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

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.