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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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Tumor regression after combination therapy. (a) BALB/c mice were injected s.c. in the flank with 5 × 105 CT26 cells. CP (50 mg/kg) and GEM (50 mg/kg) were then injected i.p. on days 10 and 18, followed by the i.t. injection of anti-CD137 mAb (5 μg) or rat IgG on days 19, 21 and 23. White arrows indicate the injection of CP and GEM, and black arrows indicate injections of Ab. Tumor size (mm2) was measured twice weekly. The untreated group contained 7 mice, and the treated groups contained 16 mice. Similar results were obtained in two experiments. The letters “P” and “S” in the right figure are representative of tumor-progressing and tumor-stable mice, respectively. These mice were used in the experiment shown in Figure4. (b) Means ± SD of the results on day 30 after tumor inoculation. **P < 0.01 (anova with Bartlett's test). (c) CT26-bearing BALB/c mice were injected i.p. with CP (50 mg/kg) and GEM (50 mg/kg) on days 10 and 18, followed by the i.t. injection of anti-CD137 mAb (5 μg) or rat IgG on days 19 and 21. On day 22, the tumor tissues were harvested and the CD137 expression of CD4+ or CD8+ T cells was examined by flow cytometry. The gray background shows an isotype-matched control. (d) Similarly, the tumor-infiltrating immune cells were analyzed. Data show the means ± SD of three samples. **P < 0.01 (Student's t-test). (e) CT26 and RENCA (2 × 105 cells) were inoculated s.c. and bilaterally on day 60 after the initial inoculation. Naïve BALB/c mice were also inoculated with CT26 and RENCA cells. Tumor growth was measured twice weekly. Each group contained six mice, and data are presented as means ± SD. (f) Total RNA was extracted from three tumor cell lines and normal spleen cells, and pg70mRNA expression was examined using RT-PCR. RT, reverse transcriptase. β-actin was used as a control.
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fig03: Tumor regression after combination therapy. (a) BALB/c mice were injected s.c. in the flank with 5 × 105 CT26 cells. CP (50 mg/kg) and GEM (50 mg/kg) were then injected i.p. on days 10 and 18, followed by the i.t. injection of anti-CD137 mAb (5 μg) or rat IgG on days 19, 21 and 23. White arrows indicate the injection of CP and GEM, and black arrows indicate injections of Ab. Tumor size (mm2) was measured twice weekly. The untreated group contained 7 mice, and the treated groups contained 16 mice. Similar results were obtained in two experiments. The letters “P” and “S” in the right figure are representative of tumor-progressing and tumor-stable mice, respectively. These mice were used in the experiment shown in Figure4. (b) Means ± SD of the results on day 30 after tumor inoculation. **P < 0.01 (anova with Bartlett's test). (c) CT26-bearing BALB/c mice were injected i.p. with CP (50 mg/kg) and GEM (50 mg/kg) on days 10 and 18, followed by the i.t. injection of anti-CD137 mAb (5 μg) or rat IgG on days 19 and 21. On day 22, the tumor tissues were harvested and the CD137 expression of CD4+ or CD8+ T cells was examined by flow cytometry. The gray background shows an isotype-matched control. (d) Similarly, the tumor-infiltrating immune cells were analyzed. Data show the means ± SD of three samples. **P < 0.01 (Student's t-test). (e) CT26 and RENCA (2 × 105 cells) were inoculated s.c. and bilaterally on day 60 after the initial inoculation. Naïve BALB/c mice were also inoculated with CT26 and RENCA cells. Tumor growth was measured twice weekly. Each group contained six mice, and data are presented as means ± SD. (f) Total RNA was extracted from three tumor cell lines and normal spleen cells, and pg70mRNA expression was examined using RT-PCR. RT, reverse transcriptase. β-actin was used as a control.

Mentions: We next examined the antitumor effect of the combination of anti-CD137 mAb and intermittent chemotherapy with low-dose CP and GEM (Fig.3a,b). Intermittent chemotherapy on days 10 and 18 suppressed tumor growth significantly, and 3 of the 16 mice were cured by chemotherapy alone. When the intermittent chemotherapy was followed by local anti-CD137 mAb therapy, more significant tumor regression was observed; 8 of the 16 mice were cured. Although some mice were not cured, they showed continuous growth suppression, so-called “stable disease,” for more than 2 weeks after the last Ab therapy.


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)

Tumor regression after combination therapy. (a) BALB/c mice were injected s.c. in the flank with 5 × 105 CT26 cells. CP (50 mg/kg) and GEM (50 mg/kg) were then injected i.p. on days 10 and 18, followed by the i.t. injection of anti-CD137 mAb (5 μg) or rat IgG on days 19, 21 and 23. White arrows indicate the injection of CP and GEM, and black arrows indicate injections of Ab. Tumor size (mm2) was measured twice weekly. The untreated group contained 7 mice, and the treated groups contained 16 mice. Similar results were obtained in two experiments. The letters “P” and “S” in the right figure are representative of tumor-progressing and tumor-stable mice, respectively. These mice were used in the experiment shown in Figure4. (b) Means ± SD of the results on day 30 after tumor inoculation. **P < 0.01 (anova with Bartlett's test). (c) CT26-bearing BALB/c mice were injected i.p. with CP (50 mg/kg) and GEM (50 mg/kg) on days 10 and 18, followed by the i.t. injection of anti-CD137 mAb (5 μg) or rat IgG on days 19 and 21. On day 22, the tumor tissues were harvested and the CD137 expression of CD4+ or CD8+ T cells was examined by flow cytometry. The gray background shows an isotype-matched control. (d) Similarly, the tumor-infiltrating immune cells were analyzed. Data show the means ± SD of three samples. **P < 0.01 (Student's t-test). (e) CT26 and RENCA (2 × 105 cells) were inoculated s.c. and bilaterally on day 60 after the initial inoculation. Naïve BALB/c mice were also inoculated with CT26 and RENCA cells. Tumor growth was measured twice weekly. Each group contained six mice, and data are presented as means ± SD. (f) Total RNA was extracted from three tumor cell lines and normal spleen cells, and pg70mRNA expression was examined using RT-PCR. RT, reverse transcriptase. β-actin was used as a control.
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fig03: Tumor regression after combination therapy. (a) BALB/c mice were injected s.c. in the flank with 5 × 105 CT26 cells. CP (50 mg/kg) and GEM (50 mg/kg) were then injected i.p. on days 10 and 18, followed by the i.t. injection of anti-CD137 mAb (5 μg) or rat IgG on days 19, 21 and 23. White arrows indicate the injection of CP and GEM, and black arrows indicate injections of Ab. Tumor size (mm2) was measured twice weekly. The untreated group contained 7 mice, and the treated groups contained 16 mice. Similar results were obtained in two experiments. The letters “P” and “S” in the right figure are representative of tumor-progressing and tumor-stable mice, respectively. These mice were used in the experiment shown in Figure4. (b) Means ± SD of the results on day 30 after tumor inoculation. **P < 0.01 (anova with Bartlett's test). (c) CT26-bearing BALB/c mice were injected i.p. with CP (50 mg/kg) and GEM (50 mg/kg) on days 10 and 18, followed by the i.t. injection of anti-CD137 mAb (5 μg) or rat IgG on days 19 and 21. On day 22, the tumor tissues were harvested and the CD137 expression of CD4+ or CD8+ T cells was examined by flow cytometry. The gray background shows an isotype-matched control. (d) Similarly, the tumor-infiltrating immune cells were analyzed. Data show the means ± SD of three samples. **P < 0.01 (Student's t-test). (e) CT26 and RENCA (2 × 105 cells) were inoculated s.c. and bilaterally on day 60 after the initial inoculation. Naïve BALB/c mice were also inoculated with CT26 and RENCA cells. Tumor growth was measured twice weekly. Each group contained six mice, and data are presented as means ± SD. (f) Total RNA was extracted from three tumor cell lines and normal spleen cells, and pg70mRNA expression was examined using RT-PCR. RT, reverse transcriptase. β-actin was used as a control.
Mentions: We next examined the antitumor effect of the combination of anti-CD137 mAb and intermittent chemotherapy with low-dose CP and GEM (Fig.3a,b). Intermittent chemotherapy on days 10 and 18 suppressed tumor growth significantly, and 3 of the 16 mice were cured by chemotherapy alone. When the intermittent chemotherapy was followed by local anti-CD137 mAb therapy, more significant tumor regression was observed; 8 of the 16 mice were cured. Although some mice were not cured, they showed continuous growth suppression, so-called “stable disease,” for more than 2 weeks after the last Ab therapy.

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