Multimodality
therapy consisting of surgery,
chemotherapy, and radiation will fail in approximately 40% of patients with pediatric
sarcomas and result in substantial long-term morbidity in those who are cured. Immunotherapeutic regimens for the treatment of solid
tumors typically generate
antigen-specific responses too weak to overcome considerable
tumor burden and
tumor suppressive mechanisms and are in need of adjuvant assistance. Previous work suggests that inhibitors of DASH (
dipeptidyl peptidase IV activity and/or structural homologs)
enzymes can mediate
tumor regression by immune-mediated mechanisms. Herein, we demonstrate that the DASH inhibitor,
ARI-4175, can induce regression and eradication of well-established solid
tumors, both as a single agent and as an adjuvant to a dendritic cell (DC)
vaccine and adoptive
cell therapy (ACT) in mice implanted with the M3-9-M
rhabdomyosarcoma cell line. Treatment with effective doses of
ARI-4175 correlated with recruitment of myeloid (CD11b) cells, particularly myeloid DCs, to secondary lymphoid tissues and with reduced frequency of intratumoral monocytic (CD11bLy6-CLy6-G) myeloid-derived suppressor cells. In immunocompetent mice, combining
ARI-4175 with a DC
vaccine or ACT with
tumor-primed T cells produced significant improvements in
tumor responses against well-established M3-9-M
tumors. In M3-9-M-bearing immunodeficient (Rag1) mice, ACT combined with
ARI-4175 produced greater
tumor responses and significantly improved survival compared with either treatment alone. These studies warrant the clinical investigation of
ARI-4175 for treatment of
sarcomas and other
malignancies, particularly as an adjuvant to
tumor vaccines and ACT.