FIGURE 4 from Activating Inducible T-cell Costimulator Yields Antitumor Activity Alone and in Combination with Anti-PD-1 Checkpoint Blockade

ICOS agonist mAbs demonstrate improved antitumor activity in combination with PD-1 blockade. EMT6 (subcutaneous) tumor-bearing BALB/c mice were administered intraperitoneally biweekly with anti-mouse ICOS mAb [7E.17G9 (mIgG1)], anti-PD-1 mAb (RMP1-14), or isotype controls (mIgG1 and rat IgG2a, respectively) alone and in combination for a total of six doses. Mice were evaluated for pharmacodynamic changes (B and C) within tumors, tumor growth (D), and survival (E). As illustrated in A, transcriptional analysis was performed (n = 5–7) on tumor tissue harvested from mice 48 hours after second (B) and third doses (C) of indicated mAbs; raw data in Supplementary Table S4. Each line in D represents an individual mouse (n = 10/group). Tumor-free mice at study termination are indicated within each subpanel. E, Kaplan–Meier plot illustrating OS in D. F,ICOS expression following ex vivo anti–PD-1 (pembrolizumab) or vehicle control treatment of tumor slices from patients with HNSCC for 48 hours. Each symbol represents an individual human tumor sample (n = 50/group). G, Fold change in IFNγ production by TILs from dissociated NSCLC tumor samples (n = 5–6 samples/group) following exposure to anti-CD3 (plate-bound, 0.6 μg/mL) in concert with anti-PD-1 (pembrolizumab, soluble) or feladilimab (plate-bound) alone or in combination for 24 hours. H, A2058 (subcutaneous) tumor-bearing NSG mice were administered intraperitoneally biweekly with feladilimab and anti-PD-1 (pembrolizumab) alone or in combination for a total of six doses and assessed for tumor growth inhibition (n = 10/group). Data in F–H are represented as mean ± s.e.m. Significance in G determined by unpaired Student t test. Despite trends in tumor growth kinetics following combination treatment, the curves in H were not significantly different as determined by one-way ANOVA. ANOVA, analysis of variance; HNSCC, head and neck squamous cell carcinoma; ICOS, inducible T cell costimulator; IFN, interferon; i.p., intraperitoneal injection; mAb, monoclonal antibody; NSCLC, non–small cell lung carcinoma; OS, overall survival; PD-1, programmed cell death protein 1; s.e.m., standard error of the mean; TIL, tumor-infiltrating lymphocyte.