Polymer Coated Vaccinia Virus for Enhanced Blood Stream Stability

病毒通常用于医疗，作为药物输送的载体，最近，通过破坏细胞或刺激对癌细胞的免疫反应，作为靶向癌症治疗的治疗剂。溶瘤病毒可以选择性地感染癌细胞，而不是正常细胞，然后在这些目标细胞内自我放大。正是这种选择性和复制能力，使得溶瘤病毒在癌症治疗中的使用如此具有启发性。最近在癌症治疗的临床试验中成功地使用了单纯疱疹病毒、痘苗病毒和腺病毒，这增加了临床和商业上对病毒治疗的兴趣。然而，在将病毒作为治疗药物用于癌症治疗成为一种标准方法之前，仍有重要的挑战需要克服。首先，通过血液传播病毒的挑战是，这样就可以到达所有遥远的癌症沉积部位。当病毒注射到体内时，病毒被识别为异源，在它们能够到达所需位置之前被攻击并从体内清除(S)。这种免疫清除阻碍了溶瘤病毒的效率。如果病毒确实设法到达了肿瘤部位，那么它就需要保持足够的活动水平，然后感染和杀死癌细胞。这导致了第二个挑战；病毒需要在血液中保持稳定，并保持高水平的传染性。第三，肿瘤是高压环境，细胞聚集密集、杂乱无章。这意味着它们没有对流通过它们，使得病毒等颗粒很难进入和穿透整个肿瘤。可能需要有适当的机制来帮助病毒继续传播，直到整个肿瘤被根除。这项提案将研究如何适应牛痘病毒并将其与机械刺激结合使用，以提供一种能够克服这三个限制障碍的方法。最终，我们希望这种方法将为使用溶瘤病毒创造一种极其选择性和强大的策略。在晚期临床试验中，痘苗病毒已被用于治疗数百名患者，但只有通过瘤内注射才有效。静脉注射后提供更好的循环动力学和更好的肿瘤吸收将扩大可以使用该载体治疗的患者的数量。痘苗病毒快速而有效的生命周期意味着它迅速摧毁它感染的细胞，并导致它在癌细胞之间有效地传播。这在细胞密集堆积的癌症治疗中是理想的。病毒疗法的一个常见问题是病毒会导致严重的疾病。痘苗病毒源于痘病毒家族，并在1970年的免疫计划中使用，该计划导致了全球范围内根除天花。因此，它有一个广泛而明确的安全概况。痘苗病毒只在细胞核外的宿主细胞的细胞质中复制，因此与宿主细胞蛋白的相互作用很少。这允许细胞外包膜病毒粒子的快速复制和产生，这种病毒粒子负责其细胞到细胞的传播，不受宿主细胞防御的负面影响。为了增加痘苗病毒的效用，重要的是改变它对宿主免疫系统的外观，以便使其能够运输到肿瘤部位。作为Carlisle博士团队中DPhil的一名学生，我将研究聚合物包被的痘苗病毒以及可用于增强其肿瘤传输的机制。

Viruses are commonly used in medical treatments as vectors for drug delivery and more recently, as therapeutics for targeted cancer treatment either via cell destruction or by stimulating an immune-response against the cancer cells. Oncolytic viruses can selectively infect cancer cells over normal cells and then self-amplify within those target cells. It is this selectivity and ability to replicate which makes the use of oncolytic viruses in cancer treatment so revelatory. Recent success using herpes simplex virus, vaccinia virus and adenovirus, in clinical trials for cancer treatment, has led to increased clinical and commercial interest in virotherapy. However, there are still important challenges to overcome before using viruses as therapeutic agents in cancer treatment becomes a standard approach. Firstly, there is the challenge of delivering the virus via the bloodstream so that all the distant sites of cancer deposition can be reached. When injected into the body, viruses are recognised as xenogens and are attacked and cleared from the body before they are able to reach the desired location(s). This immune clearance impedes the efficiency of the oncolytic virus. If the virus does manage to reach the tumour site, it then needs to have maintained a sufficient level of activity to then infect and kill cancer cells. This leads to the second challenge; the virus needs to be stable in the blood and retain a high level of infectivity. Thirdly, tumours are high pressure environments with dense disorganised collections of cells. This means they have no convective flow passing through them, making it difficult for particulates such as viruses to delivery into and penetration throughout the whole tumour. There may need to be mechanisms in place to help the virus continue to propagate until the entire tumour has been eradicated. This proposal will investigate ways in which vaccinia virus could be adapted and used in combination with mechanical stimuli to provide an approach which can overcome these three limiting barriers. Ultimately we hope the approach will create an extremely selective and powerful strategy for using oncolytic virus.Vaccinia virus has been used to treat hundreds of patients in late stage clinical trials but is only effective when delivered by intratumoural injection. Providing better circulation kinetics and better tumour uptake following intravenous injection will widen the number of patients that can be treated with this vector. The quick and efficient life cycle of vaccinia virus means it rapidly destroys the cells it infects and leads to it spreading efficiently between cancer cells. This is ideal in cancer treatment, where cells are densely packed. A common concern with virotherapy is that viruses can cause serious illness. The vaccinia virus is derived from the pox-virus family and was used in the 1970 immunity program which lead to world-wide eradication of small pox. It therefore has an extensive well defined safety profile. Vaccinia virus only replicates in the cytoplasm of host cells, outside the nucleus, and therefore has very few interactions with host cellular proteins. This allows for rapid replication and production of extracellular enveloped virions, the type of virion responsible for its cell to cell spread, which are unaffected by the negative effects of host cell defences. In order to increase the utility of vaccinia virus, it is important to alter its appearance to the immune system of the host so as to allow its transportation to the tumour site. As a DPhil student within Dr Carlisle's group I will be investigating the polymer coated vaccinia virus and the mechanisms which can be used to enhance its tumour delivery.