Disclosed herein are methods and compositions related to the treatment, prevention, and/or amelioration of cancer in a subject in need thereof. In particular aspects, the present technology relates to the use of poxviruses, including an engineered attenuated vaccinia virus (VACV) strain comprising a disruption of the N-terminal DNA binding domain of the E3L gene (E3L?A83N) with a deletion of thymidine kinase (E3L?83N-TK-) engineered to express an antibody specifically targeting cytotoxic T lymphocyte antigen 4 (E3L?83N-TK--anti- CTLA-4), alone or in combination with immune checkpoint blocking agents or immune stimulating agents, as an oncolytic and immunotherapeutic composition. In some aspects, the present technology relates to an E3L?83N-TK--anti-CTLA-4 virus further engineered to express human Fms-like tyrosine kinase 3 ligand (hFlt3L) (E3L?83N-TK--hFlt3L-anti- CTLA-4). In some embodiments, the engineered viruses are administered to a subject alone or in combination with immune checkpoint blocking agents or immune stimulating agents, as an oncolytic and immunotherapeutic composition.
