Using a murine, syngeneic, orthotopic, metastatic pancreatic cancer (PDAC) model, Muth et al. showed that adding agonistic anti-CD137 (4-1BB), but not inhibitory anti-TIM3, -LAG3 or -CTLA-4, to anti-PD-1 plus GVAX (GM-CSF-secreting autologous vaccine) improved host survival; increased OX40+CD137+ CD4+ and CD8+ liver tumor-infiltrating T cells (TILs); decreased the percentage of PD-1+ CD8+ TILs and increased IFNγ expression by exhausted TILs in vitro. GVAX plus just anti-CD137 increased effector memory TIL levels, but not cytotoxic function. IHC showed that resected PDACs from GVAX-treated patients that had higher CD137+ cell density had more CD8+ T cells.
Contributed by Paula Hochman
ABSTRACT: 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(_PD-1) are able to improve the survival. We found that an anti-CD137 agonist antibody(_CD137) most significantly improved survival in the mouse PDAC model. Moreover, _PD-1 and _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 _PD-1 or _CD137, respectively, suggesting that T cell activation within PDACs were enhanced by a synergy of _CD137 and _PD-1. On another hand, _CD137 treatment led to an increase in effector memory T cells independent of _PD-1. Although _CD137 does not increase the cytotoxic effector T cell function, the addition of _CD137 to GVAX+_PD-1 increased expression of IFN_ 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.