In an immunocompetent mouse model, Leoni and Vannini et al. tested R-115 – an IL-12-armed, HER-2-retargeted, fully virulent oncolytic herpes simplex virus (oHSV) – administered locally in HER2-transgenic/tolerant, immunocompetent mice bearing HER2-Lewis lung carcinoma tumors. The treatment showed a good safety profile and inhibited the growth of primary tumors; surviving mice were protected from tumor rechallenge at distant sites. Treatment led to increased tumor infiltration by CD4+, CD8+, CD335+, CD141+, and Foxp3+ cells, increased activation of effector cells, Th1 polarization, and durable antitumor reactivity in responders.
Oncolytic herpes simplex viruses (oHSVs) showed efficacy in clinical trials and practice. Most of them gain cancer-specificity from deletions/mutations in genes that counteract the host response, and grow selectively in cancer cells defective in anti-viral response. Because of the deletions/mutations, they are frequently attenuated or over-attenuated. We developed next-generation oHSVs, which carry no deletion/mutation, gain cancer-specificity from specific retargeting to tumor cell receptors-e.g. HER2 (human epidermal growth factor receptor 2)-hence are fully-virulent in the targeted cancer cells. The type of immunotherapy they elicit was not predictable, since non-attenuated HSVs induce and then dampen the innate response, whereas deleted/attenuated viruses fail to contrast it, and since the retargeted oHSVs replicate efficiently in tumor cells, but spare other cells in the tumor. We report on the first efficacy study of HER2-retargeted, fully-virulent oHSVs in immunocompetent mice. Their safety profile was very high. Both the unarmed R-LM113 and the IL-12-armed R-115 inhibited the growth of the primary HER2-Lewis lung carcinoma-1 (HER2-LLC1) tumor, R-115 being constantly more efficacious. All the mice that did not die because of the primary treated tumors, were protected from the growth of contralateral untreated tumors. The long-term survivors were protected from a second contralateral tumor, providing additional evidence for an abscopal immunotherapeutic effect. Analysis of the local response highlighted that particularly R-115 unleashed the immunosuppressive tumor microenvironment, i.e. induced immunomodulatory cytokines, including IFNgamma, T-bet which promoted Th1 polarization. Some of the tumor infiltrating cells, e.g. CD4+, CD335+ cells were increased in the tumors of all responders mice, irrespective of which virus was employed, whereas CD8+, Foxp3+, CD141+ were increased and CD11b+ cells were decreased preferentially in R-115-treated mice. The durable response included a breakage of tolerance towards both HER2 and the wt tumor cells, and underscored a systemic immunotherapeutic vaccine response.
Author Info: (1) Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy. (2) Department of Experimental, Diagnostic and Specialty Medicine, Univers
Author Info: (1) Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy. (2) Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy. (3) Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy. (4) Department of Veterinary Medical Sciences, University of Bologna, Bologna, Italy. (5) Department of Veterinary Medical Sciences, University of Bologna, Bologna, Italy. (6) Department of Veterinary Medical Sciences, University of Bologna, Bologna, Italy. (7) Department of Veterinary Medical Sciences, University of Bologna, Bologna, Italy. (8) Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy. (9) Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy. (10) Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy. (11) Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy.
