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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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Increased myeloid-derived suppressor cells at the sites of late-stage tumors. (a) BALB/c mice were injected s.c. in the flank with 5 × 105 CT26 cells. Tumor tissues were harvested on the indicated days, and tumor tissue cell suspensions were analyzed using flow cytometry. Each data point shows the means ± SD of four samples. Similar results were obtained from two independent experiments. *P < 0.05, **P < 0.01 (Student's t-test). (b) Representative data from tumor-infiltrating immune cells 10 or 18 days after CT26 inoculation; numbers represent the percentage of each cellular subset. (c) Ten days after CT26 inoculation, CP (50 mg/kg) and GEM (50 mg/kg) were injected i.p. On days 3, 6 and 9 after injection of CP and GEM, the tumor-infiltrating immune cells were analyzed using flow cytometry. Data show the means ± SD of three samples. Similar results were obtained from two independent experiments. *P < 0.05, **P < 0.01 (Student's t-test).
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fig02: Increased myeloid-derived suppressor cells at the sites of late-stage tumors. (a) BALB/c mice were injected s.c. in the flank with 5 × 105 CT26 cells. Tumor tissues were harvested on the indicated days, and tumor tissue cell suspensions were analyzed using flow cytometry. Each data point shows the means ± SD of four samples. Similar results were obtained from two independent experiments. *P < 0.05, **P < 0.01 (Student's t-test). (b) Representative data from tumor-infiltrating immune cells 10 or 18 days after CT26 inoculation; numbers represent the percentage of each cellular subset. (c) Ten days after CT26 inoculation, CP (50 mg/kg) and GEM (50 mg/kg) were injected i.p. On days 3, 6 and 9 after injection of CP and GEM, the tumor-infiltrating immune cells were analyzed using flow cytometry. Data show the means ± SD of three samples. Similar results were obtained from two independent experiments. *P < 0.05, **P < 0.01 (Student's t-test).

Mentions: To investigate why the therapeutic efficacy of local anti-CD137 mAb therapy was lost at the late tumor-bearing stage, we quantified the number of tumor-infiltrating immune cells (Fig.2a). The percentage of CD45+ immune cells, particularly CD11b+ Gr-1high/low MDSC, in the tumor tissues increased significantly 13 days after tumor inoculation. Although the percentage of CD4+ T cells in TIL decreased gradually, the number of CD8+ T cells increased slightly. In addition, the percentage of Tregs increased in TIL on days 13 and 18 after tumor inoculation. However, given the low percentages of total CD4+ T cells in TIL, MDSC appeared to be responsible for the impaired efficacy of local anti-CD137 mAb therapy in the late tumor-bearing stage. Representative results of the number of CD45+ immune cells and MDSC on days 10 and 18 after tumor inoculation are shown in Figure2(b).


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)

Increased myeloid-derived suppressor cells at the sites of late-stage tumors. (a) BALB/c mice were injected s.c. in the flank with 5 × 105 CT26 cells. Tumor tissues were harvested on the indicated days, and tumor tissue cell suspensions were analyzed using flow cytometry. Each data point shows the means ± SD of four samples. Similar results were obtained from two independent experiments. *P < 0.05, **P < 0.01 (Student's t-test). (b) Representative data from tumor-infiltrating immune cells 10 or 18 days after CT26 inoculation; numbers represent the percentage of each cellular subset. (c) Ten days after CT26 inoculation, CP (50 mg/kg) and GEM (50 mg/kg) were injected i.p. On days 3, 6 and 9 after injection of CP and GEM, the tumor-infiltrating immune cells were analyzed using flow cytometry. Data show the means ± SD of three samples. Similar results were obtained from two independent experiments. *P < 0.05, **P < 0.01 (Student's t-test).
© Copyright Policy - open-access
Related In: Results  -  Collection

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fig02: Increased myeloid-derived suppressor cells at the sites of late-stage tumors. (a) BALB/c mice were injected s.c. in the flank with 5 × 105 CT26 cells. Tumor tissues were harvested on the indicated days, and tumor tissue cell suspensions were analyzed using flow cytometry. Each data point shows the means ± SD of four samples. Similar results were obtained from two independent experiments. *P < 0.05, **P < 0.01 (Student's t-test). (b) Representative data from tumor-infiltrating immune cells 10 or 18 days after CT26 inoculation; numbers represent the percentage of each cellular subset. (c) Ten days after CT26 inoculation, CP (50 mg/kg) and GEM (50 mg/kg) were injected i.p. On days 3, 6 and 9 after injection of CP and GEM, the tumor-infiltrating immune cells were analyzed using flow cytometry. Data show the means ± SD of three samples. Similar results were obtained from two independent experiments. *P < 0.05, **P < 0.01 (Student's t-test).
Mentions: To investigate why the therapeutic efficacy of local anti-CD137 mAb therapy was lost at the late tumor-bearing stage, we quantified the number of tumor-infiltrating immune cells (Fig.2a). The percentage of CD45+ immune cells, particularly CD11b+ Gr-1high/low MDSC, in the tumor tissues increased significantly 13 days after tumor inoculation. Although the percentage of CD4+ T cells in TIL decreased gradually, the number of CD8+ T cells increased slightly. In addition, the percentage of Tregs increased in TIL on days 13 and 18 after tumor inoculation. However, given the low percentages of total CD4+ T cells in TIL, MDSC appeared to be responsible for the impaired efficacy of local anti-CD137 mAb therapy in the late tumor-bearing stage. Representative results of the number of CD45+ immune cells and MDSC on days 10 and 18 after tumor inoculation are shown in Figure2(b).

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