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Recombinant-modified vaccinia virus Ankara (rMVA) is known to elicit potent antitumor immune responses in preclinical models due to its inherent ability to activate the innate immune system and the activation of adaptive responses mediated by the expression of tumor antigens and costimulusproviding molecules, such as CD40L and CD137L. Here, we evaluated different rMVA vectors in preclinical peritoneal carcinomatosis models (ID8.OVA-Vegf/GFP and MC38). We compared rMVA vectors expressing a tumor antigen (OVA or gp70) either alone or co-expressed with CD40L or/and CD137L. In tumor-free mice, the vector coding for the triple combination was only slightly superior, whereas, in tumor-bearing animals, we observed a synergistic induction of T lymphocytes specific against vector-encoded and non-encoded tumor-associated antigens. The enhanced activation of the immune response was associated with improved survival in mice with peritoneal carcinomatosis treated with a rMVA vector encoding both CD40L and CD137L. Thus, the triple transgene combination in vaccinia viral vectors represents a promising strategy for the treatment of peritoneal carcinomatosis. [ABSTRACT FROM AUTHOR]