Developing dendritic cell polynucleotide vaccination for prostate cancer immunotherapy

Berlyn, Kathleen A.; Stass, Sanford A.; Malone, Jill G.; Hamlin-Green, Gina; Lim, Jong-Seok; Cottler‐Fox, Michele; Tricot, Guido; Alexander, Richard B.; Mann, Dean L.; Malone, Robert E.

doi:10.1016/s0168-1656(99)00118-2

Cited by 11 publications

(2 citation statements)

References 64 publications

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“…Genetic modification also promises longer antigen expression than protein or peptide pulsing methods (52). Multiple vectors have been evaluated for genetic modification of DCs in vitro, including polynucleotide transfection using plasmid DNA, mRNA or viral RNA (7,8,31), and viral transduction using recombinant retrovirus, Ad, vaccinia virus, poxvirus, AAV, and others (12,21,53,54,56). Despite reports from several studies on the potential utility of these vectors both in vitro and in vivo, it is unclear at this time if any of the currently tested vectors is superior for genetic modification of DCs.…”

Section: Discussionmentioning

confidence: 99%

Adeno-Associated Virus Type 2-Mediated Transduction of Human Monocyte-Derived Dendritic Cells: Implications for Ex Vivo Immunotherapy

Ponnazhagan

Mahendra²,

Curiel

et al. 2001

J Virol

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Dendritic cells (DCs) are pivotal antigen-presenting cells for regulating immune responses. A major focus of contemporary vaccine research is the genetic modification of DCs to express antigens or immunomodulatory molecules, utilizing a variety of viral and nonviral vectors, to induce antigen-specific immune responses that ameliorate disease states as diverse as malignancy, infection, autoimmunity, and allergy. The present study has evaluated adeno-associated virus (AAV) type 2 as a vector for ex vivo gene transfer to human peripheral blood monocyte (MO)-derived DCs. AAV is a nonpathogenic parvovirus that infects a wide variety of human cell lineages in vivo and in vitro, for long-term transgene expression without requirements for cell proliferation. The presented data demonstrate that recombinant AAV (rAAV) can efficiently transduce MOs as well as DCs generated by MO culture with granulocyte-macrophage colony-stimulating factor plus interleukin in vitro. rAAV transgene expression in MO-derived DCs could be enhanced by etoposide, previously reported to enhance AAV gene expression. rAAV transduction of freshly purified MO followed by 7 days of culture with cytokines to generate DCs, and subsequent sorting for coexpression of DC markers CD1a and CD40, showed robust transgene expression as well as evidence of nuclear localization of the rAAV genome in the DC population. Phenotypic analyses using multiple markers and functional assays of one-way allogeneic mixed leukocyte reactions indicated that rAAV-transduced MO-derived DCs were as equivalent to nontransduced DCs. These results support the utility of rAAV vectors for future human DC vaccine studies.Dendritic cells (DCs) are potent antigen-presenting cells (APC) for initiating T-cell immunity, due to their ability to take up and process antigens for presentation by major histocompatibility complex (MHC) class I and class II molecules, migrate to T-cell areas of lymphoid tissues, and present antigen in conjunction with the appropriate T-cell costimulatory molecules and cytokines (reviewed in references 3, 4, 44, and 51). DCs can be manipulated ex vivo to express antigens in order to generate effective vaccines for a variety of immunotherapy applications. In the simpler approaches, DCs are pulsed by incubation with purified proteins, microbial or tumor cell lysates, synthetic MHC-binding peptides, or crude peptides eluted from tumor cells, all of which have shown promising results, although the persistence of antigens on pulsed DCs is of relatively short duration (4, 44, 51). Alternatively, the transfer of genes encoding antigens into DCs offers the advantages of sustained antigen expression and a broader spectrum of MHC peptide epitopes presented by DCs and allows modulation of DC receptors and cytokine secretion to further finetune the immune response (3,4,44,51). Both nonviral and viralvector-mediated gene transfer have been used for DC-based immunotherapy in animal models and human clinical trials, with the majority of viral-mediated DC transductions employing r...

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Section: Discussionmentioning

confidence: 99%

Adeno-Associated Virus Type 2-Mediated Transduction of Human Monocyte-Derived Dendritic Cells: Implications for Ex Vivo Immunotherapy

Ponnazhagan

Mahendra²,

Curiel

et al. 2001

J Virol

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“…Thus, TAA-modified DCs through ex vivo or in vivo manipulation are attractive candidates for cancer immunotherapy. [38][39][40] In this report, we show that human monocytederived DCs express the RNA component (hTR) of the telomerase complex, but do not express the gene encoding for the catalytic subunit. Telomerase activity, however, can be reconstituted when DCs are transfected with hTERT plasmid DNA liposome complex or by AdhTERT transduction.…”

Section: G Eneration Of Antigen-specific Cytotoxic T-cell (Ctl)mentioning

confidence: 81%

Dendritic cells reconstituted with human telomerase gene induce potent cytotoxic T-cell response against different types of tumors

et al. 2003

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Human telomerase reverse transcriptase (hTERT) is the catalytic component of a functional telomerase complex, which is important in maintaining cell immortality. In most normal human adult cells, the expression of telomerase is very low and/or transient. In contrast, almost 90% of human tumors express a relatively high level of telomerase implying the possibility of using hTERT as a universal candidate tumor antigen. In this study, we show that human monocyte-derived dendritic cells (DCs) lack telomerase activity. Similar to other normal somatic cells, DCs express the RNA (hTR) component but not the catalytic component, hTERT. We also show that telomerase activity could be reconstituted using either lipid-mediated transfection of the hTERT plasmid DNA or transduction with an E1-, E3-deleted adenoviral vector containing the hTERT gene. However, relative to plasmid transfection, adenoviral gene transfer produced higher levels of hTERT expression. Nine of 10 AdhTERT-transduced DCs were able to generate CTL responses, while only three of nine plasmid-transfected DCs did. CTLs primed against hTERT exhibited killing of telomerase positive but not telomerase negative tumor lines of diverse tissue origins. Antigenic specificity of these T cells to telomerase was further determined by introducing hTERT gene into a telomerase negative cell line, U2OS, by adenoviral transduction. Although some antigenic specificity was directed against adenoviral epitopes, the majority of CTLs were targeted against telomerase-derived antigen(s). Thus, the hTERT gene, particularly as delivered via the recombinant adenovirus, may be useful as vaccine to induce specific T-cell-mediated tumor immunity in cancer patients. In addition, our results suggest that telomerase activity and/or telomerase expression after hTERT gene transfer have a predictive value in the success of hTERT/DC-based cancer vaccination.

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Generation of CD4+ and CD8+ T Lymphocyte Responses by Dendritic Cells Armed with PSA/Anti-PSA (Antigen/Antibody) Complexes

Berlyn

Schultes

Leveugle

et al. 2001

Clinical Immunology

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Developing dendritic cell polynucleotide vaccination for prostate cancer immunotherapy

Cited by 11 publications

References 64 publications

Adeno-Associated Virus Type 2-Mediated Transduction of Human Monocyte-Derived Dendritic Cells: Implications for Ex Vivo Immunotherapy

Adeno-Associated Virus Type 2-Mediated Transduction of Human Monocyte-Derived Dendritic Cells: Implications for Ex Vivo Immunotherapy

Dendritic cells reconstituted with human telomerase gene induce potent cytotoxic T-cell response against different types of tumors

Generation of CD4+ and CD8+ T Lymphocyte Responses by Dendritic Cells Armed with PSA/Anti-PSA (Antigen/Antibody) Complexes

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