Proteasome inhibition and oncolytic virotherapy are two emerging targeted cancer therapies. Bortezomib, a proteasome inhibitor, disrupts the degradation of proteins in the cell leading to accumulation of unfolded proteins inducing apoptosis. On the other hand, oncolytic virotherapy uses genetically modified oncolytic viruses (OV) to infect cancer cells, induce cell lysis, and activate an antitumour response. In this work, optimal control theory is used to minimize the cancer cell population by identifying strategic infusion protocols of bortezomib, OV and natural killer (NK) cells. Three different therapeutic protocols are explored: (i) periodic bortezomib and single administrations of both OV and NK cells therapy; (ii) alternating sequential combination therapy; and (iii) NK cell depletion and infusion therapy. In the first treatment scheme, early OV administration followed by well-timed adjuvant NK cell infusion maximizes antitumour efficacy. The second strategy supports timely OV infusion. The last treatment scheme indicates that transient NK cell depletion followed by appropriate NK cell adjuvant therapy yields the maximal benefits. Relative doses and administrative costs of the three anticancer agents for each approach are qualitatively presented. This study provides potential polytherapeutic strategies in cancer treatment.

中文翻译：

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溶瘤病毒-硼替佐米和辅助 NK 细胞在癌症治疗中的综合治疗策略

蛋白酶体抑制和溶瘤病毒疗法是两种新兴的靶向癌症疗法。硼替佐米是一种蛋白酶体抑制剂，可破坏细胞中蛋白质的降解，导致未折叠蛋白质的积累，从而诱导细胞凋亡。另一方面，溶瘤病毒疗法使用转基因溶瘤病毒 (OV) 来感染癌细胞、诱导细胞裂解并激活抗肿瘤反应。在这项工作中，最优控制理论用于通过确定硼替佐米、OV 和自然杀伤 (NK) 细胞的战略输注方案来最小化癌细胞数量。探索了三种不同的治疗方案：(i) 定期硼替佐米和单次给药 OV 和 NK 细胞治疗；(ii) 交替序贯联合治疗；(iii) NK 细胞耗竭和输注疗法。在第一个治疗方案中，早期 OV 给药，然后是适时的辅助 NK 细胞输注，可最大限度地提高抗肿瘤功效。第二种策略支持及时 OV 输注。最后一个治疗方案表明，短暂的 NK 细胞耗竭，然后进行适当的 NK 细胞辅助治疗会产生最大的益处。每种方法的三种抗癌药物的相对剂量和管理成本都定性地呈现出来。这项研究为癌症治疗提供了潜在的综合治疗策略。每种方法的三种抗癌药物的相对剂量和管理成本都定性地呈现出来。这项研究为癌症治疗提供了潜在的综合治疗策略。每种方法的三种抗癌药物的相对剂量和管理成本都定性地呈现出来。这项研究为癌症治疗提供了潜在的综合治疗策略。