UMLS:C0001486 - FACTA Search

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Query: UMLS:C0001486 (Adenovirus)
3,125 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Despite encouraging preclinical studies in many tumor types including head and neck squamous cell carcinoma (HNSCC), initial clinical trials with adenovirus-mediated gene therapy have been disappointing. Although the adenovirus is a "highly efficient vector," it is still limited by the extent of effective in vivo transduction. In our studies with multiple human HNSCC cell lines, we have noted a variation in both in vitro and in vivo responses to the same recombinant adenovirus therapeutic construct. We hypothesize that adenovirus receptor density among tumor cell populations, even of the same histology, greatly influences transduction efficiency and therapeutic results of a variety of adenovirus-based gene therapy strategies. To investigate this hypothesis, the numbers of adenovirus receptors on three well-characterized HNSCC cell lines were determined. Marker and cytokine gene transfer efficiencies as well as therapeutic outcomes after adenovirus-mediated tumor suppressor gene and suicide gene therapies were evaluated and correlated with receptor status. A 5-fold variation in adenovirus receptor density was identified among the HNSCC cell lines (P < 0.002, t test). This variation directly correlated with adenovirus type 5 (Ad5)-mediated green fluorescent protein marker gene and Ad5-interleukin 2 cytokine gene transfer efficiency and resulting protein expression in each individual cell line. The receptor density also directly correlated with therapeutic response after Ad5-thymidine kinase or Ad5-p16 gene transfer in each HNSCC line. The role of the adenovirus receptor in gene transfer efficiency was further supported by recombinant Ad5 fiber knob blocking experiments. The marker gene transfer was increasingly blocked by the same concentration of Ad5 recombinant fiber knob in relation to decreasing levels of adenovirus receptor in the HNSCC lines. An Ad5 recombinant construct that carries the shared coxsackie and adenovirus receptor (CAR) was created and used to up-regulate receptors on each cell line. Ad5-CAR infection significantly increased Ad5-beta-Gal gene transfer efficiency and expression (P = 0.0003, Mann-Whitney test). This increased marker gene expression remained consistent with the established pattern of gene transfer efficiency among the HNSCC cell lines. These data confirm the importance of the adenovirus receptor on individual tumor cell lines with respect to investigating novel adenovirus-mediated gene therapy strategies. This work further supports consideration of assaying adenovirus receptor status, even in tumors of the same histology from patients enrolled in gene therapy clinical trials. Adenovirus receptor status may prove valuable for selecting or stratifying patients as well as assessing outcomes among patients within adenovirus-based cancer gene therapy trials.
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PMID:Variability of adenovirus receptor density influences gene transfer efficiency and therapeutic response in head and neck cancer. 1063 57

Adenoviruses are currently used in a variety of bench and bedside applications. However, their employment in gene delivery to lymphocyte lineages is hampered by the lack of coxsackie virus and adenovirus receptor (CAR) on the cell surface. Exploitation of an alternative receptor on the surface of T lymphocytes can allow for utilization of adenovirus in a variety of T lymphocyte-based diseases and therapies. Here, we describe how resistance to infection can be overcome by the utilization of a bi-specific fusion protein, soluble CAR murine interleukin 2 (sCAR-mIL-2), that retargets adenovirus to the murine IL-2 receptor (IL-2R). Infection of a murine T-cell line, CTLL-2, with a sCAR-mIL-2/Adenovirus conjugate provided a ninefold increase in both green fluorescence protein-positive cells and luciferase expression. In addition, this increase in infection was also seen in isolated primary murine T lymphocytes. In this context, the sCAR-mIL-2 adapter provided a fourfold gene transduction increase in activated primary murine T lymphocytes. Our results show that recombinant sCAR-mIL-2 fusion protein promotes IL-2R-targeted gene transfer to murine T lymphocytes and that alternative targeting can abrogate their native resistance to infection.
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PMID:Augmented adenovirus transduction of murine T lymphocytes utilizing a bi-specific protein targeting murine interleukin 2 receptor. 2590 93

Adenovirus (Ad)-based immunization is a popular approach in vaccine development, and Ad-based vectors are renowned for their potential to induce strong CD8⁺ T cell responses to the encoded transgene. Surprisingly, we previously found in the mouse Friend retrovirus (FV) model that Ad-based immunization did not induce CD8⁺ T cell responses to the FV Leader-Gag-derived immunodominant epitope GagL_85-93 We show now that induction of GagL_85-93-specific CD8⁺ T cells was highly effective when leader-Gag was delivered by plasmid DNA immunization, implying a role for Ad-derived epitopes in mediating unresponsiveness. By immunizing with DNA constructs encoding strings of GagL_85-93 and the two Ad-derived epitopes DNA-binding protein_418-426 (DBP_418-426) and hexon_486-494, we confirmed that Ad epitopes prevent induction of GagL_85-93-specific CD8⁺ T cells. Interestingly, while DBP_418-426 did not interfere with GagL_85-93-specific CD8⁺ T cell induction, the H-2D^d-restricted hexon_486-494 suppressed the CD8⁺ T cell response to the H-2D^b-restricted GagL_85-93 strongly in H-2^b/d mice but not in H-2^b/b mice. This finding indicates that competition occurs at the level of responding CD8⁺ T cells, and we could indeed demonstrate that coimmunization with an interleukin 2 (IL-2)-encoding plasmid restored GagL_85-93-specific CD8⁺ T cell responses to epitope strings in the presence of hexon_486-494 IL-2 codelivery did not restore GagL_85-93 responsiveness in Ad-based immunization, however, likely due to the presence of further epitopes in the Ad vector. Our findings show that seemingly immunodominant transgene epitopes can be dominated by Ad-derived epitopes. These findings underline the importance of thorough characterization of vaccine vectors, and modifications of vectors or immunogens may be required to prevent impaired transgene-specific immune responses.IMPORTANCE Ad-based vectors are widely used in experimental preclinical and clinical immunization studies against numerous infectious agents, such as human immunodeficiency virus, Ebola virus, Plasmodium falciparum, or Mycobacterium tuberculosis Preexisting immunity to Ad-based vectors is widely recognized as a hindrance to the widespread use of Ad-based vectors for immunizations in humans; however, our data show that an immune response to Ad-derived T cell epitopes can also result in loss or impairment of transgene-specific immune responses in prenaive vaccinees due to immune competition. Our results highlight that seemingly immunodominant epitopes may be affected by dominance of vector-derived epitopes, and modifications of the vector design or the immunogens employed in immunization may lead to more effective vaccines.
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PMID:Immunodominance of Adenovirus-Derived CD8⁺ T Cell Epitopes Interferes with the Induction of Transgene-Specific Immunity in Adenovirus-Based Immunization. 2876 77