B7.1 expression by the weakly immunogenic F98 rat glioma does not enhance immunogenicity

Db, Paul; Rf, Barth; Yang, Weilian; Gh, Shen; J, Kim; Pl, Triozzi

doi:10.1038/sj.gt.3301209

Cited by 17 publications

(11 citation statements)

References 38 publications

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“…Many tumors, however, display defects in antigen processing and presentation 42 and are poorly immunogenic even after transduction with cytokines or costimulatory molecules. 13,14 To overcome these limitations, we constructed chimeric antibody receptors to activate T cells at the local tumor environment directly. We found that expression of membrane-bound anti-CD3 receptors with CD80 or CD86 induced the proliferation of both CD4 + and CD8 + T cells, reduced the threshold for T-cell activation, stimulated prolific IL-2 production and generated T-cell cytotoxicity.…”

Section: Discussionmentioning

confidence: 99%

“…[8][9][10][11][12] Tumors that express low amounts of MHC class I molecules or process antigens poorly cannot effectively trigger T cells and transduction with CD80 or CD86 fails to induce tumor rejection. 13,14 An alternative strategy to activate T cells that is less dependent on the expression of tumor-associated antigens or MHC molecules by tumor cells may extend the utility of immunotherapy to poorly immunogenic tumors. We and others have previously shown that cells modified to express chimeric anti-CD3 receptors can activate naive T cells.…”

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confidence: 99%

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Stable expression of chimeric anti-CD3 receptors on mammalian cells for stimulation of antitumor immunity

Liao¹,

Chen²,

Liu³

et al. 2003

Cancer Gene Ther

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Expression of CD80 or CD86 costimulatory molecules on tumor cells can produce rejection of immunogenic but not poorly immunogenic tumors. We have previously shown that anti-CD3 single-chain antibodies expressed on the surface of cells can directly activate T cells. We therefore investigated whether anti-CD3 ''receptors'' could enhance CD86-mediated rejection of poorly immunogenic tumors. Expression of anti-CD3 receptors on cells was increased by introduction of membrane-proximal ''spacer'' domains containing glycosylation sites between the single-chain antibody and the transmembrane domain of the chimeric receptors. Removal of glycosylation sites in the spacer reduced surface expression due to increased shedding of chimeric receptors from the cell surface. Induction of T-cell proliferation by anti-CD3 receptors did not correlate with the expression level of chimeric protein, but rather depended on the physical properties of the spacer. Anti-CD3 receptors effectively induced T-cell cytotoxicity, whereas coexpression with CD80 or CD86 was required for generating T-cell proliferation and IL-2 secretion. Although expression of CD86 did not significantly delay the growth of poorly immunogenic B16-F1 tumors, expression of anti-CD3 receptors with CD86 produced complete tumor rejections in 50% of mice and induced significant protection against wild-type B16-F1 tumor cells. Our results show that spacer domains can dramatically influence the surface expression and the biological activity of chimeric antibody receptors. The strong antitumor activity produced by anti-CD3 receptors and CD86 on tumor cells indicates that this strategy may be beneficial for the gene-mediated therapy of poorly immunogenic tumors.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Stable expression of chimeric anti-CD3 receptors on mammalian cells for stimulation of antitumor immunity

Liao¹,

Chen²,

Liu³

et al. 2003

Cancer Gene Ther

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“…© 2005 American Association for Cancer clincancerres.aacrjournals.org Downloaded from death, and trigger natural killer cell cytotoxicity (19,20). Whereas conferring B7 expression on tumor cells can enhance antitumor responses, it is also apparent that provision of B7 expression is not sufficient to induce immunity against nonimmunogenic tumors (21). Combining B7 expression with immune-stimulatory cytokine expression has been shown to augment tumor immunity.…”

Section: Discussionmentioning

confidence: 99%

Phase I Study of the Intratumoral Administration of Recombinant Canarypox Viruses Expressing B7.1 and Interleukin 12 in Patients with Metastatic Melanoma

Triozzi

Allen

Carlisle

et al. 2005

Clinical Cancer Research

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The objective of this study was to evaluate the safety and activity of the intratumoral administration of the immune costimulatory molecule, B7.1, encoded by a vector derived from the canarypox virus, ALVAC (ALVAC-B7.1), alone and with the intratumoral injection of ALVAC encoding the immune-stimulatory cytokine, interleukin 12 (ALVAC-IL-12). Fourteen patients with metastatic melanoma who had s.c. nodules received intratumoral injections on days 1, 4, 8, and 11. Nine patients were given escalating doses of up to 25 Â 10 8 plaque-forming units of ALVAC-B7.1. Five patients were given 25 Â 10 8 plaque-forming units of ALVAC-B7.1combined with ALVAC-IL-12 50% tissue culture infective dose of 2 Â 10 6 .Toxicity was mild to moderate and consisted ofinflammatory reactions at the injection site and fever, chills, myalgia, and fatigue. Higher levels of B7.1 mRNA were observed in ALVAC-B7.1^injected tumors compared with saline-injected control tumors. Higher levels of intratumoral vascular endothelial growth factor and IL-10, cytokines with immune suppressive activities, were also observed in ALVAC-B7.1^and ALVAC-IL-12^injected tumors compared with saline-injected controls. Serum levels of vascular endothelial growth factor increased at day 18 and returned to baseline at day 43. All patients developed antibody to ALVAC. Intratumoral IL-12 and IFN-g mRNA decreased. Changes in serum IL-12 and IFN-g levels were not observed. Tumor regressions were not observed. The intratumoral injections of ALVAC-B7.1and ALVAC-IL-12 were well tolerated at these dose levels and at this schedule and resulted in measurable biological response. This response included the production of factors that may suppress the antitumor immunologic activity of these vectors.

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“…The F98 glioma is poorly immunogenic (30), and ways to enhance its immunogenicity have been sought without success (31). Rats that were rendered disease free were immune to intracerebral rechallenge.…”

Section: Discussionmentioning

confidence: 99%

Antiphosphatidylserine Antibody Combined with Irradiation Damages Tumor Blood Vessels and Induces Tumor Immunity in a Rat Model of Glioblastoma

Yin

Luster

et al. 2009

Clinical Cancer Research

115

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Purpose: The vascular targeting antibody bavituximab is being combined with chemotherapy in clinical trials in cancer patients. Bavituximab targets the membrane phospholipid, phosphatidylserine, complexed with β2-glycoprotein I. Phosphatidylserine is normally intracellular but becomes exposed on the luminal surface of vascular endothelium in tumors. Phosphatidylserine exposure on tumor vessels is increased by chemotherapy and irradiation. Here, we determined whether treatment with the murine equivalent of bavituximab, 2aG4, combined with irradiation can suppress tumor growth in a rat model of glioblastoma. Experimental Design: F98 glioma cells were injected into the brains of syngeneic rats where they grow initially as a solid tumor and then infiltrate throughout the brain. Rats with established tumors were treated with 10 Gy whole brain irradiation and 2aG4. Results: Combination treatment doubled the median survival time of the rats, and 13% of animals were rendered disease free. Neither treatment given individually was as effective. We identified two mechanisms. First, irradiation induced phosphatidylserine exposure on tumor blood vessels and enhanced antibody-mediated destruction of tumor vasculature by monocytes/macrophages. Second, the antibody treatment induced immunity to F98 tumor cells, which are normally weakly immunogenic. Surviving rats were immune to rechallenge with F98 tumor cells. In vitro, 2aG4 enhanced the ability of dendritic cells (DCs) to generate F98-specific cytotoxic T cells. Phosphatidylserine exposure, which is induced on tumor cells by irradiation, likely suppresses tumor antigen presentation, and 2aG4 blocks this tolerogenic effect. Conclusion: Bavituximab combined with radiotherapy holds promise as a vascular targeting and immune enhancement strategy for the treatment of human glioblastoma. (Clin Cancer Res 2009;15(22):6871-80)

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B7.1 expression by the weakly immunogenic F98 rat glioma does not enhance immunogenicity

Cited by 17 publications

References 38 publications

Stable expression of chimeric anti-CD3 receptors on mammalian cells for stimulation of antitumor immunity

Stable expression of chimeric anti-CD3 receptors on mammalian cells for stimulation of antitumor immunity

Phase I Study of the Intratumoral Administration of Recombinant Canarypox Viruses Expressing B7.1 and Interleukin 12 in Patients with Metastatic Melanoma

Antiphosphatidylserine Antibody Combined with Irradiation Damages Tumor Blood Vessels and Induces Tumor Immunity in a Rat Model of Glioblastoma

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