Date Published: August 6, 2018
Publisher: Public Library of Science
Author(s): Valerio Leoni, Andrea Vannini, Valentina Gatta, Julie Rambaldi, Mara Sanapo, Catia Barboni, Anna Zaghini, Patrizia Nanni, Pier-Luigi Lollini, Costanza Casiraghi, Gabriella Campadelli-Fiume, Lindsey Hutt-Fletcher.
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 IFNγ, 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.
Oncolytic viruses (OVs) meet the need for novel anticancer agents characterized by low toxicity and low negative impact on the quality of life of patients [1–4]. Oncolytic herpes simplex viruses (oHSVs) stand for their efficacy in a number of clinical applications [5,6]. The most successful oHSV, OncovexGM-CSF, was approved against metastatic melanoma [7,8]. The Clinical trials.gov website lists 22 open or recently completed trials with oHSVs [9–13]. Much of the current interest in OVs stems from their immunotherapeutic properties. Thus, oHSVs, and OVs in general, boost the immune response to the tumor, exert a therapeutic vaccine effect with no requirement for the identification of the tumor-specific or patient-specific neoantigens [14–17]. In combination with checkpoint inhibitors (CPIs), they enhance the efficacy of the blockade therapy [18–21]. They can be engineered to express anti-checkpoint antibodies .
We report on the first efficacy studies of fully virulent, HER2-retargeted oHSVs, either unarmed (R-LM113) or armed with mIL-12 (R-115). Their peri- intra-tumoral administration led to a reduction in the growth of the primary tumor, particularly in the R-115-treated mice, to intratumoral and systemic immune responses which almost completely prevented the engraftment of distant untreated tumors. In essence, the intralesional vaccination promoted local and systemic immunity. Pertinent to the model system and the main results is the following.