Telomerase vaccination has no detectable effect on SCID-repopulating and colony-forming activities in the bone marrow of cancer patients

Danet-Desnoyers, Gwenn-ael; Luongo, Jennifer L.; Bonnet, Dominique; Domchek, Susan M.; Vonderheide, Robert H.

doi:10.1016/j.exphem.2005.07.011

Cited by 40 publications

(24 citation statements)

References 21 publications

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“…There was no significant decline in the frequency of granulocyte, macrophage or erythroid CFU in bone marrow from patients receiving the vaccine. In nonobese diabetic/severe combined immunodeficient mouse repopulation assays, human haematopoietic reconstitution was easily detected, without quantitative or qualitative differences between pre-and post-vaccine samples (Danet-Desnoyers et al, 2005).…”

Section: Telomerase and Cancer Stem Cellsmentioning

confidence: 99%

Telomerase and its potential for therapeutic intervention

Phatak

Burger

2007

British J Pharmacology

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Telomerase and telomeres are attractive targets for anticancer therapy. This is supported by the fact that the majority of human cancers express the enzyme telomerase which is essential to maintain their telomere length and thus, to ensure indefinite cell proliferation -a hallmark of cancer. Tumours have relatively shorter telomeres compared to normal cell types, opening the possibility that human cancers may be considerably more susceptible to killing by agents that inhibit telomere replication than normal cells. Advances in the understanding of the regulation of telomerase activity and the telomere structure, as well as the identification of telomerase and telomere associated binding proteins have opened new avenues for therapeutic intervention. Here, we review telomere and telomerase biology and the various approaches which have been developed to inhibit the telomere/telomerase complex over the past decade. They include inhibitors of the enzyme catalytic subunit and RNA component, agents that target telomeres, telomerase vaccines and drugs targeting binding proteins. The emerging role of telomerase in cancer stem cells and the implications for cancer therapy are also discussed.

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Section: Telomerase and Cancer Stem Cellsmentioning

confidence: 99%

Telomerase and its potential for therapeutic intervention

Phatak

Burger

2007

British J Pharmacology

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“…48 These recent data support other cumulative observations in animal models and in humans concerning the safety of telomerase-based immunotherapy. 9,33,49,50 However, future investigations should be conducted to address whether the duration of telomerase inhibition by active immunotherapy can affect normal tissues.In conclusion, vaccination with recombinant lv-hTERT is highly effective to break tolerance against hTERT and elicits antitumor CD8 ϩ T-cell immunity in HHD mice. Delivery of hTERT using lentivector may represent a potential approach to improve telomerase-based active immunotherapy.…”

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confidence: 99%

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confidence: 99%

Targeting human telomerase reverse transcriptase with recombinant lentivector is highly effective to stimulate antitumor CD8 T-cell immunity in vivo

Adotévi

Mollier

Neuveut

et al. 2010

Blood

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The success of active immunotherapy is based on the vaccine's ability to overcome immune tolerance through recalibrating the immune system so that it is able to recognize tumor antigens as foreign rather than self. In this study, we used a lentiviral vector system to target human telomerase reverse transcriptase (lv-hTERT), a widely expressed tumor antigen. Immunization of HLA-A*0201 transgenic HHD mice with recombinant lvhTERT vector induces potent and diversified cytotoxic T lymphocyte responses that recognize in vitro murine tumor cells, which overexpress telomerase. Compared with peptide-based vaccinations, the lv-hTERT vector triggers better and more sustained CD8 ؉ T-cell response against self/TERT epitope in vivo. The study found that the additional use of a heterologous boosted vaccination drastically improves self/TERT-specific CD8 responses in lv-hTERT primed mice. Both primary and long-lasting self/TERT-specific IntroductionThe stimulation of tumor-specific T-cell responses with active immunotherapy has several theoretical advantages over other forms of cancer treatment. 1,2 However, heterogeneous expression of most of the characterized tumor antigens limits the broad applicability of cancer vaccines that target such antigens. During the past few years, telomerase (TERT) has emerged as the first bona fide common tumor antigen and is actively investigated as the target for cancer immunotherapy. 3,4 Human telomerase reverse transcriptase (hTERT) is the catalytic subunit of telomerase enzyme that synthesizes telomeric DNA at the chromosome ends. 5,6 hTERT is overexpressed in most human tumors (Ͼ 85%) and virtually all types of cancer. 7 Telomerase activation has become one of the most important tumor escape mechanisms to circumvent the telomere-dependent pathways of cell death. 8,9 It is well established that therapeutic strategies targeting antigens not involved in tumor growth can result in the selection of antigen-loss tumor mutants that are clinically progressive. 10,11 Hence, down-regulation or loss of telomerase activity will severely inflict the growth potential of the tumor cells. All these findings justify the clinical applications of hTERT for anticancer immunotherapy. Broadly used in several anticancer vaccine trials, peptide vaccination is the most advanced strategy concerning hTERT antigen. 3,[12][13][14][15][16] Although the potential of a vaccination with minimal hTERT-derived peptides exceeds other vaccine strategies, several factors could influence the optimal success of this peptide-based strategy, such as (1) human leukocyte antigen (HLA) restriction, (2) natural processing of peptide on tumor cells, (3) antigen loss on tumors, (4) functionality of the antigen-specific T cells, and (5) persistence of the immune response in the host. 1 One main obstacle of active anticancer immunotherapy is its inability to overcome immune tolerance. hTERT, like most tumor antigens, is a self-antigen; the induction of T-cell immunity against such shared self/tumor antigen could be controlled by mechani...

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“…Importantly, no signs of autoimmunity have been described in connection with the introduction of immune responses against hTERT. In this regard, hTERT-specific CTLs are not lysing either telomerase-positive CD34 + hematopoietic progenitor cells or activated T-lymphocytes in vitro (Vonderheide et al, 1999;Minev et al, 2000;Danet-Desnoyers et al, 2005).…”

Section: Discussionmentioning

confidence: 99%