An Agent-Based Model of Combination Oncolytic Viral Therapy and Anti-PD-1 Immunotherapy Reveals the Importance of Spatial Location When Treating Glioblastoma

Oncolytic viral therapies and immunotherapies are of growing clinical interest due to their selectivity for tumor cells over healthy cells and their immunostimulatory properties. These treatment modalities provide promising alternatives to the standard of care, particularly for cancers with poor prognoses, such as the lethal brain tumor glioblastoma (GBM). However, uncertainty remains regarding optimal dosing strategies, including how the spatial location of viral doses impacts therapeutic efficacy and tumor landscape characteristics that are most conducive to producing an effective immune response. We develop a three-dimensional agent-based model (ABM) of GBM undergoing treatment with a combination of an oncolytic Herpes Simplex Virus and an anti-PD-1 immunotherapy. We use a mechanistic approach to model the interactions between distinct populations of immune cells, incorporating both innate and adaptive immune responses to oncolytic viral therapy and including a mechanism of adaptive immune suppression via the PD-1/PD-L1 checkpoint pathway. We utilize the spatially explicit nature of the ABM to determine optimal viral dosing in both the temporal and spatial contexts. After proposing an adaptive viral dosing strategy that chooses to dose sites at the location of highest tumor cell density, we find that, in most cases, this adaptive strategy produces a more effective treatment outcome than repeatedly dosing in the center of the tumor.

Fighting cancer with oncolytic viral therapy: identifying threshold parameters for success

We model interactions between cancer cells and free virus during oncolytic viral therapy. One of our main goals is to identify parameter regions which yield treatment failure or success. We show that the tumor size under therapy at a certain time is less than the tumor size without therapy. We determine the minimum tumor size by the therapy and parameter regions under which this minimum is attained. Our analysis shows there are two thresholds for the horizontal transmission rate: a "Control threshold", the threshold above which treatment is efficient, and an "optimum threshold'', the threshold beyond which infection prevalence reaches 100% and the tumor shrinks to its smallest size. Moreover, we explain how changes in the virulence level of the free virus alters the optimum threshold and the minimum tumor size. We identify a threshold for the virulence level of the virus and show how this threshold depends on timescale of virus dynamics. Our results suggests that when timescale of virus dynamics is fast, administration of a more virulent virus leads into more tumor reduction. When viral timescale is slow, a higher virulence will have drawbacks on the results, such as high amplitude oscillations. Furthermore, our numerical observation depicts fast and slow dynamics. Our numerical simulations indicate there exists a two-dimensional globally attracting surface that includes unstable manifold of the interior equilibrium. All solutions with positive initial conditions rapidly approach this two-dimensional attracting surface. In contrast, the trajectories on the attracting surface slowly tend to the periodic solution.

Safety and interim survival data after intracranial administration of M032, a genetically engineered oncolytic HSV-1 expressing IL-12, in pet dogs with sporadic gliomas

OBJECTIVEThe diagnosis of glioma remains disheartening in the clinical realm. While a multitude of studies and trials have shown promise, improvements in overall survival have been disappointing. Modeling these tumors in the laboratory setting has become increasingly challenging, given their complex in situ behavior and interactions for therapeutic evasion. Dogs, particularly brachycephalic breeds, are known to spontaneously develop gliomas that resemble human gliomas both clinically and pathophysiologically, making canines with sporadic tumors promising candidates for study. Typically, survival among these dogs is approximately 2 months with palliation alone.METHODSThe authors have completed the first stage of a unique phase I dose-escalating canine clinical trial in which the safety and tolerability of M032, a nonneurovirulent oncolytic herpes simplex virus–1 vector genetically engineered to express interleukin-12, are being studied in pet dogs with gliomas undergoing maximum safe tumor resection and inoculation of the cavity with the viral infusate.RESULTSTwenty-five canine patients were enrolled between January 2018 and August 2020. One patient was electively withdrawn from the trial by its owner, and 3 did not receive the virus. For the 21 dogs that remained, 13 had high-grade gliomas, 5 had low-grade gliomas, and 3 were undetermined. According to histopathological analysis, 62% of the tumors were oligodendrogliomas. At the time of this report, the median overall survival from the date of treatment was 151 days (± 78 days). No significant adverse events attributable to M032 or dose-limiting toxicities have been observed to date.CONCLUSIONSIn this largest study of oncolytic viral therapy for canine brain tumors to date, treatment with M032 did not cause harm and the combination of surgery and oncolytic viral therapy may have contributed to prolonged survival in pet dogs with spontaneous gliomas. Forthcoming in-depth radiographic, immunohistochemical, and genetic analyses will afford a more advanced understanding of how this treatment impacts these tumors and the immune system. Our goal is to utilize these findings bitranslationally to inform human studies and refine therapies that will improve outcomes in both humans and pet dogs with gliomas.

Clinical trials using oncolytic viral therapy to treat adult glioblastoma: a progress report

OBJECTIVEAdult glioblastoma (GBM) has proven refractory to decades of innovation. Oncolytic viral therapy represents a novel therapy that uses viral vectors as both a delivery and therapeutic mechanism to target GBM cells. Despite the growing body of basic science data supporting the feasibility of viral therapy to treat GBM, the reporting of clinical trial results is heterogeneous. Correspondingly, the aim of this study was to present a contemporary summary of the progress all clinical trials have made to date.METHODSThe ClinicalTrials.gov database was reviewed in August 2020 for all possible interventional clinical trials involving viral vector–based therapy to treat adult GBM. These were then screened against selection criteria to identify pertinent clinical trials.RESULTSA total of 29 oncolytic viral therapy trials treating adult GBM were identified. The median start and expected completion years were 2014 and 2020, respectively. At the time of this writing, 10 (35%) trials were reported to have completed recruitment, whereas 7 (24%) were actively recruiting. The median target enrollment number was 36 (range 13–108), with the majority of trials being phase I (n = 18, 62%), and involving secondary GBM among other malignant glioma (n = 19, 66%). A total of 10 unique viral vectors were used across all trials, with the most common being adenovirus (n = 16, 55%). Only 2 (7%) phase I trials to date have reported outcomes on the ClinicalTrials.gov portal. Results of 12 additional clinical trials were found in academic publications, with median progression-free and overall survival times of 3 and 15 months, respectively, after the first viral dose at recurrence. The coordination of the large majority of trials originated from the US (n = 21, 72%), and the median number of testing sites per trial was 1 (range 1–15), via industry funding (n = 18 trials, 62%).CONCLUSIONSThere are multiple early-stage oncolytic viral therapy clinical trials for adult GBM currently active. To date, limited results and outcomes are promising but scarce. The authors expect this to change in the near future because many trials are scheduled to have either nearly or actually reached their expected recruitment completion time. How exactly oncolytic viral therapy will fit into the current treatment paradigms for primary and secondary GBM remains to be seen, and will not be known until safety and toxicity profiles are established by these clinical trials.

Vitamin D as a Primer for Oncolytic Viral Therapy in Colon Cancer Models

Oncolytic viroimmunotherapy is an exciting modality that can offer lasting anti-tumor immunity for aggressive malignancies like colon cancer. The impact of oncolytic viruses may be extended by combining them with agents to prime a tumor for viral susceptibility. This study investigates vitamin D analogue as an adjunct to oncolytic viral therapy for colon cancer. While vitamin D (VD) has historically been viewed as anti-viral, our in vitro investigations using human colon cancer cell lines showed that VD does not directly inhibit replication of recombinant chimeric poxvirus CF33. VD did restrict growth in HT29 but not HCT116 human colon cancer cells. In vivo investigations using HCT116 and HT29 xenograft models of colon cancer demonstrated that a VD analogue, calcipotriol, was additive with CF33-based viral therapy in VD-responsive HT29 but not in HCT116 tumors. Analyses of RNA-sequencing and gene expression data demonstrated a downregulation in the Jak-STAT signaling pathway with the addition of VD to viral therapy in HT29 models suggesting that the anti-inflammatory properties of VD may enhance the effects of viral therapy in some models. In conclusion, VD may prime oncolytic viral therapy in certain colon cancers.