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

Abstract

<p>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>B</b> and <b>C</b>) within tumors, tumor growth (<b>D</b>), and survival (<b>E</b>). As illustrated in <b>A</b>, transcriptional analysis was performed (<i>n</i> = 5–7) on tumor tissue harvested from mice 48 hours after second (<b>B</b>) and third doses (<b>C</b>) of indicated mAbs; raw data in <a href="#SMT4" target="_blank">Supplementary Table S4</a>. Each line in <b>D</b> represents an individual mouse (<i>n</i> = 10/group). Tumor-free mice at study termination are indicated within each subpanel. <b>E,</b> Kaplan–Meier plot illustrating OS in D. <b>F,</b><i>ICOS</i> expression following <i>ex vivo</i> 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 (<i>n</i> = 50/group). <b>G,</b> Fold change in IFNγ production by TILs from dissociated NSCLC tumor samples (<i>n</i> = 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. <b>H,</b> 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 (<i>n</i> = 10/group). Data in F–H are represented as mean ± s.e.m. Significance in G determined by unpaired Student <i>t</i> 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.</p>