Mathematical modeling of tumor therapy with oncolytic viruses: Effects of parametric heterogeneity on cell dynamics

One of the mechanisms that ensure cancer robustness is tumor heterogeneity, and its effects on tumor cells dynamics have to be taken into account when studying cancer progression. There is no unifying theoretical framework in mathematical modeling of carcinogenesis that would account for parametric heterogeneity. Here we formulate a modeling approach that naturally takes stock of inherent cancer cell heterogeneity and illustrate it with a model of interaction between a tumor and an oncolytic virus. We show that several phenomena that are absent in homogeneous models, such as cancer recurrence, tumor dormancy, an others, appear in heterogeneous setting. We also demonstrate that, within the applied modeling framework, to overcome the adverse effect of tumor cell heterogeneity on cancer progression, a heterogeneous population of an oncolytic virus must be used. Heterogeneity in parameters of the model, such as tumor cell susceptibility to virus infection and virus replication rate, can lead to complex, time-dependent behaviors of the tumor. Thus, irregular, quasi-chaotic behavior of the tumor-virus system can be caused not only by random perturbations but also by the heterogeneity of the tumor and the virus. The modeling approach described here reveals the importance of tumor cell and virus heterogeneity for the outcome of cancer therapy. It should be straightforward to apply these techniques to mathematical modeling of other types of anticancer therapy.Comment: 45 pages, 6 figures; submitted to Biology Direc

Oncolytic herpes viruses, chemotherapeutics, and other cancer drugs

Oncolytic viruses are emerging as a potential new way of treating cancers. They are selectively replication-competent viruses that propagate only in actively dividing tumor cells but not in normal cells and, as a result, destroy the tumor cells by consequence of lytic infection. At least six different oncolytic herpes simplex viruses (oHSVs) have undergone clinical trials worldwide to date, and they have demonstrated an excellent safety profile and intimations of efficacy. The first pivotal Phase III trial with an oHSV, talimogene laherparepvec (T-Vec [OncoVex<sup>GM-CSF</sup>]), is almost complete, with extremely positive early results reported. Intuitively, therapeutically beneficial interactions between oHSV and chemotherapeutic and targeted therapeutic drugs would be limited as the virus requires actively dividing cells for maximum replication efficiency and most anticancer agents are cytotoxic or cytostatic. However, combinations of such agents display a range of responses, with antagonistic, additive, or, perhaps most surprisingly, synergistic enhancement of antitumor activity. When synergistic interactions in cancer cell killing are observed, chemotherapy dose reductions that achieve the same overall efficacy may be possible, resulting in a valuable reduction of adverse side effects. Therefore, the combination of an oHSV with “standard-of-care” drugs makes a logical and reasonable approach to improved therapy, and the addition of a targeted oncolytic therapy with “standard-of-care” drugs merits further investigation, both preclinically and in the clinic. Numerous publications report such studies of oncolytic HSV in combination with other drugs, and we review their findings here. Viral interactions with cellular hosts are complex and frequently involve intracellular signaling networks, thus creating diverse opportunities for synergistic or additive combinations with many anticancer drugs. We discuss potential mechanisms that may lead to synergistic interactions

Advances in the design and development of oncolytic measles viruses.

A successful oncolytic virus is one that selectively propagates and destroys cancerous tissue without causing excessive damage to the normal surrounding tissue. Oncolytic measles virus (MV) is one such virus that exhibits this characteristic and thus has rapidly emerged as a potentially useful anticancer modality. Derivatives of the Edmonston MV vaccine strain possess a remarkable safety record in humans. Promising results in preclinical animal models and evidence of biological activity in early phase trials contribute to the enthusiasm. Genetic modifications have enabled MV to evolve from a vaccine agent to a potential anticancer therapy. Specifically, alterations of the MV genome have led to improved tumor selectivity and delivery, therapeutic potency, and immune system modulation. In this article, we will review the advancements that have been made in the design and development of MV that have led to its use as a cancer therapy. In addition, we will discuss the evidence supporting its use, as well as the challenges associated with MV as a potential cancer therapeutic

The Effect of Oncolytic Viruses in Aiding Cancer Immunotherapy

Oncolytic viruses are known as genetically engineered viruses or ones that can be found in nature, that are used to selectively reproduce in cancer cells and kill them without harming the normal and healthy cells. Oncolytic viruses have been considered an effective form of immunotherapy and offer a new approach for cancer treatment. Only one oncolytic virus has been approved by the Food and Drug Administration (FDA) in the USA, which is T-Vec (talimogene laherparepvec). This is a second-generation oncolytic herpes simplex virus type 1 (HSV-1). Another oncolytic virus has been approved only in China in 2005, which is called Oncorine. It is an E1B-deleted adenovirus, which is used for head and neck cancer and esophagus cancer (Fukuhara, Ino, Todo, 2016). This paper will demonstrate the clinical effectiveness of oncolytic viruses and how they have proven to help with cancer immunotherapy

Mesenchymal stem cells as vectors for lung cancer therapy

Despite recent advances in treatment, lung cancer accounts for one third of all cancer-related deaths, underlining the need of development of new therapies. Mesenchymal stem cells (MSCs) possess the ability to specifically home into tumours and their metastases. This property of MSCs could be exploited for the delivery of various anti-tumour agents directly into tumours. However, MSCs are not simple delivery vehicles but cells with active physiological process. This review outlines various agents which can be delivered by MSCs with substantial emphasis on TRAIL (tumour necrosis factor-related apoptosis-inducing ligand)

Tumor Associated Macrophages Mitigate Oncolytic Herpes Simplex Virus Anti-Tumor Efficacy in Ewings Sarcoma

Professional Biological Sciences: 2nd Place (The Ohio State University Edward F. Hayes Graduate Research Forum)Introduction: Ewing sarcoma is a highly aggressive bone tumor that is often lethal following recurrence or metastasis. Oncolytic viruses (OVs), such as the rRp450 herpes simplex virus, are promising anticancer therapeutics designed to selectively replicate in cancer cells. While OV anti-tumor efficacy is partially caused by direct infection and lysis of cancer cells, stimulation of an anti-cancer immune response also contributes to virus-mediated efficacy. Immunologic responses to infections are known to be modulated by macrophages via various cytokines and chemokines and it is now appreciated that tumors are replete with tumor associated macrophages (TAMs). M2 alternatively activated macrophages in particular express pro-tumor immunosuppressive cytokines, such as IL-10 and TGF-β. We hypothesize that TAMs reduce therapeutic efficacy by producing an immunosuppressive tumor microenvironment via IL-10 and TGF-β signaling. Research methods: Human Ewing sarcoma xenografts were implanted into athymic nude mice and macrophages were depleted using liposomal clodronate prior to intratumoral injection of rRp450 oncolytic HSV. Tumors were allowed to grow for tumor progression. In vitro cytotoxicity was determined using MTS assay. In vitro and in vivo virus replication was determined through plaque assay. Bone marrow derived macrophages were cocultured with Ewing sarcoma cell lines and harvested for flow cytometry and PCR analysis of tumor inflammatory signaling and M1/M2 macrophage gene profiles. F4/80+ tumor associated macrophages were extracted from tumors using magnetic bead separation. TGF-β cytokine superfamily receptor signaling was inhibited with A83-01 (Sigma-Aldrich) small molecule treatment prior to intratumoral injection of rRp450. Results: Macrophage depletion significantly inhibited tumorigenesis and enhanced rRp450 anti-tumor efficacy in A673, but not 5838 Ewing sarcoma xenografts. No change in virus titer was observed in the macrophage depleted tumors, suggesting the effect isn’t due to enhanced virus replication. Macrophages cocultured with A673 cells had higher expression of M2 pro-tumor macrophage genes than macrophages cocultured with 5838 cells. Macrophages in A673 tumors also demonstrated higher expression of IL-10 and TGF-β than 5838 tumor associated macrophages. Inhibition of TGF-β signaling enhanced rRp450 oncolytic virus anti-tumor efficacy in A673 tumors. Conclusions: Macrophages play a significant role in mitigating OV anti-tumor efficacy. Specifically, our tumor models that promote M2 macrophage polarization are significantly more resistant to oncolytic virus therapy, in part due to TGF-β signaling. Our results suggest that the combination of oncolytic virus therapy with a macrophage modulatory therapy will improve OV anti-tumor efficacy in patients with highly immunosuppressive tumors.A three-year embargo was granted for this item