Ponatinib Averts αCD40 Antibody Mediated Toxicity by Lowering MAPK38 Expression and Shows Proimmunogenic Effects in a...

The use of the agonist CD40 antibody (αCD40) is associated with several disadvantages including the cytokine release syndrome (CRS), hepatotoxicity, and induced PD-L1 expression. Previously, we have demonstrated that ponatinib, a tyrosine kinase inhibitor, could inhibit induced programmed death ligand 1 (PD-L1) expression. In this study, we showed that combinatorial treatment of αCD40 and ponatinib delayed the tumor growth and overall survival in mice bearing B16-F10 melanoma and 4T1 orthotopic tumors. The combination treatment increased the CD45⁺CD8⁺ T cell population in the tumor; induced CD86 expression; and lowered the expression of PD-L1, FOXP3, and Arginase-1 in both the tumor and spleen. Interestingly, ponatinib averted both immuno- and hepatotoxicity of αCD40 monotherapy by lowering alanine aminotransferase (ALT), aspartate aminotransferase (AST), IL-6, IL-10, and IL-1β levels through downregulating MAPK38 and ERK1/2 expression. Our results suggest that this combination can be further explored in clinics to improve the in vivo antitumor efficacy of αCD40 while reducing the associated toxicities.