Immunotherapy and specifically
oncolytic virotherapy has emerged as a promising option for
cancer patients, with oncolytic
herpes simplex virus-1 (oHSV-1) expressing
granulocyte macrophage colony stimulating factor being the first OV to be approved by the FDA for treatment of
melanoma. However, not all
cancers are sensitive and responsive to oncolytic viruses (OVs). Our group has demonstrated that fumaric and
maleic acid esters (FMAEs) are very effective in sensitizing
cancer cells to OV
infection. Of note, these FMAEs include
dimethyl fumarate (DMF, also known as Tecfidera®), an approved treatment for
multiple sclerosis and
psoriasis. This study aimed to assess the efficacy of DMF in combination with oncolytic HSV-1 in preclinical
cancer models. We demonstrate herewith that pre-treatment with DMF or other FMAEs leads to a significant increase in viral growth of oHSV-1 in several
cancer cell lines, including
melanoma, while decreasing cell viability. Additionally, DMF was able to enhance ex vivo oHSV-1
infection of mouse-derived
tumor cores as well as human patient
tumor samples but not normal tissue. We further reveal that the increased viral spread and oncolysis of the combination
therapy occurs via inhibition of type I IFN production and response. Finally, we demonstrate that DMF in combination with oHSV-1 can improve therapeutic outcomes in aggressive syngeneic murine
cancer models. In sum, this study demonstrates the synergistic potential of two approved
therapies for clinical evaluation in
cancer patients.