Preclinical validation of a novel oncolytic viral therapy for multiple myeloma targeting readiness for clinical trials

多发性骨髓瘤（MM）是一种无法治愈的血癌，每年影响约5800名英国公民。预后差，10年生存率<29%。MM治疗是在三联化疗、免疫和皮质类固醇联合治疗的周期中给予的。随着疾病产生耐药性，周期之间的缓解期越来越短（从2年以上到<6个月），直到最终死亡。现有治疗方法的主要局限性是它们的靶向方法，作用于特定的分子位点/途径。MM对这些治疗有几种防御（基因组变异性/异质性，表型可塑性/适应性和免疫抑制/抗性）。虽然新的先进疗法（CAR - t细胞等）正在出现，但这些疗法本质上也是靶向性的，不太可能提供持久的治疗/治愈。现有治疗的另一个限制是它们的成本（每个治疗5万至20万英镑，联合治疗20万英镑以上，4/5个治疗周期中每个患者80万英镑以上）。溶瘤病毒（OVs）是一种新兴的治疗方法，为难以治疗的癌症（如MM）带来了希望。OVs选择性地感染/溶解/杀死癌细胞，同时刺激强烈的免疫反应（解除癌症相关的免疫抑制）。重要的是，OVs攻击癌症是基于其表型而不是分子靶点。这使得对全身性异质性癌症具有高效力（同时防止进化的抵抗/免疫），提供持久的缓解/治愈潜力（并缩短治疗周期）。然而，现有的OVs主要是重新利用血清价实验室/野生型病毒，没有进化/优化用于对抗人类癌症，因此显示有限的功效/系统稳定性。此外，现有的开发方法利用实验室细胞系/动物模型，这些模型不能很好地反映真实的肿瘤/人类反应，经常不选择对患者有效的病毒。神学通过一个新颖的OV平台克服了这些挑战。

Multiple myeloma (MM) is an incurable blood cancer affecting ~5,800 UK citizens each year. Prognosis is poor with a <29% 10-year survival rate.MM treatments are given in cycles of triplet chemo-, immuno-, and corticosteroid- therapeutic combinations. Periods of remission between cycles become increasingly shorter (from 2+ years to <6-months) as the disease builds resistance, until eventual death. The primary limitation of existing treatments is their targeted approach, acting on a specific molecular site/pathway. MM has several defences to such therapies (genomic variability/heterogeneity, phenotypic plasticity/adaptability, and immune suppression/resistance).Whilst novel advanced therapies (CAR T-cell etc.) are emerging, these are also targeted in nature and unlikely to offer a durable treatment/cure.A further limitation of existing treatments is their cost (£50K-£200K/therapy, £200K+/combination treatment, and £800K+/patient across 4/5-treatment cycles).Oncolytic viruses (OVs) are an emerging therapy offering hope for difficult to treat cancers such as MM. OVs selectively infect/lyse/kill cancer cells, whilst simultaneously stimulating strong immune responses (lifting cancer-associated immune suppression). Importantly, OVs attack the cancer based on its phenotype rather than molecular targets. This enables high potency against systemic heterogeneous cancers (whilst preventing evolved resistance/immunity), providing durable remission/curative potential (and reduced treatment cycles).However, existing OVs are primarily re-purposed seroprevalent laboratory/wild-type viruses, not evolved/optimised for combating human cancers, and thus demonstrate limited efficacy/systemic stability. Furthermore, existing development approaches utilise laboratory cell lines/animal models that poorly reflect real tumour/human responses, frequently de-selecting viruses with efficacy in patients.Theolytics overcome these challenges through a novel OV Platform.