PMC

Anti-CD137 mAb efficacy is time dependent. BALB/c mice were inoculated subcutaneously with 5 × 10⁶ A20 tumor cells. Mice received either no treatment (● and ) or 1 intraperitoneal injection of anti-CD137 mAb (■ and —) at various time points after tumor inoculation: day 0, day 3, day 6, or day 9. Mice (10 per group) were monitored for tumor growth (A, mean ± SEM) and overall survival (B).

Anti-CD137 agonistic mAb has potent antilymphoma activity in vivo. BALB/c mice were inoculated subcutaneously with 5 × 10⁶ A20 tumor cells. Mice received either no treatment or 2 intraperitoneal injections of mAb anti-OX40 mAb, anti-CTLA4 mAb, anti-GITR mAb, or anti-CD137 mAb at days 5 and 10 after tumor inoculation as described in “Tumor transplantation and immunotherapy.” Mice (10 per group) were then monitored for tumor growth (A, mean ± SEM) and overall survival (B).

Selective depletion of T_regs enhances anti-CD137 therapy. BALB/c mice were inoculated subcutaneously with 5 × 10⁶ A20 tumor cells. Mice then received 1 intraperitoneal injection of either rat IgG or anti-CD137 mAb at day 6 after tumor inoculation. FR4 depletion was initiated before tumor challenge as described in “Depletion of NK cells, CD4 T cells, CD8 T cells, and Tregs.” Groups include the following: rat IgG alone, rat IgG + anti-FR4, anti-CD137 mAb alone, and anti-CD137 mAb + anti-FR4. Mice were then monitored for tumor growth (A) and overall survival (B).

Mice cured with anti-CD137 mAb develop long-lasting antitumor immunity. (A-B) BALB/c mice treated and cured by anti-CD137 mAb therapy for more than 100 days or naive mice were (re)challenged subcutaneously with 5 × 10⁶ A20 tumors at a different site from original tumor challenge. Mice were then monitored for tumor growth (A, mean ± SEM) and overall survival (B). (C-D) After tumor rechallenge, splenocytes from αCD137-cured mice or control splenocytes from naive mice were harvested, restimulated in vitro with irradiated A20 tumor cells for 24 hours, and assessed for intracellular IFN-γ secretion by flow cytometry. Dot plots from FACS analysis show the proportion of IFN-γ–positive cells among all CD3⁺ T cells (C) and CD8 T cells (D).

Anti-CD137 therapy requires NK and CD8 T cells and is enhanced by CD4 T-cell depletion. (A-B) BALB/c mice were inoculated subcutaneously with 5 × 10⁶ A20 tumor cells. Depletion was initiated before tumor challenge as described in “Depletion of NK cells, CD4 T cells, CD8 T cells, and Tregs.” Mice received 1 intraperitoneal injection of either rat IgG or anti-CD137 mAb at day 6 after tumor inoculation. Groups include: rat IgG alone, anti-CD137 alone, CD4 depletion + anti-CD137, CD8 depletion + anti-CD137, or asialo GM1 depletion + anti-CD137. Mice were monitored for tumor growth (A, mean ± SEM) and overall survival (B). (C-E) BALB/c mice were inoculated subcutaneously with 5 × 10⁶ A20 tumor cells and received either no treatment (Tx) or 1 intraperitoneal injection of anti-CD137 mAb at day 8 after tumor inoculation. Five days after treatment, mice were killed and tumors and spleens were collected for analysis. (C) Representative data of the percentage of CD25⁺FoxP3⁺ T_regs among CD4 T cells in both spleen and tumor from untreated and treated groups. (D-E) The average percentage of CD25⁺FoxP3⁺ T_regs among CD4 T cells (D) and CD8 T cells (E) among total lymphocytes between the untreated and treated groups (3 mice per group).

Tumor-involved lymph nodes from lymphoma patients express high levels of CD137 mRNA and are infiltrated by CD137⁺ T cells. (A) Publicly available microarray gene expression data^, from bulk tumor specimens of 184 patients were analyzed for the expression of CD137 across histopathological groups. DLBCL and FL specimens significantly overexpressed CD137 compared with nonlymphoma specimens (P < .001 for each comparison). Aside from FL (n = 11) and DLBCL (n = 11), no other histopathological group significantly overexpressed CD137 compared with other tumor types. CA indicates carcinoma; NSCLC, non–small cell lung adenocarcinoma; CRC, colorectal adenocarcinoma; TCC, transitional cell carcinoma; AML, acute myeloid leukemia; and ALL, acute lymphoblastic leukemia. (B-C) Tumor-involved lymph nodes from untreated lymphoma patients (FL, MCL, and DLBCL) and PBMCs from healthy donors were analyzed by flow cytometry for CD137 expression on B and T cells. (B) CD137 expression on tumor B cells, and CD4 and CD8 T cells for 1 representative lymphoma sample (DLBCL). (C) The percentage of CD137⁺ cells among CD8 T cells in healthy PBMCs and lymphoma samples from different histologies.