Effects of Survivin Antagonists on Growth of Established Tumors and B7-1 Immunogene Therapy

Kanwar, Jagat R.; Shen, Weiping; Kanwar, Rupinder K.; Berg, Randal W.; Krissansen, Geoffrey W.

doi:10.1093/jnci/93.20.1541

Cited by 156 publications

(130 citation statements)

References 52 publications

(68 reference statements)

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“…Previous studies have indicated that large tumors are likewise refractory to B7-1 immunogene therapy. [16][17][18][19][20] The efficacy of B7-1 immunogene therapy appears to be dependent on the inherent antigenicity of the tumor. 22 While the murine EL-4 lymphoma is an immunogenic tumor cell line, EL-4 tumors become increasingly immunosuppressive as they grow larger and begin to express the anti-apoptotic factor survivin, which may render them less susceptible to immune attack.…”

Section: Discussionmentioning

confidence: 99%

“…22 While the murine EL-4 lymphoma is an immunogenic tumor cell line, EL-4 tumors become increasingly immunosuppressive as they grow larger and begin to express the anti-apoptotic factor survivin, which may render them less susceptible to immune attack. 19 At increased density, they upregulate expression of fas ligand, 16 which has the potential to kill fasexpressing antitumor effector T cells. In addition, they secrete TGF-b, which downregulates antitumor immunity by inducing IL-10-mediated development of Th2 responses, and inhibition of Th1 responses.…”

Section: Discussionmentioning

confidence: 99%

“…[13][14][15] Intratumoral gene transfer of mouse B7-1 and -2, which can eradicate already established tumors, has been shown to costimulate antitumor activity mediated by CD8 + T cells and NK cells, accompanied by augmented tumor-specific cytolytic T-cell (CTL) activity involving both the perforin and Fas-ligand pathways. [16][17][18][19][20] B7-H3 is also a potential anticancer agent as it can induce many of the pathways required for a potent antitumor immune response. However, unlike B7-1, it is a poor costimulator of naïve T cells, and is predicted to play a critical role in the regulation of T-cell responses after the initial priming stage.…”

Section: Introductionmentioning

confidence: 99%

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Mouse B7-H3 induces antitumor immunity

et al. 2003

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Members of the B7 family costimulate the proliferation of lymphocytes during the initiation and maintenance of antigen-specific humoral and cell-mediated immune responses. While B7-1 and -2 are restricted to lymphoid tissues, and activate naïve T cells, recently identified members including B7-H2 and -H3 are widely expressed on nonlymphoid tissues, and regulate effector lymphocytes in the periphery. B7-H3 has properties that suggested it may display antitumor activity, including the ability to stimulate Th1 and cytotoxic T-cell responses. Here, we test this notion by determining whether intratumoral injection of an expression plasmid encoding a newly described mouse homologue of B7-H3 is able to eradicate EL-4 lymphomas. Intratumoral injection of a mouse B7-H3 pcDNA3 expression plasmid led to complete regression of 50% tumors, or otherwise significantly slowed tumor growth. Mice whose tumors completely regressed resisted a challenge with parental tumor cells, indicating systemic immunity had been generated. B7-H3-mediated antitumor immunity was mediated by CD8 + T and NK cells, with no apparent contribution from CD4 + T cells. In summary, the results indicate that B7-H3 interactions may play a role in regulating cell-mediated immune responses against cancer, and that B7-H3 is a potential therapeutic tool.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Mouse B7-H3 induces antitumor immunity

et al. 2003

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“…The tumor volume was measured every day. In this group, attenuated activated T cells were injected every week until the mice of control group were evaluated as dead according to the tumor size as described in pervious papers [30,31]. At the end of experiment, the mice were killed.…”

Section: Tumor Growth Inhibition Assaymentioning

confidence: 99%

Immunization with autologous T cells enhances in vivo anti-tumor immune responses accompanied by up-regulation of GADD45β

Wang

Cao

et al. 2006

Cell Res

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Immunization with inactivated autoreactive T cells may induce idiotype anti-idiotypic reactions to deplete autoreactive T cells, which are involved in autoimmune diseases. However, it is unknown whether attenuated activated healthy autologous T-cell immunization could increase anti-tumor immune responses. To this end, C57Bl/6 mice were immunized with attenuated activated autologous T cells. The splenocytes from immunized mice showed a higher proliferative ability than that from naive mice. The special phenotype analysis showed that there were more CD8+ T cells and CD62L+ T cells in immunized mice after 24 h of culture with 10% fetal calf serum complete medium in vitro (P<0.01). These results demonstrated that this immunization may activate T cells in vivo. Furthermore, the splenocytes from immunized mice revealed resistance to activation-induced cell death (AICD) in vitro. To further study the relative genes that are responsible for the higher proliferation and resistance to AICD, the expression of Fas/Fas ligand (FasL) and GADD45b was measured by real-time PCR. The results indicated that GADD45b transcription was higher in the splenocytes from immunized mice than that in the naive mice. In addition, the Fas expression showed a parallel higher, but FasL did not change obviously. To investigate the biologic functions induced by immunization in vivo, a tumor model was established by EL-4 tumor cell inoculation in C57/Bl mice. Mice receiving autologous T-cell immunization had significantly inhibited tumor growth in vivo (P<0.01). This study implicated that immunization with attenuated activated autologous T cells enhances anti-tumor immune responses that participate in tumor growth inhibition.

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“…As NSCLC cells express the highest level of survivin found in humor tumor, 4 inhibition of survivin would block the anti-apoptosis and mitotic progression in NSCLC. The molecular antagonists of survivin, including antisense, ribozymes, siRNA or dominant negative mutants have been successfully utilized to inhibit survivin expression or to interfere with its functions, inducing apoptosis and inhibiting tumor growth in vitro and in vivo, [21][22][23][24][25][26][27][28][29] As there are only two survivin alleles in each cell compared with hundreds of thousands of survivin mRNA molecules, an antigene strategy at the transcriptional level probably possesses advantage over antisense, RNAi or ribozyme-based techniques. Recently, Yao et al 20 have devised a method to inhibit transcriptional initiation by constructing short methylated oligonucleotides which induce DNA methylation at specific loci.…”

Section: Discussionmentioning

confidence: 99%

Induction of apoptosis of non-small cell lung cancer by a methylated oligonucleotide targeting survivin gene

2010

Cancer Gene Ther

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Survivin overexpression is closely linked to lung oncogenesis. Silencing of survivin gene by molecular antagonists has shown promise as novel anticancer strategies. DNA methylation is a critical epigenetic modification that silences gene transcription. In this study, we used a new methylated oligonucleotide, which mediates sequence-specific DNA methylation in cell, as a strategic alternative to survivin-targeting treatment, and investigated its efficacy in suppressing survivin expression and the consequent apoptotic induction potential in NCI-H460 cells. SurKex1, a methylated sense oligonucleotide, was shown to reduce specifically survivin mRNA expression and induce cell apoptosis. In addition, it has been supposed that the methylated oligonucleotide exerts its effect of gene silencing through the activation of DNA methyltransferase (DNMT1), but the exact mechanism is still unknown. Our data suggest for the first time that the SurKex1 exerts its down-regulatory effects on survivin expression through the activation of DNMT1.

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Effects of Survivin Antagonists on Growth of Established Tumors and B7-1 Immunogene Therapy

Abstract: Intratumoral injection of plasmids that block survivin expression and stimulate the generation of tumor-specific CTLs may be beneficial for the treatment of large lymphomas.

Cited by 156 publications

References 52 publications

Mouse B7-H3 induces antitumor immunity

Mouse B7-H3 induces antitumor immunity

Immunization with autologous T cells enhances in vivo anti-tumor immune responses accompanied by up-regulation of GADD45β

Induction of apoptosis of non-small cell lung cancer by a methylated oligonucleotide targeting survivin gene

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