Antitumor Activity of the PD-1/PD-L1 Inhibitor SCL-1 in Various Mouse Tumor Models.

Background/aim: Immune checkpoint blockade has achieved great success as a targeted immunotherapy for solid cancers. However, small molecules that inhibit programmed death 1/programmed death ligand 1 (PD-1/PD-L1) binding are still being developed and have several advantages, such as high bioavailability. Previously, we reported a novel PD-1/PD-L1-inhibiting small compound, SCL-1, which showed potent antitumor effects on PD-L1 tumors. These effects were dependent on CD8 T-cell infiltration and PD-L1 expression on tumors. The present study investigated the in vivo antitumor activity of SCL-1 in various mouse syngeneic tumor models.

Materials And Methods: Twelve syngeneic mice models of tumors, such as colon, breast, bladder, kidney, pancreatic, non-small cell lung cancers, melanoma, and lymphomas, were used for in vivo experiments. Tumor mutation burden (TMB) was analyzed by whole exome sequencing (WES) using reference DNA from mouse blood. The proportion of CD8 T-cells infiltrating tumors before and after treatment was assessed using flow cytometry and immunohistochemistry (IHC).

Results: SCL-1 had a markedly greater antitumor effect (11 sensitive tumors and 1 resistant tumor among the 12 tumor types) than the anti-mouse PD-1 antibody (8 sensitive tumors and 4 resistant tumors). In addition, the tumor growth inhibition rate (%) was more closely associated with TMB in the SCL-1 group than in the anti-PD-1 antibody group. Furthermore, in vivo experiments using PD-L1 gene knockout and lymphocyte-depletion technologies demonstrated that the antitumor activity of SCL-1 was dependent on CD8 T-cell infiltration and PD-L1 expression in tumors.

Conclusion: SCL-1 has great potential as an oral immunotherapy that targets immune checkpoint molecules in cancer treatment.