Allogeneic hematopoietic
cell transplantation is an established treatment for hematologic and nonhematologic
malignancies. Donor-derived immune cells can identify and attack host
tumor cells, producing a graft-versus-
tumor (GVT) effect that is crucial to the effectiveness of the
transplantation therapy.
CBLB502 is a novel agonist for TLR5 derived from Salmonella
flagellin. On the basis of TLR5-mediated immunomodulatory function, we examined the effect of
CBLB502 on GVT activity. Using two
tumor models that do not express TLR5, and thereby do not directly respond to
CBLB502, we found that
CBLB502 treatment significantly enhanced allogeneic CD8(+) T cell-mediated GVT activity, which was evidenced by decreased
tumor burden and improved host survival. Importantly, histopathologic analyses showed that
CBLB502 treatment did not exacerbate the moderate
graft-versus-host disease condition caused by the allogeneic CD8(+) T cells. Moreover, mechanistic analyses showed that
CBLB502 stimulates CD8(+) T cell proliferation and enhances their
tumor killing activity mainly indirectly through a mechanism that involves the
IL-12 signaling pathway and the CD11c(+) and CD11b(+) populations in the bone marrow cells. This study demonstrates a new beneficial effect of
CBLB502, and suggests that TLR5-mediated immune modulation may be a promising approach to improve GVT immunity without exacerbating
graft-versus-host disease.