen was performed before each ACT.…”

Harnessing the Immune System to Fight Cancer: The Promise of Genetic Cancer Vaccines

“…We believe this discrepancy is due to the fact that in the first case the anti-HER2 vaccine acts primarily through the induction of antitumoural antibody responses that are strongly enhanced by systemic IMO in mice . In contrast, the telomerase vaccine mechanism of action is exerted via the induction of antigen-specific cytotoxic CD8 + responses (Mennuni et al, 2008) which are not increased by systemic IMO delivery. Among the most promising approaches to combinations is the one with agents capable to target Tregs (Golovina and Vonderheide, 2010).…”