Gene electro‐transfer improves transduction by modifying the fate of intramuscular DNA

Cappelletti, Manuela; Zampaglione, Immacolata; Rizzuto, Gabriella; Ciliberto, Gennaro; Monica, Nicola La; Fattori, Elena

doi:10.1002/jgm.352

Cited by 68 publications

(62 citation statements)

References 36 publications

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“…Delivery of antigens by DNA injection allows access to multiple antigen-presenting pathways. Moreover, increased expression of the antigen and enhanced immunogenicity can be achieved by physical methods, including in vivo electroporation (7,8), and molecular modifications, such as the use of codon-optimized sequences and the fusion of the target antigen to microbial-derived proteins (9,10). DNA vaccines are safe and easy to produce; moreover, they can be used repeatedly for longterm maintenance of antitumor CMI.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2008

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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]

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Section: Introductionmentioning

confidence: 99%

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

et al. 2008

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“…26 The 3 hTERT immunogenic regions that were found corresponded to epitopes already described (supplemental Figure 3A-C). 25,27,28 T cells specific for the 2 epitopes hTERT 865-872 and hTERT [30][31][32][33][34][35][36][37][38] , showing the strongest reactivity ex vivo (supplemental Figure 3D), were further enriched from splenocytes through repeated peptide stimulations.…”

Section: B-cell Reduction Induced By Tert Ctls Is Transientmentioning

confidence: 56%

“…CTLs specific for both TERT and ␤-gal antigen were maintained by culture with ␥-irradiated syngenic splenocytes pulsed with either 0.1M TERT or 1M ␤-gal 96-103 (DAPIYTNV) peptides. Gp100 [25][26][27][28][29][30][31][32][33] CTLs derived from Pmel-1 splenocytes were stimulated once with 1M specific hgp100 [25][26][27][28][29][30][31][32][33] (KVPRN-QDWL) peptide. Cultures were grown for 7 days in complete medium containing 20 IU/mL of recombinant human IL-2 (Novartis).…”

Section: In Vitro Leukocyte Culturesmentioning

confidence: 99%

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

Ugel

Scarselli

Iezzi

et al. 2010

Blood

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IntroductionAttempts to treat experimental tumors with adoptive T lymphocyte transfer started in 1960, soon after the demonstration that the cellular arm of the immune system was responsible for tissue rejection. 1 The translation of this approach to the clinic, however, became possible when human tumor-infiltrating lymphocytes (TILs) could be expanded in vitro and injected back into cancer patients. 2 Only recently, however, an objective cancer regression was achieved in approximately 50% of patients with metastatic tumor after the introduction of host preconditioning by lymphodepletion before the treatment, followed by high-dose interleukin-2 (IL-2) to sustain in vivo expansion of T cells. 3,4 So far, this approach has been limited to melanoma patients, from whom TILs of known specificity are easily cultured in vitro, whereas for tumors other than melanoma the rescue of TILs is problematic.Telomerase is considered an attractive target as universal antigen for the immunotherapy of cancer. Telomerase reverse transcriptase (TERT) is the protein component of the telomerase complex responsible for elongation of telomeres and plays an essential role in sustaining cancerous cell proliferation. 5 TERT is silent in most human somatic tissues but reactivated in 85% of tumors. Active immunization against telomerase and cancer vaccination clinical trials have been attempted that demonstrate little toxicity, but results concerning therapeutic efficacy are not conclusive. 6,7 Although T lymphocytes against telomerase were isolated and extensively characterized in vitro, 8,9 the use of adoptive cell therapy (ACT) with telomerase-specific lymphocytes has never been investigated. To evaluate therapeutic efficacy and determine the potential immunopathology associated with TERT-based ACT, we generated and analyzed the activity of TERT-specific CD8 ϩ T cells. Methods Mice and cell linesC57BL/6 mice were from Charles River Laboratories Inc. Transgenic adenocarcinoma mouse prostate (TRAMP) mice, a gift from N. M. Greenberg (Fred Hutchinson Cancer Research Center), were maintained in the mouse facility of Istituto Oncologico Veneto. Heterozygous TRAMP used in the experiments were obtained and screened as described. 10 C57BL/6-CD45.1 ϩ mice were a gift from M. P. Colombo (National Institutes of Tumors), pmel-1 TCR transgenic mice were a gift from N. Restifo (National Institutes of Health), and human leukocyte antigen (HLA)-A*0201-transgenic (HHD) mice were obtained by F. A. Lemonnier (Institut Pasteur) and maintained at Istituto di Ricerca di Biologia Molecolare. Rag2 Ϫ/Ϫ ␥ c Ϫ/Ϫ were purchased form Taconic. Mice were treated in accordance with European guidelines (http://ec.europa.eu/environment/chemicals/ lab_animals/legislation_en.htm). B16 melanoma cells were provided by N. Restifo (NIH). B16-B7.1 cells, genetically modified to express mouse B7.1 (provided by P. Della Bona, Istituto Scientifico San Raffaele) were cultured in the An Inside Blood analysis of this article appears at the front of this issue.The online version of thi...

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“…In experiments with tumors, mice were ear tagged, randomized after treatment, and tumor growth was monitored 3 times a week with a caliper by an investigator blinded to the treatment. Mice were euthanized when the tumor size index (the product of 2 perpendicular diameters) was bigger than 100 mm 2 . Vaccination with the DNA-nanoparticle complexes was carried out by subcutaneous injection of 200 mL of DNA-nanoparticle complexes at an N:P ratio ¼ 10:1 in Opti-MEM (Invitrogen).…”

Section: Mice and Vaccinationmentioning

confidence: 99%

“…The use of naked plasmid DNA as a vaccine to prime the immune system provides a variety of practical benefits for large-scale production that are not as easily achievable with other forms of vaccines including recombinant proteins or whole tumor cells (1)(2)(3)(4). While numerous clinical trials have proven the safety of this cost effective vaccination strategy, they have also revealed its limitations, as the immune response elicited is insufficient to clear established tumors or infections.…”

Section: Introductionmentioning

confidence: 99%

Peptide-Conjugated PAMAM Dendrimer as a Universal DNA Vaccine Platform to Target Antigen-Presenting Cells

Daftarian

Kaifer

et al. 2011

Cancer Research

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DNA-based vaccines hold promise to outperform conventional antigen-based vaccines by virtue of many unique features. However, DNA vaccines have thus far fallen short of expectations, due in part to poor targeting of professional antigen-presenting cells (APC) and low immunogenicity. In this study, we describe a new platform for effective and selective delivery of DNA to APCs in vivo that offers intrinsic immuneenhancing characteristics. This platform is based on conjugation of fifth generation polyamidoamine (G5-PAMAM) dendrimers, a DNA-loading surface, with MHC class II-targeting peptides that can selectively deliver these dendrimers to APCs under conditions that enhance their immune stimulatory potency. DNA conjugated with this platform efficiently transfected murine and human APCs in vitro. Subcutaneous administration of DNA-peptide-dendrimer complexes in vivo preferentially transfected dendritic cells (DC) in the draining lymph nodes, promoted generation of high affinity T cells, and elicited rejection of established tumors. Taken together, our findings show how PAMAM dendrimer complexes can be used for high transfection efficiency and effective targeting of APCs in vivo, conferring properties essential to generate effective DNA vaccines. Cancer Res; 71(24); 7452-62. Ó2011 AACR.

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Gene electro‐transfer improves transduction by modifying the fate of intramuscular DNA

Cited by 68 publications

References 36 publications

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

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

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

Peptide-Conjugated PAMAM Dendrimer as a Universal DNA Vaccine Platform to Target Antigen-Presenting Cells

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