ICOS Stimulation and PD-1 Inhibition Demonstrate Pathway Interplay and Combine to Improve Antitumor Activity in Mice
NSCLC, tumor, pembrolizumab, human malignant melanoma tumors
TUMOR, NSCLC
Given the role of ICOS signaling in the expansion and improved function of recently activated T cells (To test whether a PD-1 blocking antibody could augment the antitumor activity of an ICOS agonist mAb, we administered EMT6 tumor-bearing mice with the mIgG1 ICOS agonist mAb (7E.17G9) alone and in combination with anti-PD-1 antibody (clone RMP1-14) via intraperitoneal injection. Transcriptional analysis was conducted on tumor tissue harvested 48 hours after second and third doses of control or therapeutic mAbs (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 (Analysis by multiplex IHC showed that ICOS and PD-1 are often coexpressed on CD3These findings were extended to a primary dissociated tumor assay, wherein tumor samples from patients with NSCLC were enzymatically dissociated and expanded TILs were stimulated with plate-bound anti-CD3 and exposed to feladilimab, pembrolizumab, or the combination. While ICOS costimulation alone resulted in a significant increase in IFNγ compared with control, the combination of feladilimab and pembrolizumab induced a significantly greater fold change in IFNγ production than pembrolizumab alone (Finally, we extended these observations to a humanized murine model, wherein human PBMC-engrafted NSG mice bearing A2058 human malignant melanoma tumors were administered feladilimab and pembrolizumab. While both feladilimab and PD-1 blockade demonstrated modest monotherapeutic effects, the combination of feladilimab and pembrolizumab resulted in enhanced tumor control relative to the monotherapies, though this was not statistically significant (