Figure 5.
The level and heterogeneity of tumor antigen expression shape combination therapy outcome. (A) In vivo efficacy study design. Humanized BRGS-CD47 mice with SC OCI-Ly18 tumors were randomized into 5 groups (12 mice each) and treated with either vehicle (histidine buffer), glofitamab (0.5 mg/kg), R-CHOP (rituximab 30 mg/kg, cyclophosphamide 30 mg/kg, doxorubicin 2.5 mg/kg, vincristine 0.375 mg/kg, methylprednisolone 0.12 mg/kg), or glofitamab in combination with either R-CHOP (staggered) or CD19–4-1BBL (1 mg/kg) as per the administration scheme. Methylprednisolone was given IV for 3 consecutive days during each cycle of treatment. All treatments were administered IV according to the displayed schedule. Glofitamab monotherapy and its combination with CD19–4-1BBL received Gpt (30 mg/kg). The study was terminated on day 45 after continuous weekly treatment. (B) Representative IHC staining of untreated OCI-Ly18 tumors for CD19 and CD20. Upper row, lower magnification; lower row, higher magnification. Images were captured using a VS120 Virtual Slide Microscope (Olympus). (C) Average tumor volumes are presented as means + SEM for all treatment groups over time. Tumor-free mice are indicated as x/12. (D) Experimental design of the in vivo efficacy study. Humanized BRGS-CD47 mice with SC SU-DHL-8 tumors were randomized into 5 groups (14 mice each). Mice were treated with either vehicle (histidine buffer), glofitamab (2 mg/kg), or glofitamab in combination with CD19–4-1BBL (1 mg/kg) or CD19-CD28 (1 mg/kg). An additional combination group received a single treatment with CD19-CD28 followed by continuous treatment with CD19–4-1BBL in combination with glofitamab, as per the administration scheme. All treatments were administered IV according to the displayed schedule. All groups received Gpt (30 mg/kg). Four scout animals per group were taken at day 18. (E) Representative IHC staining of untreated SU-DHL-8 tumors for CD19 and CD20. Upper row, lower magnification; lower row, higher magnification. Images were captured using a VS120 Virtual Slide Microscope (Olympus). (F) Average tumor volumes are illustrated as means + SEM for all treatment groups over time. Tumor-free mice are indicated as x/10. (G) Ex vivo flow cytometry analysis of tumors from scout animals reveals normalized CD8+ and CD4+ T-cell counts in all groups. Statistical analysis was performed using 1-way ANOVA, and significant P values are indicated as follows: ∗P < .05; ∗∗P < .01; ∗∗∗P < .001; ∗∗∗∗P < .0001.

The level and heterogeneity of tumor antigen expression shape combination therapy outcome. (A) In vivo efficacy study design. Humanized BRGS-CD47 mice with SC OCI-Ly18 tumors were randomized into 5 groups (12 mice each) and treated with either vehicle (histidine buffer), glofitamab (0.5 mg/kg), R-CHOP (rituximab 30 mg/kg, cyclophosphamide 30 mg/kg, doxorubicin 2.5 mg/kg, vincristine 0.375 mg/kg, methylprednisolone 0.12 mg/kg), or glofitamab in combination with either R-CHOP (staggered) or CD19–4-1BBL (1 mg/kg) as per the administration scheme. Methylprednisolone was given IV for 3 consecutive days during each cycle of treatment. All treatments were administered IV according to the displayed schedule. Glofitamab monotherapy and its combination with CD19–4-1BBL received Gpt (30 mg/kg). The study was terminated on day 45 after continuous weekly treatment. (B) Representative IHC staining of untreated OCI-Ly18 tumors for CD19 and CD20. Upper row, lower magnification; lower row, higher magnification. Images were captured using a VS120 Virtual Slide Microscope (Olympus). (C) Average tumor volumes are presented as means + SEM for all treatment groups over time. Tumor-free mice are indicated as x/12. (D) Experimental design of the in vivo efficacy study. Humanized BRGS-CD47 mice with SC SU-DHL-8 tumors were randomized into 5 groups (14 mice each). Mice were treated with either vehicle (histidine buffer), glofitamab (2 mg/kg), or glofitamab in combination with CD19–4-1BBL (1 mg/kg) or CD19-CD28 (1 mg/kg). An additional combination group received a single treatment with CD19-CD28 followed by continuous treatment with CD19–4-1BBL in combination with glofitamab, as per the administration scheme. All treatments were administered IV according to the displayed schedule. All groups received Gpt (30 mg/kg). Four scout animals per group were taken at day 18. (E) Representative IHC staining of untreated SU-DHL-8 tumors for CD19 and CD20. Upper row, lower magnification; lower row, higher magnification. Images were captured using a VS120 Virtual Slide Microscope (Olympus). (F) Average tumor volumes are illustrated as means + SEM for all treatment groups over time. Tumor-free mice are indicated as x/10. (G) Ex vivo flow cytometry analysis of tumors from scout animals reveals normalized CD8+ and CD4+ T-cell counts in all groups. Statistical analysis was performed using 1-way ANOVA, and significant P values are indicated as follows: ∗P < .05; ∗∗P < .01; ∗∗∗P < .001; ∗∗∗∗P < .0001.

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