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Oncolytic ability to direct target and lyse tumor cells makes oncolytic virus therapy (OVT) a promising approach to treating cancer. Despite its therapeutic potential to stimulate anti-tumor immune responses, it also has immunosuppressive effects. The efficacy of OVTs as monotherapies can be enhanced by appropriate adjuvant therapy such as anti-CTLA-4. In this paper, we propose a mathematical model to explore the interactions of combined therapy of oncolytic viruses and a checkpoint inhibitor, anti-CTLA-4. The model incorporates both the susceptible and infected tumor populations, natural killer cell population, virus population, tumor-specific immune populations, virus-specific immune populations, tumor suppressive cytokine IFN-g, and the effect of immune checkpoint inhibitor CTLA-4. In particular, we distinguish the tumor-specific immune abilities of CD8+ T, NK cells, and CD4+ T cells and describe the destructive ability of cytokine on tumor cells as well as the inhibitory capacity of CTLA-4 on various components. Our model is validated through the experimental results. We also investigate various dosing strategies to improve treatment outcomes. Our study reveals that tumor killing rate by cytokines, cytokine decay rate, and tumor growth rate play important roles on both the OVT monotherapy and the combination therapy. Moreover, parameters related to CD8+ T cell killing have a large impact on treatment outcomes with OVT alone, whereas parameters associated with IFN-g strongly influence treatment responses for the combined therapy. We also found that virus killing by NK cells may halt the desired spread of OVs and enhance the probability of tumor escape during the treatment. Our study reveals that it is the activation of host anti-tumor immune system responses rather than its direct destruction of the tumor cells plays a major biological function of the combined therapy. [ABSTRACT FROM AUTHOR]

While cancer immune therapy has revolutionized the treatment of metastatic disease across a wide range of cancer diagnoses, a major limiting factor remains with regard to relying on adequate homing of anti-tumor effector cells to the tumor site both prior to and after therapy. Adoptive cell transfer (ACT) of autologous T cells have improved the outlook of patients with metastatic melanoma. Prior to the approval of checkpoint inhibitors, this strategy was the most promising. However, while response rates of up to 50% have been reported, this strategy is still rather crude. Thus, improvements are needed and within reach. A hallmark of the developing tumor is the evasion of immune destruction. Achieved through the recruitment of immune suppressive cell subsets, upregulation of inhibitory receptors and the development of physical and chemical barriers (such as poor vascularization and hypoxia) leaves the microenvironment a hostile destination for anti-tumor T cells. In this paper, we review the emerging strategies of improving the homing of effector T cells (TILs, CARs, TCR engineered T cells, etc.) through genetic engineering with chemokine receptors matching the chemokines of the tumor microenvironment. While this strategy has proven successful in several preclinical models of cancer and the strategy has moved into the first phase I/II clinical trial in humans, most of these studies show a modest (doubling) increase in tumor infiltration of effector cells, which raises the question of whether road blocks must be tackled for efficient homing. We propose a role for physical exercise in modulating the tumor microenvironment and preparing the platform for infiltration of anti-tumor immune cells. In a time of personalized medicine and genetic engineering, this "old tool" may be a way to augment efficacy and the depth of response to immune therapy. [ABSTRACT FROM AUTHOR]