Regional, but not systemic recruitment/expansion of dendritic cells by a pluronic-formulated Flt3-ligand plasmid with vaccine adjuvant activity

Sang, Hongxun; Писарев, В. М.; Munger, Corey M.; Robinson, Simon N.; Chavez, Jennifer; Hatcher, Lori; Parajuli, Prahlad; Guo, Yajun; Talmadge, James E.

doi:10.1016/s0264-410x(03)00143-9

Cited by 25 publications

(19 citation statements)

References 40 publications

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“…18,19 The expansion of DCs is important because of their unique ability to efficiently internalize, process, and present Ags, as well as stimulate naı¨ve and memory T cells. 6,12,20 Adjuvant activity by Flt3L has been observed with plasmid Flt3L, [21][22][23][24][25][26][27] Flt3L protein, 18,19,[28][29][30][31][32][33][34] Flt3L-transfected tumor cells, [35][36][37][38] and vaccines composed of a plasmid linking an Ag and the receptor-binding domain of Flt3L. [39][40][41] Clinical studies using recombinant Flt3L have also shown adjuvant activity.…”

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confidence: 99%

Murine mammary adenocarcinoma cells transfected with p53 and/or Flt3L induce antitumor immune responses

et al. 2005

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Transfection of tumors with tumor-associated antigens (Ags) or cytokines can increase immunogenicity and slow down tumor growth. However, the effect of cotransfection with genes that encode a tumor-associated Ag, such as the tumor suppressor gene p53, and a cytokine has been rarely investigated. We report that transfection of 4T1 mammary tumor cells (p53-null) with the dendritic cell (DC) growth factor, fms-like tyrosine kinase 3 ligand (Flt3L), significantly delayed their growth in vivo, resulting in the rejection of 100% of the tumors formed by injection of tumor cells cotransfected with Flt3L and p53. Immunization with irradiated 4T1 cells transfected with Flt3L induced DC infiltration of the immunization site and significantly increased the antitumor T-cell responses. Further, immunization with irradiated 4T1 cells cotransfected with p53 and Flt3L significantly increased p53-specific immune responses, as compared to vaccination with 4T1 cells transfected with either Flt3L or p53 alone. These responses included increased activity against clone 66 (Cl-66), a sister tumor to 4T1 with high murine mutant p53 expression levels. Challenge with Cl-66 revealed that immunization with irradiated 4T1-Flt3L-p53 cells significantly slowed growth, prolonged survival, and resulted in complete remissions. Further, immunization with irradiated 4T1-Flt3L also slowed Cl-66 growth, although to a lesser extent than 4T1-Flt3L-p53. We suggest that immunization with DCs transfected with the Flt3L transgene and a tumor Ag may potentially heighten T-cell responses and therapeutic activity.

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confidence: 99%

Murine mammary adenocarcinoma cells transfected with p53 and/or Flt3L induce antitumor immune responses

et al. 2005

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“…Our previous reports showed that the mouse colon carcinoma cell line, when transfected with hu-FL gene in vitro became immunogenic and could be used for vaccine to prevent tumor cell challenge. 16 However, the FL gene in these experiments was of human origin and this makes the data hard to interpret because several human antigens, such as melanoma antigen p97, have been shown to increase their immunogenicity. 22 Rejection of transplanted tumors mediated by local injection of Ad-mFL is more effective than that induced by vaccination with tumor cells transfected with hu-FL or m-FL genes in vitro.…”

Section: Systemic Splenocytes Adoptive Therapymentioning

confidence: 98%

“…The findings are different from those obtained in similar experiments with a breast carcinoma model for which CD4 þ T cells are not required for tumor rejection. 16 The specificity of antitumor immunity was also assessed with ELISpot assays, which revealed a significantly higher frequency of IFN-g producing cells, but not IL-4-secreting cells in the mice treated with Ad-mFL, as compared to the Ad-GFP and PBS controls (Fig 5). In a comparable study, the nature of the frequency of IFN-g T cells in the spleen cells from the treated animals, which were restimulated in vitro with either parental hepa 1-6 or Ad-mFL-transfected cell lines, was further determined.…”

Section: Enhancement Of Antitumor Immunity With Flt3 Ligand H Wang Et Almentioning

confidence: 99%

“…Present data is different from the results we obtained in another mouse tumor model, which was treated with hu-FL gene-modified tumor vaccines. 16 The explanation for this difference may be contributed to the expression of different rejection antigens on these tumors.…”

Section: Systemic Splenocytes Adoptive Therapymentioning

confidence: 99%

“…14,15 Although modification of tumor cells in vitro with Flt3L-expressing vectors could also generate immunogenic tumor cells, the current studies are still insufficient in supporting that the modified tumor cells in this manner can serve as therapeutic vaccines to treat established large tumors. 16 Moreover, techniques used in the previous experiments was in vitro gene transferring approaches, which were mediated with retroviral vectors and could not be efficiently used for in vivo gene delivery. It is urgently to be known if local high concentration of Flt3L proteins produced by tumor cells modified with intratumoral gene transfer procedure can effectively stimulate host immune response to cure established tumors and prevent subsequent tumor challenge and recurrence.…”

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Treatment of hepatocellular carcinoma with adenoviral vector-mediated Flt3 ligand gene therapy

et al. 2005

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Fms-like tyrosine kinase 3 ligand (Flt3L) plays an important role in development and activation of dendritic cells (DCs) and natural killer cells (NK). It has been shown that administration of either tumor cells transfected in vitro with Flt3L vectors or soluble Flt3L fusion protein in a high dose can enhance host antitumor immunity in animal model systems. In this study, we developed a recombinant defective adenovirus with an insert of gene encoding extracellular domain of mouse Flt3L (Ad-mFlt3L) under control of cytomegalovirus promoter and investigated its biological efficacy in eliciting tumor-specific immune response against hepatocellular carcinoma in mouse hepatoma model. The constructed Ad-mFlt3L efficiently infected hepa 1-6 hepatoma cells both in vitro and in vivo, leading to a high production of mFlt3L proteins in association with accumulation of DCsNK cells and lymphocytes in local tumor tissues. Tumor cells infected with Ad-mFlt3L lost tumorigenicity and became more immunogenic in syngeniec animal models. Intratumoral injection of Ad-mFlt3L (10 9 expression-forming unit) Â 3 significantly inhibited tumor growth with elicitation of long-lasting antitumor immunity, which is both preventive and curative. The tumor-specific immunity can be partially abrogated by depletion of either CD3 þ CD4 þ T cells or NK cells and can be also re-established in naïve animals by adoptive transfer of splenocytes from treated mice. The results suggest that adenovirus-mediated Flt3L gene therapy may provide a useful strategy for treatment of cancers.

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In vitro and in vivo evaluation of intrinsic immunogenicity of reporter and insulin gene therapy plasmids

Ratanamart

Huggins

Kirby

et al. 2007

The Journal of Gene Medicine

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Regional, but not systemic recruitment/expansion of dendritic cells by a pluronic-formulated Flt3-ligand plasmid with vaccine adjuvant activity

Cited by 25 publications

References 40 publications

Murine mammary adenocarcinoma cells transfected with p53 and/or Flt3L induce antitumor immune responses

Murine mammary adenocarcinoma cells transfected with p53 and/or Flt3L induce antitumor immune responses

Treatment of hepatocellular carcinoma with adenoviral vector-mediated Flt3 ligand gene therapy

In vitro and in vivo evaluation of intrinsic immunogenicity of reporter and insulin gene therapy plasmids

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