Human Telomerase Reverse Transcriptase-Transduced Human Cytotoxic T Cells Suppress the Growth of Human Melanoma in Immunodeficient Mice

Verra, Natascha; Jorritsma, Annelies; Weijer, Kees; Ruizendaal, Janneke J.; Voordouw, A. C.; Weder, Pauline; Hooijberg, Erik; Schumacher, Ton N.; Haanen, John B.A.G.; Spits, Hergen; Luiten, Rosalie M.

doi:10.1158/0008-5472.can-03-1339

Cited by 42 publications

(42 citation statements)

References 35 publications

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“…It is likely that many previous clinical adoptive immunotherapy trials have been unsuccessful because the prolonged ex vivo culture process resulted in a population of cells that had reached replicative senescence. Consistent with this 40 a strategy that may increase the efficacy of adoptive transfer approaches.…”

Section: Homeostatic Lymphocyte Proliferation and Memorymentioning

confidence: 68%

“…Novel approaches to use genetic engineering may enhance the survival of adoptively transferred T cells. 40,58 Presently, genetic marking is the only technique that can be used in clinical studies to determine engraftment and survival parameters of adoptively transferred T cells. However, combinations of new approaches using complementarity region (CDR3) size spectratyping and high-resolution magnetic imaging using T cells labeled with physiologically inert nanoparticles should enable studies of adoptively transferred T cells in the absence of genetic marking.…”

Section: Engraftmentmentioning

confidence: 99%

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T-cell reconstitution and expansion after hematopoietic stem cell transplantation: ‘T’ it up!

Porter

June

2005

Bone Marrow Transplant

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Summary:Adoptive immunotherapy is the isolation and infusion of antigen-specific or nonspecific lymphocytes. Adoptive therapy with T cells may have a role in replacing, repairing, or enhancing immune function damaged by cytotoxic therapies, and rapid lymphocyte recovery may improve outcome after autologous and allogeneic stem cell transplantation (SCT). Recently, a plethora of information on the basic mechanisms of T-cell biology and regulation of cellular immune responses has emerged, permitting the development of new forms of adoptive cell therapy. Efficient ex vivo culture method for T-cell subsets affords the possibility of adoptive transfer of T cells engineered with enhanced capacity for central memory, effector cytotoxicity, Th1, Th2, veto cell, and T regulatory functions. Studies show that homeostatic Tcell proliferation is important for effective adoptive immunotherapy and pretreatment with chemotherapy may enhance the effects of infused T cells. Replicative senescence, in part due to telomere erosion, likely limits successful adoptive immunotherapy, though it may be possible to maintain T-cell pools by enforced expression of telomerase. Clinical trials now demonstrate that it is possible to enhance immune reconstitution after SCT with cytokines or infusions of ex vivo costimulated expanded T cells. These data all support the premise that adoptive therapy can accelerate reconstitution of cellular immunity with enhanced antitumor effects following SCT. Bone Marrow Transplantation (2005) 35, 935-942.

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Section: Homeostatic Lymphocyte Proliferation and Memorymentioning

confidence: 68%

Section: Engraftmentmentioning

confidence: 99%

T-cell reconstitution and expansion after hematopoietic stem cell transplantation: ‘T’ it up!

Porter

June

2005

Bone Marrow Transplant

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“…Allophycocyanin (APC)-labeled HLA-A2.1 tetramers (T A2) presenting the HPV16 E7 [11][12][13][14][15][16][17][18][19][20] and influenza A virus MP 58-66 epitopes were prepared in house as described previously. 27 Tetramer and/or antibody staining of cells was performed in fluorescence-activated cell sorting (FACS) buffer (phosphate-buffered saline [PBS] supplemented with 0.1% bovine serum albumin [BSA] and 0.01% azide) for 15 minutes at 37°C and/or 20 minutes on ice, followed by washing with FACS buffer.…”

Section: Antibodies Tetramers and Flow Cytometrymentioning

confidence: 99%

“…10 The HPV16 E7 [11][12][13][14][15][16][17][18][19][20] -specific human CTL clone A9 was obtained as described previously in detail. 11 CTLs were maintained in vitro in Yssel medium 25 supplemented with 1% human serum (HS; Perbio, Helsingborg, Sweden) and antibiotics (penicillin/streptomycin; Gibco, Paisley, Scotland) in 24-well plates (Nunc, Intermed, Denmark).…”

Section: Ctl Culture and Htert Transductionmentioning

confidence: 99%

“…17 Moreover, a recent in vivo study in immunodeficient mice has reported the safe and effective use of hTERTtransduced human CTLs for immunotherapy of melanoma. 20 These results have raised enthusiasm for clinical evaluation of adoptive immunotherapy using hTERT-transduced T lymphocytes. However, constitutive expression of hTERT has been observed in greater than 85% of human tumor cells of various histologic origins to maintain their replicative potential.…”

mentioning

confidence: 99%

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Genomic stability and functional activity may be lost in telomerase-transduced human CD8+ T lymphocytes

Schreurs¹,

Hermsen²,

Geltink³

et al. 2005

Blood

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To obtain the large amount of T cells required for adoptive immunotherapy in a clinical setting, T-cell lifespan extension by human telomerase reverse transcriptase (hTERT) transduction is of particular interest. However, constitutive expression of hTERT is associated with malignant transformation and thus warrants a detailed evaluation of the safety of hTERTtransduced T cells before clinical application. In view of this, we performed an extensive cytogenetic analysis of hTERTtransduced MART-1 (melanoma antigen recognized by T cell 1)-and human papillomavirus type 16 (HPV16) E7-specific human CD8 ؉ cytotoxic T lymphocytes (CTLs), reactive against melanoma and cervical carcinoma, respectively. Our results, obtained by (spectral) karyotyping and array comparative genomic hybridization, showed the development of minor chromosomal aberrations in an hTERTtransduced MART-1-specific CTL clone, whereas severe clonal aberrations were detected in an hTERT-transduced HPV16 E7-specific CTL clone. Furthermore, hTERT transduction did not protect CTLs from immunosenescence, because the HPV16 E7-specific, hTERT-transduced CTL clone showed a decreased functional activity on prolonged culture. Although the general frequency of major chromosomal aberrations in hTERTtransduced CTLs and the in vivo significance of our observations remain still unclear at this point, the currently available data suggest that clinical application of hTERT-transduced CTLs should pro- IntroductionAdoptive immunotherapy using tumor-reactive T lymphocytes represents an alternative strategy to treat malignant disease. In different animal models, adoptive transfer of specific cytotoxic T lymphocytes (CTLs) has resulted in the eradication of established tumors. [1][2][3][4] Also in patients with melanoma, adoptive CTL therapy has resulted in objective tumor regressions 5,6 and thus holds promise as a treatment modality against malignant disease in a clinical setting. 7 Given the poor immunogenicity of most tumor cells, the in vitro selection prior to adoptive transfer of high-avidity tumor reactive CTL clones could further improve the efficacy of in vivo tumor rejection. 8,9 However, the expansion for therapeutic purposes of CTL clones with considerable in vitro replicative history can be severely hampered by replicative senescence. 10,11 It has become clear that the catalytic subunit of the human telomerase complex, human telomerase reverse transcriptase (hTERT), can efficiently reverse replicative senescence (reviewed in Ducrest et al 12 ). The ability of hTERT to elongate and stabilize telomeric ends can be exploited to restore the replicative potential of presenescent cells. Ectopic expression of hTERT has successfully mediated the in vitro lifespan extension of various human cell types, including fibroblasts, endothelial cells, muscle cells, and neuronal cells. [13][14][15][16] Additionally, hTERT transduction of human T lymphocytes has resulted in restoration of their replicative potential in vitro. This has allowed the successful lifespan extension o...

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Immortalization of Human and Rhesus Macaque Primary Antigen‐Specific T Cells by Retrovirally Transduced Telomerase Reverse Transcriptase

Barsov

2011

CP in Immunology

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Human and rhesus macaque primary antigen-specific T cells derived from infected or immunized individuals or animals are a valuable material with which to study cellular immune responses against pathogens and tumors. Antigen-specific T cells can be expanded in vitro but have a finite proliferative life span. After a limited period in culture, primary T cells undergo replicative senescence and stop dividing. This restricts their applicability to short term experiments and complicates their use in adoptive immunotherapy. The proliferative life span of primary human and rhesus macaque T cells can be considerably extended by ectopically expressed human telomerase reverse transcriptase (TERT). Antigen-specific T cells transduced with TERT-expressing retroviral vectors can proliferate and expand in culture for long periods of time while maintaining their primary T cell characteristics including antigen-specific responses. Thus, TERT-immortalized T cells are an important and valuable resource for studying T cell immune responses and, potentially, for adoptive immunotherapy.

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Human Telomerase Reverse Transcriptase-Transduced Human Cytotoxic T Cells Suppress the Growth of Human Melanoma in Immunodeficient Mice

Abstract: ABSTRACT

Cited by 42 publications

References 35 publications

T-cell reconstitution and expansion after hematopoietic stem cell transplantation: ‘T’ it up!

T-cell reconstitution and expansion after hematopoietic stem cell transplantation: ‘T’ it up!

Genomic stability and functional activity may be lost in telomerase-transduced human CD8+ T lymphocytes

Immortalization of Human and Rhesus Macaque Primary Antigen‐Specific T Cells by Retrovirally Transduced Telomerase Reverse Transcriptase

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