- [IMMUNOLOGY AND IMMUNOTHERAPY]
- [COMBINATION STRATEGIES FOR TRANSLATIONAL IMMUNOTHERAPY]
- [CYTOKINE-BASED THERAPEUTICS]
Intratumoral virotherapy with 4-1BBL armed modified vaccinia Ankara eradicates solid tumors and promotes protective immune memory
Maria Hinterberger, Raphael Giessel, Giovanna Fiore, Fabienne Graebnitz, Barbara Bathke, Sonia Wennier, Paul Chaplin, Ignacio Melero, Mark Suter, Henning Lauterbach, Pedro Berraondo, Hubertus Hochrein, José Medina-Echeverz
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.
CITATION J Immunother Cancer. 2021 Feb;9(2):e001586. doi: 10.1136/jitc-2020-001586.