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Intermittent chemotherapy can retain the therapeutic potential of anti-CD137 antibody during the late tumor-bearing state.

Tongu M, Harashima N, Tamada K, Chen L, Harada M - Cancer Sci. (2014)

Bottom Line: Although a significant antitumor effect was observed when local anti-CD137 mAb therapy (5 μg) was started early in the tumor-bearing stage (day 10), no therapeutic efficacy was observed when the mAb therapy was started at a later tumor-bearing stage (day 17).In a bilateral tumor inoculation model, this combination therapy achieved systemic therapeutic effects and suppressed the growth of mAb-untreated tumors.These results suggest that intermittent immunochemotherapy using CP and GEM could retain the therapeutic potential of anti-CD137 mAb that is normally impaired during the late tumor-bearing stage.

View Article: PubMed Central - PubMed

Affiliation: Department of Experimental Animals, Center for Integrated Research in Science, Shimane University, Izumo, Japan.

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Antitumor effects of local anti-CD137 mAb therapy in early or late stage tumors. (a) Twelve days after CT26 inoculation, draining LN, spleen and tumor tissues were harvested and their cells were analyzed using flow cytometry. The results of gating for CD4+ or CD8+ cells are shown, and the gray background shows an isotype-matched control. Similar results were obtained from two independent experiments. (b) BALB/c mice were injected s.c. in the flank with 5 × 105 CT26 cells. They were then injected i.t. with anti-CD137 mAb (5 μg) or rat IgG on days 10, 12 and 14. Tumor size (mm2) was measured twice weekly. Each group contained six or seven mice, and lines represent tumor growth. The arrowheads represent the timing of mAb injection. Data are presented as means ± SD (lower right panel). Similar results were obtained from two independent experiments. **P < 0.01 (anova with Bartlett's test). (c) CT26-bearing BALB/c nude mice were treated as described in (b). (d) CT26-bearing BALB/c mice were treated with anti-CD137 mAb (5 μg) on days 17, 19 and 21 after tumor inoculation. Each group contained seven mice, and lines show tumor growth. Arrowheads indicate the timing of mAb injection.
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fig01: Antitumor effects of local anti-CD137 mAb therapy in early or late stage tumors. (a) Twelve days after CT26 inoculation, draining LN, spleen and tumor tissues were harvested and their cells were analyzed using flow cytometry. The results of gating for CD4+ or CD8+ cells are shown, and the gray background shows an isotype-matched control. Similar results were obtained from two independent experiments. (b) BALB/c mice were injected s.c. in the flank with 5 × 105 CT26 cells. They were then injected i.t. with anti-CD137 mAb (5 μg) or rat IgG on days 10, 12 and 14. Tumor size (mm2) was measured twice weekly. Each group contained six or seven mice, and lines represent tumor growth. The arrowheads represent the timing of mAb injection. Data are presented as means ± SD (lower right panel). Similar results were obtained from two independent experiments. **P < 0.01 (anova with Bartlett's test). (c) CT26-bearing BALB/c nude mice were treated as described in (b). (d) CT26-bearing BALB/c mice were treated with anti-CD137 mAb (5 μg) on days 17, 19 and 21 after tumor inoculation. Each group contained seven mice, and lines show tumor growth. Arrowheads indicate the timing of mAb injection.

Mentions: We first examined the expression of CD137 on draining LN cells, spleen cells and tumor-infiltrating lymphocytes (TIL) of CT26-bearing mice 12 days after tumor inoculation. Both CD4+ and CD8+ T cells in TIL, but not draining LN or splenic cells, were weakly positive for CD137 (Fig.1a), consistent with a previous report.10 We next examined the antitumor effects induced by the intratumoral delivery of low-dose (5 μg) anti-CD137 mAb. The i.t. injection with anti-CD137 mAb on days 10, 12 and 14 after tumor inoculation suppressed tumor growth significantly compared with the injection of control rat IgG (Fig.1b). This antitumor effect was T-cell-dependent because no antitumor effect was observed in CT26-bearing nude mice (Fig.1c). We also assessed whether the anti-CD137 mAb therapy was effective when started at a later tumor-bearing stage. Although the tumor in one mouse regressed and another mouse showed continuous suppression of the tumor growth, i.t. injections of anti-CD137 mAb on days 17, 19 and 21 were not effective (Fig.1d).


Intermittent chemotherapy can retain the therapeutic potential of anti-CD137 antibody during the late tumor-bearing state.

Tongu M, Harashima N, Tamada K, Chen L, Harada M - Cancer Sci. (2014)

Antitumor effects of local anti-CD137 mAb therapy in early or late stage tumors. (a) Twelve days after CT26 inoculation, draining LN, spleen and tumor tissues were harvested and their cells were analyzed using flow cytometry. The results of gating for CD4+ or CD8+ cells are shown, and the gray background shows an isotype-matched control. Similar results were obtained from two independent experiments. (b) BALB/c mice were injected s.c. in the flank with 5 × 105 CT26 cells. They were then injected i.t. with anti-CD137 mAb (5 μg) or rat IgG on days 10, 12 and 14. Tumor size (mm2) was measured twice weekly. Each group contained six or seven mice, and lines represent tumor growth. The arrowheads represent the timing of mAb injection. Data are presented as means ± SD (lower right panel). Similar results were obtained from two independent experiments. **P < 0.01 (anova with Bartlett's test). (c) CT26-bearing BALB/c nude mice were treated as described in (b). (d) CT26-bearing BALB/c mice were treated with anti-CD137 mAb (5 μg) on days 17, 19 and 21 after tumor inoculation. Each group contained seven mice, and lines show tumor growth. Arrowheads indicate the timing of mAb injection.
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Related In: Results  -  Collection

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fig01: Antitumor effects of local anti-CD137 mAb therapy in early or late stage tumors. (a) Twelve days after CT26 inoculation, draining LN, spleen and tumor tissues were harvested and their cells were analyzed using flow cytometry. The results of gating for CD4+ or CD8+ cells are shown, and the gray background shows an isotype-matched control. Similar results were obtained from two independent experiments. (b) BALB/c mice were injected s.c. in the flank with 5 × 105 CT26 cells. They were then injected i.t. with anti-CD137 mAb (5 μg) or rat IgG on days 10, 12 and 14. Tumor size (mm2) was measured twice weekly. Each group contained six or seven mice, and lines represent tumor growth. The arrowheads represent the timing of mAb injection. Data are presented as means ± SD (lower right panel). Similar results were obtained from two independent experiments. **P < 0.01 (anova with Bartlett's test). (c) CT26-bearing BALB/c nude mice were treated as described in (b). (d) CT26-bearing BALB/c mice were treated with anti-CD137 mAb (5 μg) on days 17, 19 and 21 after tumor inoculation. Each group contained seven mice, and lines show tumor growth. Arrowheads indicate the timing of mAb injection.
Mentions: We first examined the expression of CD137 on draining LN cells, spleen cells and tumor-infiltrating lymphocytes (TIL) of CT26-bearing mice 12 days after tumor inoculation. Both CD4+ and CD8+ T cells in TIL, but not draining LN or splenic cells, were weakly positive for CD137 (Fig.1a), consistent with a previous report.10 We next examined the antitumor effects induced by the intratumoral delivery of low-dose (5 μg) anti-CD137 mAb. The i.t. injection with anti-CD137 mAb on days 10, 12 and 14 after tumor inoculation suppressed tumor growth significantly compared with the injection of control rat IgG (Fig.1b). This antitumor effect was T-cell-dependent because no antitumor effect was observed in CT26-bearing nude mice (Fig.1c). We also assessed whether the anti-CD137 mAb therapy was effective when started at a later tumor-bearing stage. Although the tumor in one mouse regressed and another mouse showed continuous suppression of the tumor growth, i.t. injections of anti-CD137 mAb on days 17, 19 and 21 were not effective (Fig.1d).

Bottom Line: Although a significant antitumor effect was observed when local anti-CD137 mAb therapy (5 μg) was started early in the tumor-bearing stage (day 10), no therapeutic efficacy was observed when the mAb therapy was started at a later tumor-bearing stage (day 17).In a bilateral tumor inoculation model, this combination therapy achieved systemic therapeutic effects and suppressed the growth of mAb-untreated tumors.These results suggest that intermittent immunochemotherapy using CP and GEM could retain the therapeutic potential of anti-CD137 mAb that is normally impaired during the late tumor-bearing stage.

View Article: PubMed Central - PubMed

Affiliation: Department of Experimental Animals, Center for Integrated Research in Science, Shimane University, Izumo, Japan.

Show MeSH
Related in: MedlinePlus