Intratumoral administration of modified vaccinia Ankara expressing a tumor associated antigen and the costimulatory molecules IL-12 and 4-1BBL induces potent systemic long-term immune responses against murine tumors

Abstract In the last decade, immunotherapy has revolutionized cancer treatment. However, the lack of potent therapy-induced immune responses against solid tumors due to the immune-suppressive tumor microenvironment (TME) is still a major drawback. One approach to reprogram TME is virotherapy, which can target tumors via destruction of infected tumor cells as well as activating immune cell populations in the TME. A versatile and safe tool for virotherapy is modified vaccinia virus Ankara (MVA), which has already been approved by the FDA as a non-replicating vaccine against smallpox and monkeypox and is also in clinical trials against other infectious diseases and cancer. In the current study, we deciphered the anti-tumorigenic effect of a novel MVA vector encoding a tumor associated antigen (TAA) and the costimulatory molecules IL-12 and 4-1BBL, called MVA-TAA-4-1BBL-IL12. We could show that repetitive intratumoral (IT) injection of MVA-TAA-4-1BBL-IL12 resulted in strong tumor growth control, shrinkage and/or complete elimination of tumors and induction of tumor-specific CD8 T cell response. Furthermore, MVA-TAA-4-1BBL-IL12 treatment promoted a systemic anti-tumor immune response not only against the treated tumor but also untreated, distant tumors. Importantly, local virotherapy also resulted in the generation of tumor-specific memory response, which protected mice against local recurrence after rechallenge. As a conclusion, our findings show that MVA-TAA-4-1BBL-IL12 IT treatment induces an effective anti-tumorigenic immune response in different solid tumor models, which gives rise to long-term protection against cancer recurrence. Citation Format: Cigdem Atay Langbein, Raphael Giessel, Mahmad Ismail Housni, Kerstin Lämmermann, Barbara Bathke, André Riedl, Jürgen Hausmann, Markus Kalla, Paul Chaplin, Hubertus Hochrein, José Medina-Echeverz, Maria Hinterberger. Intratumoral administration of modified vaccinia Ankara expressing a tumor associated antigen and the costimulatory molecules IL-12 and 4-1BBL induces potent systemic long-term immune responses against murine tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB223.