Anti–Programmed Death-1 Synergizes with Granulocyte Macrophage Colony-Stimulating Factor–Secreting Tumor Cell Immunotherapy Providing Therapeutic Benefit to Mice with Established Tumors

Abstract

The purpose of the present study was to evaluate granulocyte macrophage colony-stimulating factor (GM-CSF)-secreting tumor cell immunotherapy, which is known to stimulate potent and long-lasting antigen-specific immune responses, in combination with PD-1 blockade, which has been shown to augment cellular immune responses. Survival studies were done in the B16 melanoma and CT26 colon carcinoma tumor models. Immune monitoring studies were done in the B16 model. GM-CSF-secreting tumor cell immunotherapy was administered s.c. and the anti-PD-1 antibody was administered i.p. The studies reported here show that combining PD-1 blockade with GM-CSF-secreting tumor cell immunotherapy prolonged the survival of tumor-bearing animals compared with animals treated with either therapy alone. Prolonged survival correlated with strong antigen-specific T-cell responses detected by tetramer staining and an in vivo CTL assay, higher secretion levels of proinflammatory cytokines by splenocytes, and the persistence of functional CD8+ T cells in the tumor microenvironment. Furthermore, in the biweekly multiple treatment setting, repeated antigen-specific T-cell expansion was only observed following administration of the cellular immunotherapy with the PD-1 blockade and not when the cellular immunotherapy or PD-1 blockade was used as monotherapy. The combination of PD-1 blockade with GM-CSF-secreting tumor cell immunotherapy leads to significantly improved antitumor responses by augmenting the tumor-reactive T-cell responses induced by the cellular immunotherapy. Readministration of the cellular immunotherapy with the anti-PD-1 antibody in subsequent immunotherapy cycles was required to reactivate these T-cell responses.