Combination of Cbl-b inhibitor NX-1607 and CDK4/6 inhibitor abemaciclib enhances anti-tumor immunity through PLCγ1/ERK-mediated T cell activation

The Cbl-b inhibitor NX-1607 has shown significant antitumor activity and extended survival in murine models; however, its efficacy remains limited in certain patients. In order to expand the clinical application of Cbl-b inhibitors and to provide new therapeutic options for Cancer patients with unmet therapeutic needs, we utilized flow cytometry to screen compounds for potentiation in combination with Cbl-b inhibitors and to investigate the mechanism of action of the combination. In this study, we identify that the combination of NX-1607 with the CDK4/6 inhibitor abemaciclib directly augments T cell activation. Additionally, the combination therapy resulted in elevated levels of phosphorylated PLCγ1 and ERK1/2, as well as an upregulation of IFNG and IL2 gene expression compared to either monotherapy. Moreover, abemaciclib was effective in reducing the protein levels of Cbl-b. Notably, this combination therapy demonstrated superior antitumor efficacy compared to either monotherapy in the MC38-Ova tumor model, accompanied by increased infiltration of immune cells within the tumors. These findings suggest that the combination of Cbl-b inhibitors with CDK4/6 inhibitors may have significant synergistic effects in promoting immune cell infiltration and facilitating immune activation. Therefore, this combination represents a promising therapeutic strategy for the treatment of solid tumors.

Abemaciclib; Cbl-b; Combination therapy; NX-1607; T cell activation.