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Background Human cancers are extraordinarily heterogeneous in terms of tumor antigen expression, immune infiltration and composition. A common feature, however, is the host's inability to mount potent immune responses that prevent tumor growth effectively. Often, naturally primed CD8+ T cells against solid tumors lack adequate stimulation and efficient tumor tissue penetration due to an immune hostile tumor microenvironment.Methods To address these shortcomings, we cloned tumor-associated antigens (TAA) and the immune-stimulatory ligand 4-1BBL into the genome of modified vaccinia Ankara (MVA) for intratumoral virotherapy.Results Local treatment with MVA-TAA-4-1BBL resulted in control of established tumors. Intratumoral injection of MVA localized mainly to the tumor with minimal leakage to the tumor-draining lymph node. In situ infection by MVA-TAA-4-1BBL triggered profound changes in the tumor microenvironment, including the induction of multiple proinflammatory molecules and immunogenic cell death. These changes led to the reactivation and expansion of antigen-experienced, tumor-specific cytotoxic CD8+ T cells that were essential for the therapeutic antitumor effect. Strikingly, we report the induction of a systemic antitumor immune response including tumor antigen spread by local MVA-TAA-4-1BBL treatment which controlled tumor growth at distant, untreated lesions and protected against local and systemic tumor rechallenge. In all cases, 4-1BBL adjuvanted MVA was superior to MVA.Conclusion Intratumoral 4-1BBL-armed MVA immunotherapy induced a profound reactivation and expansion of potent tumor-specific CD8+ T cells as well as favorable proinflammatory changes in the tumor microenvironment, leading to elimination of tumors and protective immunological memory.

Original publication

DOI

10.1136/jitc-2020-001586

Type

Journal article

Journal

Journal for immunotherapy of cancer

Publication Date

02/2021

Volume

9

Addresses

Bavarian Nordic GmbH, Planegg, Germany mahi@bavarian-nordic.com jome@bavarian-nordic.com.

Keywords

CD8-Positive T-Lymphocytes, Cell Line, Tumor, Animals, Mice, Vaccinia virus, Melanoma, Experimental, Antigens, Neoplasm, Treatment Outcome, Combined Modality Therapy, Cloning, Molecular, Immunologic Memory, Drug Synergism, Female, Oncolytic Virotherapy, 4-1BB Ligand, Tumor Microenvironment