numidargistat (INCB001158)

P1, N=260, Completed, Incyte Corporation | Phase classification: P1/2 --> P1

Our previous work showed that in vivo the treatment with arginase inhibitor CB1158 could reduce MM growth while increasing serum arg concentrations without affecting the infiltrates of myeloid cells... Taken together, our findings suggest that arginine deprivation, while inducing immune dysfunction, conveys a complex adaptive response which causes a chromatin remodeling that leads to the acquisition of a senescencephenotype to select the most fit clone and favors genomic instability, providing new insights to improve immunotherapy and induce synthetic lethality in MM.

In treatment-naïve DLBCL adults, a high surface-TREM2 level on circulating M-MDSCs is a poor prognostic factor for both PFS and OS and warrants further investigation for its potential as a novel target in immunotherapy.

Treatment of established tumors with the arginase inhibitor CB-1158 exhibited further increased CD8 T cell infiltration, beyond that seen with the macrophage-specific knockout, and sensitized the tumors to anti-PD1 immune checkpoint blockade. Our data demonstrate that Arg1 drives immune suppression in pancreatic cancer by depleting Arginine and inhibiting T cell activation.

After 8 weeks post transplantation, we investigated the role of Arg-1 and PD-L1 in Shp2* recipients using pharmacological inhibitors, CB-1158 (Arg-1 inhibitor; 100 mg/kg, orally) + anti-PD-L1 antibody (10 mg/kg, i.p) for 30 days...These data suggest that the suppression of arginase-1 allows for the arginine levels to increase, which promotes the proliferation of T-cells. Increasing arginine levels also promotes an anti-tumor immune response resulting in the emergence of CD45.1 WT HSCs as opposed to mutant CD45.2 HSCs, suggesting that Arg-1 + PD-L1 treatment is a novel therapeutic approach to treat patients with JMML and for preventing leukemia relapse after BM transplantation.