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Even with progressive combination treatments, the prognosis of patients with glioblastoma (GBM) remains extremely poor. OV is one of the new promising therapeutic strategies to treat human GBM. OVs stimulate immune cells to release cytokines such as IFN-γ during oncolysis, further improve tumor microenvironment (TME) and enhance therapeutic efficacy. IFN-γ plays vital role in the apoptosis of tumor cells and recruitment of tumor-infiltrating T cells. We hypothesized that oncolytic herpes simplex virus-1 (oHSV-1) enhanced the antitumor efficacy of novel CD70-specific chimeric antigen receptor (CAR) T cells by T cell infiltration and IFN-γ release. In this study, oHSV-1 has the potential to stimulate IFN-γ secretion of tumor cells rather than T cell secretion and lead to an increase of T cell activity, as well as CD70-specific CAR T cells can specifically recognize and kill tumor cells in vitro. Specifically, combinational therapy with CD70-specific CAR T and oHSV-1 promotes tumor degradation by enhancing pro-inflammatory circumstances and reducing anti-inflammatory factors in vitro. More importantly, combined therapy generated potent antitumor efficacy, increased the proportion of T cells and natural killer cells in TME, and reduced regulatory T cells and transformed growth factor-β1 expression in orthotopic xenotransplanted animal model of GBM. In summary, we reveal that oHSV-1 enhance the therapeutic efficacy of CD70-spefific CAR T cells by intratumoral T cell infiltration and IFN-γ release, supporting the use of CAR T therapy in GBM therapeutic strategies.

This paper investigates the problem of setting target finish times (due dates) for project activities with random durations. Using two-stage integer linear stochastic programming, target times are determined in the first stage followed by the development of a detailed project schedule in the second stage. The objective is to balance (1) the cost of project completion as a function of activity target times with (2) the expected penalty incurred by deviating from the specified values. It is shown that the results may be significantly different when deviations are considered, compared to when activities are scheduled as early as possible in the traditional way. For example, the optimal target completion time for a project may be greater than the makespan of the early-start schedules under any scenario. To find solutions, an exact algorithm is developed for the case without a budget constraint and is used as a part of a heuristic when crashing is permitted. All computational procedures are demonstrated on a set of 150 benchmark problems consisting of 90 activities each.