CD137 agonist-based combination immunotherapy enhances activated, effector memory T cells and prolongs survival in pancreatic adenocarcinoma

Pancreatic ductal adenocarcinoma(PDAC) is resistant to the PD-1/PD-L1 blockade therapy. Previously, the combination of PD-1 blockade and vaccine therapy was shown to have a modest antitumor activity in murine models of PDAC. We used a murine syngeneic model of metastatic PDAC to identify, among multiple T cell modulators tested, which therapeutic agents in combination with the GVAX cancer vaccine and an anti-PD-1 antagonist antibody(alpha PD-1) are able to improve the survival. We found that an anti-CD137 agonist antibody (alpha CD137) most significantly improved survival in the mouse PDAC model. Moreover, alpha PD-1 and alpha CD137 together in combination with vaccine therapy more significantly increased the expression of costimulatory molecules CD137 and OX40 on CD4+PD-1+ and CD8+PD-1+ T cells comparing to alpha PD-1 or aCD137, respectively, suggesting that T cell activation within PDACs were enhanced by a synergy of alpha CD137 and alpha PD-1. On another hand, alpha CD137 treatment led to an increase in effector memory T cells independent of alpha PD-1. Although alpha CD137 does not increase the cytotoxic effector T cell function, the addition of alpha CD137 to GVAX+alpha PD-1 increased expression of IFN gamma in EOMES + exhausted tumor-infiltrating T cells. Taken together, this preclinical study established the mechanism of targeting CD137 to enhance effector memory and activated T cells in PDAC. Immunohistochemistry analysis of resected human PDACs following the neo-adjuvant GVAX treatment showed increased levels of CD8(+) T cells in those with high levels of CD137 expression, supporting an ongoing clinical trial of testing CD137 as a potential target in treating PDACs that are inflamed with T cells by vaccine therapy.

Automated summary

This study found that the combination of an anti-CD137 agonist antibody αCD137 with an anti-PD-1 antagonist antibody αPD-1 significantly improved survival in a mouse model of PDAC, and enhanced T cell activation.