This disclosure provides a method for inhibiting, delaying, or reducing malignant cell growth in a subject with cancer, comprising administering to the subject a combination therapy comprising an effective amount of an isolated antibody or antigen-binding fragment thereof that specifically binds to semaphorin-4D (SEMA4D) and an effective amount of an epigenetic modulating agent, e.g., a histone deacetylase (HDAC) inhibitor (HDACi) a DNA methyltransferase (DNMT) inhibitor (DNMTi), or any combination thereof. The disclosure further provides a pharmaceutical composition comprising the combination therapy.